Vonoprazan; amoxicillin; clarithromycin is a co-packaged oral product containing vonoprazan, a potassium-competitive acid blocker (PCAB), amoxicillin, a penicillin class antibacterial, and clarithromycin, a macrolide antimicrobial. The product is indicated for the treatment of Helicobacter pylori (H. pylori) infection in adults. During clinical trials, treatment-naive H. pylori-positive adult patients with at least one of the following clinical conditions were candidates: dyspepsia lasting for at least 2 weeks, functional dyspepsia, recent or new diagnosis of peptic ulcer, peptic ulcer not treated for H. pylori infection, or a stable dose of long-term NSAID treatment. H. pylori eradication was confirmed with a negative urea breath test at 27 days or more post-therapy. The vonoprazan; amoxicillin; clarithromycin triple therapy product was shown to be noninferior to LAC (standard lansoprazole, amoxicillin, clarithromycin H. pylori regimen) in patients who did not have a clarithromycin or amoxicillin resistant strain of H. pylori at baseline. The vonoprazan; amoxicillin; clarithromycin triple therapy product was shown to be superior to LAC in patients who had a clarithromycin resistant strain of H. pylori at baseline and in the overall population. Vonoprazan; amoxicillin; clarithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. Vonoprazan reduces intragastric acidity and can affect the oral absorption of certain oral medications, leading to changes in safety and/or effectiveness and clarithromycin may also cause significant drug interactions; review drug interactions. Appropriate treatment of H. pylori reduces symptoms, improves gastric healing, helps prevent future ulceration, and reduces the risk of complications from peptic ulcer disease (e.g., bleeding). The vonoprazan; amoxicillin; clarithromycin triple therapy product was FDA approved in May 2022.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer vonoprazan; amoxicillin; clarithromycin twice daily (in the morning and evening). Vonoprazan tablets, amoxicillin capsules, and clarithromycin tablets are supplied in separate blister cavities within the same blister card for the needed doses each day. Each treatment pack contains 14 blister cards; one blister card for each day of the 14-day regimen.
-Administer with or without food.
-Missed dose: If a dose is missed, administer the missed dose as soon as possible, within 4 hours after the missed dose. If more than 4 hours have passed, skip the missed dose and administer the next dose on the regularly scheduled time. Patients should continue the normal dosing schedule until the medication is completed.
Hypersensitivity and dermatologic reactions may occur with the use of vonoprazan; amoxicillin; clarithromycin triple pack. Drug hypersensitivity, rash, dermatitis, and xerosis (dry skin) were reported in less than 2% of patients receiving vonoprazan; amoxicillin; clarithromycin triple pack during clinical trials. Vonoprazan has been reported to cause hypersensitivity or dermatologic reactions during postmarketing use such as anaphylactic shock, urticaria, drug eruption, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Dermatologic or hypersensitivity reactions reported clinically since marketing with amoxicillin include serum sickness-like reactions, erythematous maculopapular rash, erythema multiforme, exfoliative dermatitis, urticaria, SJS, TEN, acute generalized exanthematous pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hypersensitivity vasculitis, Henoch-Schonlein purpura (IgA vasculitis), and linear IgA bullous dermatosis. Penicillin allergy has been reported in up to 20% of patients receiving penicillin-class antibiotics; however, around 90% of reported allergies are incorrectly reported and many patients lack penicillin-specific IgE antibodies. The actual prevalence of penicillin allergy is likely no greater than 5%. The severity of these reactions range from a benign rash to anaphylactoid reactions, angioedema, or anaphylactic shock. Dermatologic and hypersensitivity reactions additionally reported with use of clarithromycin postmarketing include acne vulgaris, anaphylactic reactions, angioedema, TEN, SJS, DRESS, AGEP, and Henoch-Schonlein purpura (IgA vasculitis). If hypersensitivity is suspected or a skin reaction occurs, discontinue vonoprazan; amoxicillin; clarithromycin triple pack and institute appropriate evaluation and treatment.
The most common gastrointestinal (GI) adverse reactions reported with vonoprazan; amoxicillin; clarithromycin triple pack use during clinical trials diarrhea (4%), abdominal pain (2.3%), and dysgeusia or taste disorder (4.6%). The most common GI adverse reaction leading to discontinuation of treatment was diarrhea (0.6%). Other GI adverse reactions occurring in less than 2% of patients included decreased appetite (anorexia), abdominal distension, constipation, dry mouth (xerostomia), peptic ulcer (duodenal or gastric ulcer), dyspepsia, flatulence, gastroesophageal reflux disease, nausea and/or vomiting, hematochezia, duodenal polyp, large intestine polyp, rectal polyp, stomatitis, tongue discomfort. GI adverse effects that have been reported with amoxicillin use postmarketing include black hairy tongue (tongue discoloration) and colitis accompanied by GI bleeding (hemorrhagic colitis). GI adverse effects reported with clarithromycin include acute pancreatitis and tongue discoloration.
Microbial overgrowth and superinfection can occur with antibiotic use. Vaginal candidiasis (inclusive of urogenital infection fungal, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginal pruritus, genital pruritus, genital infection fungal) was reported in 3.2% of patients taking vonoprazan; amoxicillin; clarithromycin triple pack during clinical trials. Naso-pharyngitis was reported in 0.3% of treated patients. Infections reported in less than 2% of treated patients included anal fungal infection, gastrointestinal viral infection, oral fungal infection, pneumonia, tongue fungal infection, upper respiratory tract infection, urinary tract infection, and viral infection. Mucocutaneous candidiasis has been reported with postmarketing use of amoxicillin. The use of gastric acid suppressive therapy, such as vonoprazan, may increase the risk of enteric infection or superinfection by encouraging the growth of gut microflora. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with amoxicillin and clarithromycin use, and may occur during or following completion of treatment. CDAD may range in severity from mild diarrhea to fatal colitis or a need for colectomy. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.
Hematologic adverse reactions occurring in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack include anemia, leukocytosis, leukopenia, and neutropenia. Amoxicillin and other penicillin-class antibiotics have been reported to cause hemolytic anemia, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), eosinophilia, and agranulocytosis; these reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Hematologic effects reported with use of clarithromycin include thrombocytopenia, agranulocytosis, prothrombin time prolonged, decreased white blood cell count, and INR increased. Hemorrhage (bleeding) has also been reported with clarithromycin use postmarketing.
Headache was reported in 2.6% of patients treated during clinical trials with vonoprazan; amoxicillin; clarithromycin triple pack. Central nervous system adverse events that have been reported in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack include ageusia, dizziness, and tension headache. Psychiatric disorders reported in less than 2% of treated patients include anxiety, depression, and insomnia. Reversible hyperactivity, agitation, confusion, convulsions or seizures, aseptic meningitis, and behavioral changes have rarely been reported with the use of amoxicillin postmarketing. Clarithromycin has been associated with a variety of nervous system events postmarketing including parosmia, anosmia, paresthesias, and convulsions. Psychiatric events such as abnormal behavior, confusional state, depersonalization, disorientation, hallucinations, mania or manic behaviour, abnormal dreams, and psychosis or psychotic disorder have been reported with clarithromycin use. These disorders usually resolve upon discontinuation of clarithromycin.
Hypertension or increased blood pressure was reported in 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack during clinical trials. Hypertension led to discontinuation of the triple pack in 0.6% of patients.
Cardiovascular side effects reported in less than 2% of patients receiving vonoprazan; amoxicillin; clarithromycin triple pack included QT prolongation and sinus tachycardia. As with other macrolide antimicrobials, clarithromycin has been associated with QT prolongation, torsade de pointes (TdP), ventricular tachycardia, or other ventricular cardiac arrhythmias. Patients with certain underlying cardiac conditions, who have electrolyte abnormalities, or who are receiving concurrent medications associated with QT prolongation may be at increased risk.
Orbital edema (blepharedema and other edema around the eyes) was reported in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack during clinical trials.
General adverse reactions reported in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack during clinical trials included fatigue and pyrexia (increased body temperature or fever).
Elevated hepatic enzymes were reported in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack during clinical trials. Hepatic adverse events that have been reported in patients receiving vonoprazan postmarketing have included hepatic injury, hepatic failure, and jaundice. Hepatic dysfunction, including elevated hepatic enzymes, cholestasis, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Urine discoloration (associated with hepatic failure) has also been reported during postmarketing surveillance with clarithromycin. Discontinue the triple pack immediately if signs and symptoms of drug-induced liver injury or hepatitis occur.
Hypoglycemia has been reported during clarithromycin therapy when used in patients taking oral hypoglycemic agents or insulin.
Musculoskeletal adverse reactions reported in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack during clinical trials included bone fractures. Myalgia and myopathy rhabdomyolysis has been reported with use of clarithromycin, and in some reports, clarithromycin was administered concomitantly with other medications that may be associated with these adverse reactions.
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.
Renal and urinary tract adverse reactions reported in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack during clinical trials included renal hypertrophy and tubulo-interstitial nephritis. Crystalluria has been reported with the postmarketing use of amoxicillin. Renal failure has been reported postmarketing with clarithromycin.
Reproductive and breast system disorders reported in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack included vaginal discharge.
Respiratory, thoracic, and mediastinal disorders reported in less than 2% of patients treated with vonoprazan; amoxicillin; clarithromycin triple pack included cough, nasal polyps, and oropharyngeal pain.
Hearing loss (deafness) has been reported with postmarketing use of clarithromycin and has been reported chiefly in elderly women and has usually been reversible.
Tooth discoloration (brown, yellow, or gray staining) has rarely been reported with amoxicillin therapy postmarketing and the majority of reports have been in children. Clarithromycin has also been reported to cause tooth discoloration. In most cases, discoloration was reduced or eliminated by brushing or professional dental cleaning.
Drug-induced enterocolitis syndrome (DIES) has been reported with amoxicillin use. Most cases occur in pediatric patients. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, and diarrhea within 24 hours after ingesting amoxicillin as well as leukocytosis with neutrophilia. If DIES occurs, discontinue vonoprazan; amoxicillin; clarithromycin and institute appropriate therapy.
Vonoprazan; amoxicillin; clarithromycin triple pack is contraindicated for use with rilpivirine-containing products and several other medications. Review drug interactions prior to prescribing.
This product contains amoxicillin, a penicillin, and is contraindicated in patients who have a history of severe hypersensitivity reactions to beta-lactam antibiotics (i.e., penicillin hypersensitivity, cephalosporin hypersensitivity, and carbapenem hypersensitivity). This product contains clarithromycin, a macrolide antimicrobial, and therefore is contraindicated in patients who have shown clarithromycin or other macrolide hypersensitivity. Patients who have a hypersensitivity to vonoprazan are also contraindicated to receive this product. Serious and occasionally fatal reactions (e.g., anaphylaxis, angioedema) have been reported with the various components of this product. Severe cutaneous adverse reactions (SCAR) have also been reported. Discontinue this triple pack at the first signs or symptoms of a serious rash and consider further evaluation. If hypersensitivity reactions occur, discontinue vonoprazan; amoxicillin; clarithromycin triple pack and institute immediate therapy (e.g., anaphylaxis management).
A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Avoid use of vonoprazan; amoxicillin; clarithromycin triple pack in patients with mononucleosis.
Consider pseudomembranous colitis in patients presenting with diarrhea during or after vonoprazan; amoxicillin; clarithromycin use. Careful medical history is necessary, as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. Acid suppressive therapy may also be associated with an increased risk of C. difficile-associated diarrhea (CDAD), especially in hospitalized patients. If CDAD is confirmed, discontinue vonoprazan; amoxicillin; clarithromycin triple pack. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Avoid use of the vonoprazan; amoxicillin; clarithromycin triple pack in patients with known QT prolongation or receiving drugs known to prolong the QT interval, ventricular arrhythmias (torsade de pointes), hypokalemia/hypomagnesemia, significant bradycardia, or taking Class IA or III antiarrhythmics. Geriatric patients may be more susceptible to the QT-prolonging effects of clarithromycin. Use clarithromycin with caution in patients with cardiac disease, and consider using alternative antibiotics in these patients. An increase in all-cause mortality up to 10 years after clarithromycin exposure (hazard ratio 1.10; 95% CI 1 to 1.21) was observed in a clinical trial of patients with coronary artery disease. The cause of the increased mortality has not been established. Due to the potential for QT prolongation, avoid clarithromycin in patients with congenital or acquired QT prolongation syndromes or in patients with a history of ventricular arrhythmias, including torsade de pointes (TdP). Patients taking concurrent medications that increase the QT interval and are metabolized by CYP3A4 should be closely monitored; concurrent administration of clarithromycin with certain other drugs is contraindicated (e.g., astemizole, cisapride, pimozide, terfenadine). Use clarithromycin with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, adults 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Vonoprazan; amoxicillin; clarithromycin triple pack should be avoided in patients with moderate or severe (Child-Pugh B or C) hepatic disease. The triple pack is contraindicated in patients with a history of cholestatic jaundice and/or hepatic dysfunction associated with the prior use of clarithromycin. Use this triple pack with caution in patients with mild hepatic impairment (Child-Pugh A). Cases of hepatic dysfunction (i.e., increased liver enzymes, hepatocellular and/or cholestatic hepatitis, jaundice) have been associated with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue use of vonoprazan; amoxicillin; clarithromycin triple pack immediately if signs/symptoms of hepatitis develop.
Avoid use of vonoprazan; amoxicillin; clarithromycin triple pack in patients with severe renal impairment (eGFR less than 30 mL/minute) or renal failure. The pack does not allow for appropriate dosage adjustments needed for these patients.
Monitor patients for symptoms of myasthenia gravis during use of vonoprazan; amoxicillin; clarithromycin triple pack. Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.
Vonoprazan; amoxicillin; clarithromycin is not recommended for use during pregnancy unless no alternative therapy is appropriate. There are no adequate and well-controlled studies of vonoprazan; amoxicillin; clarithromycin triple pack during pregnancy or in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No reproductive and developmental toxicity studies with the combination of vonoprazan, amoxicillin, and clarithromycin were conducted. Except in very unusual cases, H. pylori eradication treatment can generally be deferred until after delivery. If pregnancy occurs while taking clarithromycin, advise the patient of the potential risk to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or embryo fetal development, in pregnant animals administered oral clarithromycin. Observational studies in pregnant women also demonstrated adverse effects on pregnancy outcomes, including an increased risk of miscarriage and in some studies an increased incidence of fetal malformations. For amoxicillin, available data from published epidemiologic studies and pharmacovigilance over several decades have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. For vonoprazan, there are only limited animal data. In pregnant rats, no adverse effects were noted after oral administration of vonoprazan during organogenesis at approximately 27-times the maximum recommended human dose (MRHD) based on AUC exposure comparisons. In a pre- and postnatal development (PPND) study, pups from dams orally administered vonoprazan during organogenesis and through lactation, exhibited liver discoloration, which in follow-up mechanistic animal studies was associated with necrosis, fibrosis and hemorrhage at a dose approximately 22-times the MRHD based on AUC comparisons which were likely attributable to exposure during lactation. These effects were not observed at the next lower dose in this study, which was approximately equal to the MRHD based on AUC comparison, however they were seen at clinically relevant exposures in dose-range finding studies in rats. The manufacturer requests that pregnancy exposures be reported to the Phathom Pharmaceuticals, Inc. Adverse Event reporting line at 1-888-775-PHAT (7428).
Avoid breast-feeding while taking vonoprazan; amoxicillin; clarithromycin triple pack and for 2 days after use. There are no data regarding the presence of vonoprazan in humans while breast-feeding, the effects on the breastfed infant or the effects on milk production. Vonoprazan and its metabolites are present in rat milk. Liver injury occurred in offspring from pregnant and lactating rats administered oral vonoprazan at AUC exposures approximately equal to and greater than the maximum recommended human dose (MRHD). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential risk of adverse liver effects shown in animal studies with vonoprazan, a woman should pump and discard human milk for the duration of vonoprazan; amoxicillin; clarithromycin triple pack therapy, and for 2 days after therapy ends, and feed her infant stored human milk (collected prior to therapy) or formula. Clarithromycin and its active metabolite are excreted in human milk. No data are available to assess the effects of clarithromycin or its metabolite on milk production. In a separate observational study of lactating women exposed to clarithromycin, reported adverse effects on breast-fed children such as rash, diarrhea, loss of appetite, and somnolence were comparable to amoxicillin.
The safety and efficacy of vonoprazan; amoxicillin; clarithromycin triple pack have not been established in children and infants below 18 years of age.
Administration of vonoprazan; amoxicillin; clarithromycin triple pack may result in diagnostic or laboratory test interference. High urine concentrations of ampicillin or amoxicillin may cause false-positive results when using glucose tests based on the Benedict's copper reduction reaction that determines the amount of reducing substances like glucose in the urine. Use a test based on enzymatic glucose oxidase reactions when testing for glucose in the urine of patients treated with this triple pack. Vonoprazan reduces intragastric acidity, which increases chromogranin A (CgA) levels and may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 14 days after triple pack treatment and repeat the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), use the same commercial laboratory for testing, as reference ranges between tests may vary.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Helicobacter pylori
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For Helicobacter pylori (H. pylori) eradication:
Oral dosage:
Adults: 20 mg vonoprazan PO; 1,000 mg amoxicillin PO; and 500 mg clarithromycin PO twice daily for 14 days.
Maximum Dosage Limits:
-Adults
Vonoprazan 40 mg/day PO; amoxicillin 2,000 mg/day PO; clarithromycin 1,000 mg/day PO.
-Geriatric
Vonoprazan 40 mg/day PO; amoxicillin 2,000 mg/day PO; clarithromycin 1,000 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (Child-Pugh A): No dosage adjustment is needed.
Moderate to severe hepatic impairment (Child-Pugh B or C): Avoid use.
Patients with Renal Impairment Dosing
Mild to moderate renal impairment (eGFR 30 to 89 mL/minute/1.73 m2): No dosage adjustment is needed.
Severe renal impairment (eGFR less than 30 mL/minute/1.73 m2): Avoid use.
*non-FDA-approved indication
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Abemaciclib: (Major) If coadministration with clarithromycin is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If clarithromycin is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of clarithromycin. Abemaciclib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with clarithromycin increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Acalabrutinib: (Major) Avoid concomitant use of acalabrutinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of acalabrutinib reducing its efficacy. (Major) Avoid the concomitant use of acalabrutinib and clarithromycin; significantly increased acalabrutinib exposure may occur. If short-term clarithromycin use is unavoidable, interrupt acalabrutinib therapy. Wait at least 24 hours after clarithromycin has been discontinued before resuming acalabrutinib at the previous dosage. Acalabrutinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
Acarbose: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Aspirin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with clarithromycin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Clarithromycin is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with vonoprazan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Vonoprazan is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid coadministration of clarithromycin with adagrasib due to the potential for increased exposure to adagrasib and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation) and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure. Adagrasib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of clarithromycin with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until clarithromycin has cleared from the circulation (approximately 3 half-lives of clarithromycin) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; clarithromycin is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of clarithromycin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of clarithromycin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If vonoprazan is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil. (Moderate) Use together with caution. Alfentanil is metabolized by the CYP3A4 isoenzyme. Clarithromycin is an inhibitor of CYP3A4 may decrease systemic clearance of alfentanil leading to increased or prolonged effects. Postmarketing reports of interactions with concomitant use have been noted.
Alfuzosin: (Contraindicated) Alfuzosin is contraindicated for use with clarithromycin due to the potential for serious/life-threatening reactions, including hypotension. Additive effects on the QT interval may also occur. Alfuzosin is a CYP3A4 substrate that may prolong the QT interval in a dose-dependent manner. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of another strong CYP3A4 inhibitor increased the alfuzosin AUC by 2.5-fold to 3.2-fold.
Allopurinol: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with clarithromycin is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and clarithromycin should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alogliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Alogliptin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Alogliptin; Pioglitazone: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Alosetron: (Moderate) Concomitant use of alosetron with clarithromycin may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; clarithromycin is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alpha-glucosidase Inhibitors: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Alprazolam: (Contraindicated) Coadministration of clarithromycin and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with clarithromycin, as these benzodiazepines are not oxidatively metabolized. There have been postmarketing reports of central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin. Alprazolam is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold. (Major) Avoid coadministration of alprazolam and vonoprazan due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with vonoprazan, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amiodarone: (Major) Avoid concomitant use of amiodarone and clarithromycin due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with clarithromycin. Amisulpride causes dose- and concentration- dependent QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Amlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Atorvastatin: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Amlodipine; Benazepril: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Celecoxib: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Olmesartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Valsartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Amphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Amphetamine; Dextroamphetamine Salts: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Amphetamine; Dextroamphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include clarithromycin.
Apalutamide: (Major) Avoid concomitant use of vonoprazan and apalutamide due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Consider alternatives to clarithromycin if treatment with apalutamide is necessary. Clarithromycin is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Exposure to apalutamide may also be increased. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
Apixaban: (Moderate) Pharmacokinetic data suggest that no dose adjustment is necessary if apixaban is coadministered with clarithromycin. However, because clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, there is a potential for increased apixaban exposure and increased risk of bleeding with concurrent use of clarithromycin. Monitor patients closely if coadministration is necessary. When combined with other P-gp and strong CYP3A4 inhibitors, the manufacturer recommends reducing the apixaban dose by 50% and avoiding concomitant administration if patients are already receiving 2.5 mg twice daily.
Apomorphine: (Major) Avoid coadministration of clarithromycin with apomorphine when possible. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of clarithromycin with aprepitant due to substantially increased exposure of aprepitant; increased clarithromycin exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in clarithromycin- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Clarithromycin is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Clarithromycin is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Concomitant use of aripiprazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form and CYP2D6 metabolizer status. For aripiprazole oral dosage forms, administer half of the usual dose; administer a quarter of the usual dose to patients known to be poor metabolizers of CYP2D6. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month; administer 200 mg/month to patients known to be poor metabolizers of CYP2D6. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP3A and CYP2D6 substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Major) Concomitant use of aripiprazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form and CYP2D6 metabolizer status. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP3A and CYP2D6 substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of vonoprazan. Patients receiving both a CYP2D6 inhibitor plus vonoprazan may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; vonoprazan is a weak CYP3A inhibitor.
Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as clarithromycin are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with QT prolongation and TdP. QT prolongation, TdP, and complete atrioventricular block have also been reported with the administration of arsenic trioxide.
Artemether; Lumefantrine: (Major) Concurrent use of artemether; lumefantrine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if clarithromycin must be used with or after artemether; lumefantrine treatment. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Artemether; lumefantrine is also associated with a possible risk for QT prolongation and TdP. In addition, clarithromycin is an inhibitor and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of artemether; lumefantrine.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with clarithromycin is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with clarithromycin increased asciminib exposure by 36%.
Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
Aspirin, ASA: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Dipyridamole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Omeprazole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Atazanavir: (Major) Avoid concomitant use of atazanavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of atazanavir reducing its efficacy. (Major) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC).
Atazanavir; Cobicistat: (Major) Avoid concomitant use of atazanavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of atazanavir reducing its efficacy. (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC).
Atogepant: (Major) Avoid use of atogepant and clarithromycin when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with clarithromycin. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and OATP1B1/3; clarithromycin is a strong CYP3A inhibitor and an OATP1B1/3 inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atomoxetine: (Major) Concomitant use of atomoxetine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of clarithromycin is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Concomitant use of avanafil and clarithromycin is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; clarithromycin would be expected to have similar effects.
Avapritinib: (Major) Avoid coadministration of avapritinib with clarithromycin due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Urinary concentrations of clarithromycin could interfere with the therapeutic effectiveness of BCG. Postpone instillation of BCG if the patient is receiving antibiotics.
Barbiturates: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as clarithromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, clarithromycin may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of vonoprazan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with clarithromycin may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of clarithromycin in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Clarithromycin is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving clarithromycin. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving clarithromycin. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; clarithromycin inhibits P-gp.
Bexagliflozin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Bexarotene: (Major) Avoid concomitant use of vonoprazan and bexarotene due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Coadministration of bexarotene and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Bortezomib: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and may increase the serum concentration of CYP3A4 substrates, such as bortezomib, due to the potential for reduced metabolism and drug accumulation.
Bosentan: (Major) Avoid concomitant use of vonoprazan and bosentan due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Coadministration of bosentan and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Coadministration may also increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored.
Bosutinib: (Major) Avoid concomitant use of bosutinib and clarithromycin; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as clarithromycin. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level. Similar precautions apply to combination products containing clarithromycin such as amoxicillin; clarithromycin; lansoprazole or amoxicillin; clarithromycin; omeprazole.
Brigatinib: (Major) Avoid coadministration of brigatinib with clarithromycin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of clarithromycin, resume the brigatinib dose that was tolerated prior to initiation of clarithromycin. Brigatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Brincidofovir: (Moderate) Postpone the administration of clarithromycin for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and clarithromycin is necessary. Brincidofovir is an OATP1B1/3 substrate and clarithromycin is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with clarithromycin ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; clarithromycin is a strong inhibitor of CYP3A4.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4. (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration. (Moderate) Concomitant use of buprenorphine and vonoprazan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when vonoprazan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping vonoprazan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If vonoprazan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and vonoprazan is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration. (Moderate) Concomitant use of buprenorphine and vonoprazan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when vonoprazan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping vonoprazan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If vonoprazan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and vonoprazan is a CYP3A inhibitor.
Buspirone: (Moderate) Concomitant administration of clarithromycin with buspirone may result in increases in buspirone AUC; the mechanism is probably reduced buspirone metabolism via CYP3A4. A low dose of buspirone is recommended if administered with significant CYP3A4 inhibitors. Subsequent dose adjustments should be based on clinical assessment.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with clarithromycin if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and clarithromycin due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with clarithromycin 2 to 3 days after discontinuation of clarithromycin. Cabozantinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Caffeine; Sodium Benzoate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with clarithromycin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with clarithromycin. Clarithromycin, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Canagliflozin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Canagliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Capivasertib: (Major) Avoid coadministration of capivasertib with clarithromycin due to increased capivasertib exposure which may increase the risk for capivasertib-related adverse effects. If coadministration is necessary, reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off; monitor for adverse reactions. Capivasertib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.7-fold.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with clarithromycin is necessary. Capmatinib is a CYP3A substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
Carbamazepine: (Major) Avoid concomitant use of vonoprazan and carbamazepine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase carbamazepine concentrations. Vonoprazan is a CYP3A substrate and weak CYP3A inhibitor and carbamazepine is a CYP3A substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Coadministration of carbamazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Drugs known to inhibit CYP3A4, such as clarithromycin, may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations. Serum carbamazepine concentrations should be monitored closely during coadministration; reduce carbamazepine doses may be necessary. Clarithromycin also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10, 11- epoxide, which may be more hepatotoxic than the parent drug. Several case reports have documented that clarithromycin can significantly decrease carbamazepine clearance, producing increases in the serum concentration of carbamazepine. Carbamazepine concentrations increased from 12 mcg/ml to 19.1 mcg/ml in a 17-year-old boy after 2 days of clarithromycin 250 mg PO bid. Patients should be monitored for carbamazepine toxicity if clarithromycin is added. Carbamazepine toxicity may be avoided if clarithromycin therapy is begun first and stabilized prior to beginning carbamazepine therapy, however, carbamazepine dosages may need to be increased if clarithromycin is subsequently discontinued.
Cardiac glycosides: (Major) Clarithromycin has been reported to increase the digoxin AUC by 70% when digoxin is administered orally. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of clarithromycin. A more important factor is clarithromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating clarithromycin. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as clarithromycin, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
Cefpodoxime: (Moderate) Monitor for altered response to cefpodoxime if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of cefpodoxime reducing its efficacy.
Cefuroxime: (Major) Avoid concomitant use of cefuroxime and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of cefuroxime reducing its efficacy.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Major) Avoid concomitant use of vonoprazan and cenobamate due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Consider alternatives to clarithromycin if treatment with cenobamate is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Ceritinib: (Major) Avoid coadministration of clarithromycin with ceritinib due to the additive risk of QT prolongation and increased ceritinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, further dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After clarithromycin is discontinued, resume the dose of ceritinib taken prior to initiating clarithromycin. Ceritinib is a CYP3A substrate associated with concentration-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Amitriptyline: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chloroquine: (Major) Avoid coadministration of chloroquine with clarithromycin due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpromazine: (Major) Concurrent use of chlorpromazine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both clarithromycin and chlorpromazine are specifically associated with an established risk of QT prolongation and TdP.
Choline Salicylate; Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with clarithromycin. Monitor for an increase in cilostazol-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%. (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with vonoprazan and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor. Coadministration with another CYP2C19 inhibitor did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of clarithromycin and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ciprofloxacin: (Major) Concomitant use of clarithromycin and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Postmarketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Because of the potential severity of these drug interactions (increased plasma cisapride concentrations and QT prolongation), cisapride use is contraindicated with clarithromycin which inhibits the CYP3A4 isoenzyme. (Major) Avoid concomitant use of cisapride and vonoprazan; use increases cisapride exposure and the risk for adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program.
Citalopram: (Major) Concomitant use of citalopram and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with vonoprazan. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation or serotonin-related side effects. Citalopram is a sensitive CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of clarithromycin as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4.
Clofazimine: (Major) Concomitant use of clofazimine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clonazepam: (Moderate) Use clarithromycin cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Clarithromycin is a CYP3A4 inhibitor.
Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of vonoprazan. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19 and vonoprazan is a CYP2C19 inhibitor.
Clorazepate: (Moderate) CYP3A4 inhibitors may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Clozapine: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Consider a clozapine dose reduction if coadministered with vonoprazan and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A and vonoprazan is a weak CYP3A inhibitor. If vonoprazan is discontinued, monitor for lack of clozapine effect and increase dose if necessary.
Cobicistat: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with clarithromycin due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; clarithromycin is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Promethazine: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Colchicine: (Major) Avoid concomitant use of colchicine and clarithromycin due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and clarithromycin is a dual strong CYP3A and P-gp inhibitor. Concomitant use has been observed to increase colchicine overall exposure by 3.8-fold.
Conivaptan: (Contraindicated) Coadministration of conivaptan and clarithromycin is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; clarithromycin is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and clarithromycin if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; clarithromycin is a strong CYP3A inhibitor.
Crizotinib: (Major) Avoid concomitant use of crizotinib and clarithromycin due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Cyclosporine: (Major) Clarithromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Clarithromycin may also reduce the intestinal metabolism of cyclosporine. It has been recommended to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolides concurrently. Increased cyclosporine concentrations may be seen with 2 days of beginning combination therapy. In managing potential interactions between macrolides and cyclosporine, appropriate monitoring of cyclosporine concentrations is critical to help avoid graft failure or drug-related toxicity. (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with vonoprazan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with clarithromycin, a P-gp inhibitor. Although the coadministration of dabigatran and clarithromycin has no effect on the pharmacokinetics of dabigatran or clarithromycin in healthy subjects, patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like clarithromycin in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with clarithromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Dabrafenib: (Major) Avoid concomitant use of vonoprazan and dabrafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and clarithromycin, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of clarithromycin efficacy.
Dacomitinib: (Major) Avoid concomitant use of dacomitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of dacomitinib reducing its efficacy.
Dapagliflozin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Dapagliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Dapagliflozin; Saxagliptin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Daridorexant: (Major) Avoid concomitant use of daridorexant and clarithromycin. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with clarithromycin due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with clarithromycin is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Clarithromycin is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir: (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
Darunavir; Cobicistat: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%. (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Dasatinib: (Major) Avoid coadministration of dasatinib and clarithromycin due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to clarithromycin with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of clarithromycin in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue clarithromycin or stop dasatinib until clarithromycin is discontinued. Allow a washout of approximately 1 week after clarithromycin is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and TdP. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively. (Major) Avoid concomitant use of dasatinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of dasatinib reducing its efficacy.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with clarithromycin. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: (Major) Avoid coadministration of clarithromycin with degarelix. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) In a study involving 6 HIV-1-infected patients, coadministration of delavirdine 300 mg 3 times daily with clarithromycin 500 mg twice daily resulted in no significant change in delavirdine pharmacokinetics. However, for patients with renal dysfunction, dosage adjustment of clarithromycin is required during concurrent delavirdine treatment due to decreased clarithromycin elimination. The dose of clarithromycin should be reduced by 50% for patients with a creatinine clearance of 30 to 60 ml/min and for patients with a creatinine clearance of < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
Demeclocycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
Desogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Deutetrabenazine: (Major) Avoid coadministration of clarithromycin with deutetrabenazine. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of clarithromycin with dexamethasone is necessary, due to increased dexamethasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Consider the use of corticosteroids such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A inhibitors, especially for long-term use. Dexamethasone is primarily metabolized by CYP3A and clarithromycin is a strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextroamphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Dextromethorphan; Quinidine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Quinidine (including dextromethorphan; quinidine) and disopyramide are also associated with QT prolongation and TdP. There have been post-marketing reports of TdP occurring with the coadministration of clarithromycin and quinidine or disopyramide. If used concomitantly, monitor ECGs for QT prolongation and consider monitoring serum concentrations of quinidine or disopyramide.
Diazepam: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam. (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with vonoprazan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A and CYP2C19 substrate and vonoprazan is a CYP3A and CYP2C19 inhibitor.
Dichlorphenamide: (Moderate) Use dichlorphenamide and amoxicillin together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including amoxicillin. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Dienogest; Estradiol valerate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Digoxin: (Major) Clarithromycin has been reported to increase the digoxin AUC by 70% when digoxin is administered orally. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of clarithromycin. A more important factor is clarithromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating clarithromycin. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV. (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
Dihydroergotamine: (Contraindicated) Concomitant use of ergotamine with clarithromycin is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Diltiazem: (Major) Avoid coadministration of clarithromycin and diltiazem, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving diltiazem therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Disopyramide: (Major) Concurrent administration of clarithromycin and disopyramide has been associated with post-marketing reports of torsades de pointes (TdP) and hypoglycemia. If these drugs are administered together, closely monitor ECGs for QT prolongation, blood glucose concentrations, and consider monitoring disopyramide serum concentrations. Both clarithromycin and disopyramide have been associated with an established risk for QT prolongation and TdP. (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with vonoprazan is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors.
Docetaxel: (Major) Avoid coadministration of docetaxel with clarithromycin if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Major) Coadministration of dofetilide and clarithromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP. (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with vonoprazan is necessary as concurrent use may increase dofetilide exposure. Vonoprazan is a weak CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dolasetron: (Contraindicated) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin should be used cautiously with other agents known to cause QT prolongation. Agents with potential to prolong the QT interval include: dolasetron.
Dolutegravir; Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
Doravirine: (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
Doxepin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of vonoprazan is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and vonoprazan is a CYP2C19 inhibitor.
Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like clarithromycin, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
Doxorubicin Liposomal: (Major) Avoid coadministration of clarithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of clarithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxycycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Dronabinol: (Major) Use caution if coadministration of dronabinol with clarithromycin is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) Concomitant use of dronedarone with clarithromycin is contraindicated. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include clarithromycin.
Drospirenone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Drospirenone; Estetrol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Drospirenone; Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Drospirenone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Dulaglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of clarithromycin. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as clarithromycin, should be avoided.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with clarithromycin. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; clarithromycin is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as clarithromycin.
Edoxaban: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with clarithromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of clarithromycin; monitor for increased adverse effects of edoxaban.
Efavirenz: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Elacestrant: (Major) Avoid concomitant use of elacestrant and clarithromycin due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as clarithromycin is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Clarithromycin significantly inhibits OATP1B1, and also inhibits CYP3A and P-gp. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. Consider an alternative to clarithromycin in a patient receiving elagolix. (Major) Avoid concomitant use of vonoprazan and elagolix due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as clarithromycin is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Clarithromycin significantly inhibits OATP1B1, and also inhibits CYP3A and P-gp. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. Consider an alternative to clarithromycin in a patient receiving elagolix. (Major) Avoid concomitant use of vonoprazan and elagolix due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of clarithromycin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Eletriptan: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of clarithromycin due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
Elexacaftor; tezacaftor; ivacaftor: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with clarithromycin; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; clarithromycin is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with clarithromycin; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); clarithromycin is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Major) Coadministration of eliglustat and vonoprazan is not recommended in poor CYP2D6 metabolizers (PMs). In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Eliglustat is a CYP3A and CYP2D6 substrate; vonoprazan is a weak CYP3A inhibitor. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of clarithromycin and eliglustat is contraindicated. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both clarithromycin and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and clarithromycin can independently prolong the QT interval, and coadministration increases this risk. Clarithromycin is a strong CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors such as clarithromycin increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
Eluxadoline: (Major) Consider a reduction of the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with clarithromycin. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and clarithromycin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Empagliflozin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Empagliflozin; Linagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Empagliflozin; Linagliptin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Empagliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin. (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Encorafenib: (Major) Avoid concomitant use of encorafenib and clarithromycin due to the risk for decreased clarithromycin exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clarithromycin is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A inducer. (Major) Avoid concomitant use of vonoprazan and encorafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A inducer.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with clarithromycin is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; clarithromycin is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Entrectinib: (Major) Avoid concomitant use of entrectinib with clarithromycin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Enzalutamide: (Major) Avoid concomitant use of vonoprazan and enzalutamide due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Coadministration of enzalutamide and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction; consider alternatives to clarithromycin if treatment with enzalutamide is necessary. Clarithromycin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible.
Eplerenone: (Contraindicated) Coadministration of clarithromycin and eplerenone is contraindicated. Clarithromycin potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and clarithromycin due to the risk for increased plasma concentrations of erdafitinib. If concomitant use is necessary, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. Erdafitinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased erdafitinib overall exposure by 134%.
Ergotamine: (Contraindicated) Concomitant use of ergotamine with clarithromycin is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Ergotamine; Caffeine: (Contraindicated) Concomitant use of ergotamine with clarithromycin is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with eribulin include clarithromycin.
Erlotinib: (Major) Avoid coadministration of erlotinib with clarithromycin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid concomitant use of erlotinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of erlotinib reducing its efficacy.
Ertugliflozin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Ertugliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Ertugliflozin; Sitagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as clarithromycin, should be done with caution and close monitoring. In addition, escitalopram is metabolized by CYP3A4. Theoretically, clarithromycin may inhibit this enzyme and lead to elevated plasma levels of this SSRI. However, because escitalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance.
Eslicarbazepine: (Major) Avoid concomitant use of vonoprazan and eslicarbazepine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Coadministration of eslicarbazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Estazolam: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Estradiol: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estradiol; Progesterone: (Moderate) Use caution if coadministration of clarithromycin with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as clarithromycin. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Although other macrolide antibiotics, such as erythromycin, inhibit CYP3A4 to a lesser extent than clarithromycin, a clinically relevant interaction is possible, and dose adjustments of eszopiclone may be necessary.
Ethacrynic Acid: (Minor) Ethacrynic acid may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Ethinyl Estradiol; Norelgestromin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Ethinyl Estradiol; Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of etonogestrel.
Etrasimod: (Major) Avoid concomitant use of etrasimod and clarithromycin in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Etrasimod is a CYP2C9 and CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Etravirine: (Major) Avoid concomitant use of vonoprazan and etravirine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and etravirine is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Coadministration of etravirine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Everolimus: (Major) Avoid coadministration of everolimus with clarithromycin due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Exenatide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Ezetimibe; Simvastatin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Fedratinib: (Major) Avoid coadministration of fedratinib with clarithromycin as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If clarithromycin is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felodipine: (Major) Avoid coadministration of clarithromycin and felodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving felodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Felodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Moderate) Concurrent use of felodipine and vonoprazan should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Concurrent use of another weak CYP3A inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If clarithromycin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If vonoprazan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Ferric Maltol: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with clarithromycin. Avoid use of fesoterodine and clarithromycin in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Fexinidazole: (Major) Concomitant use of fexinidazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, monitor for decreased fexinidazole efficacy if coadministration is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and clarithromycin is a strong CYP3A inhibitor.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Finerenone: (Contraindicated) Concomitant use of finerenone and clarithromycin is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%. (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or vonoprazan; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Fingolimod: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include clarithromycin.
Flecainide: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with flecainide. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as clarithromycin, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin. (Moderate) The concomitant use of flibanserin and multiple weak CYP3A inhibitors, including vonoprazan, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A inhibitors and flibanserin should be discussed with the patient.
Fluconazole: (Contraindicated) Coadministration is contraindicated. Fluconazole has been associated with QT prolongation and clarithromycin has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP). Additionally, fluconazole is an inhibitor of CYP3A4 and clarithromycin is a known inhibitor and substrate of CYP3A4. In healthy volunteers, the coadministration of clarithromycin (500 mg orally twice daily) with fluconazole (200 mg once daily) led to increases in clarithromycin mean steady-state Cmin (33%) and AUC (18%); however, mean steady-state concentrations of 14-OH clarithromycin were not affected. The changes appeared to be of minor consequence in healthy subjects. The potential for a more significant interaction between fluconazole and clarithromycin might exist at higher dosages of either drug; caution is advised in such circumstances but should not normally alter therapy. Fluconazole is usually considered a less potent inhibitor of CYP3A4 than other azole-family systemic antifungal agents (e.g., ketoconazole, itraconazole), especially at dosages of < 200 mg/day. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
Fluoxetine: (Major) Concomitant use of clarithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with fluphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while fluphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Flurazepam: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with clarithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluvastatin: (Moderate) Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and fluvastatin. Use together with caution and monitor for symptoms of myopathy and/or rhabdomyolysis.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and TdP while QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Food: (Major) Advise patients to avoid cannabis use during clarithromycin treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and clarithromycin is a strong CYP3A inhibitor. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Moderate) Concomitant administration of clarithromycin and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with clarithromycin long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Fosamprenavir: (Major) Avoid concomitant use of vonoprazan and fosamprenavir due to altered plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and fosamprenavir is both a strong CYP3A inhibitor and moderate CYP3A inducer. The net effect on CYP3A4 substrates is unclear. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with clarithromycin. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as clarithromycin. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Clarithromycin is also associated with an established risk for QT prolongation and TdP. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Major) Avoid concomitant use of vonoprazan and fosphenytoin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase fosphenytoin concentrations. Vonoprazan is a CYP3A substrate and CYP2C19 inhibitor and fosphenytoin is a CYP2C19 substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Coadministration of fosphenytoin and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. Additionally, there have been postmarketing reports of interactions of clarithromycin and phenytoin, which may also occur with fosphenytoin. The clarithromycin manufacturer recommends caution if coadministered.
Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
Fostemsavir: (Major) Avoid coadministration of clarithromycin with fostemsavir. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Furosemide: (Minor) Furosemide may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Futibatinib: (Major) Avoid concurrent use of futibatinib and clarithromycin. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; clarithromycin is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Gefitinib: (Major) Avoid concomitant use of gefitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of gefitinib reducing its efficacy. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with gemifloxacin. Clarithromycin is associated with an established risk for QT prolongation and TdP. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and clarithromycin together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Gilteritinib: (Major) Consider an alternative to clarithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with clarithromycin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and clarithromycin as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3; clarithromycin is an inhibitor of P-gp and OATP1B1/3. (Moderate) Caution is advised with the coadministration of pibrentasvir and clarithromycin as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); clarithromycin is an inhibitor of P-gp.
Glimepiride: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Glipizide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Glipizide; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Glyburide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Glyburide; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Goserelin: (Major) Avoid coadministration of clarithromycin with goserelin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with granisetron. Both granisetron and clarithromycin are associated with prolongation of the QT interval, and clarithromycin has also been associated with an established risk for TdP.
Grapefruit juice: (Minor) Grapefruit juice has been reported to decrease the metabolism of drugs metabolized via cytochrome CYP 3A4 isozyme. Grapefruit juice contains compounds that inhibit CYP3A4 in enterocytes in the GI tract. In a randomized crossover study in healthy volunteers, grapefruit juice did not have a significant affect on the bioavailability of clarithromycin nor did it affect the metabolism of clarithromycin to its active metabolite.
Guanfacine: (Major) Clarithromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If clarithromycin is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and clarithromycin is a strong CYP3A4 inhibitor.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
Haloperidol: (Major) Concurrent use of clarithromycin and haloperidol should be avoided if possible. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) of haloperidol may be associated with a higher risk of QT prolongation. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval. Because clarithromycin is also associated with an increased risk for QT prolongation and TdP, the need to coadminister clarithromycin with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits. Clarithromycin is an inhibitor of CYP3A4. Elevated haloperidol concentrations occurring through inhibition of CYP3A4 or CYP2D6 may increase the risk of adverse effects, including QT prolongation.
Histrelin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocortisone: (Moderate) Clarithromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with clarithromycin. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Idelalisib: (Major) Coadministration of idelalisib with clarithromycin may increase idelalisib exposure; use alternative agents if possible. If concomitant use of these drugs is required, monitor patients frequently for signs and symptoms of idelalisib-related adverse reactions (e.g., hepatotoxicity, diarrhea, neutropenia, and infection). Idelalisib and clarithromycin are both CYP3A4 substrates and strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased idelalisib exposure by 1.8-fold.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with clarithromycin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Clarithromycin is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid coadministration of iloperidone and clarithromycin due to the potential for QT prolongation; iloperidone exposure may also increase. If coadministration cannot be avoided, decrease the iloperidone dose by one-half. Resume the prior iloperidone dose if clarithromycin is discontinued. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Iloperidone is a CYP3A4 substrate that has been associated with QT prolongation. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
Imatinib: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and should be used cautiously with CYP3A4 substrates, such as imatinib, due to the potential for reduced metabolism and drug accumulation.
Incretin Mimetics: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Indinavir: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may decrease the systemic clearance of indinavir, a CYP3A4 substrate. Patients with impaired renal function may require a reduced dosage of clarithromycin.
Indomethacin: (Minor) Indomethacin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Infigratinib: (Major) Avoid concomitant use of infigratinib and clarithromycin. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%. (Major) Avoid concomitant use of infigratinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of infigratinib reducing its efficacy.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with clarithromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Insulin Aspart: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Degludec: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Degludec; Liraglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Detemir: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Glargine: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Glargine; Lixisenatide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Glulisine: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Lispro: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin, Inhaled: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulins: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Irinotecan Liposomal: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Iron Salts: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Iron: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with clarithromycin may result in increased serum concentrations of both drugs. Clarithromycin is a substrate and moderate inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Clarithromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. As compared with the plasma concentration obtained with clarithromycin 500 mg twice daily as monotherapy, the clarithromycin plasma concentration was reduced by 87% when rifampin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 0.7 +/- 0.6 mcg/ml when given in combination with rifampin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Clarithromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. As compared with the plasma concentration obtained with clarithromycin 500 mg twice daily as monotherapy, the clarithromycin plasma concentration was reduced by 87% when rifampin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 0.7 +/- 0.6 mcg/ml when given in combination with rifampin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Isophane Insulin (NPH): (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Isradipine: (Major) Avoid coadministration of clarithromycin and isradipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving isradipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Isradipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with vonoprazan is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with clarithromycin as istradefylline exposure and adverse effects may increase. Clarithromycin is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Itraconazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Consider use of azithromycin in place of clarithromycin. Both clarithromycin and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. (Moderate) Administer vonoprazan at least 2 hours before or 2 hours after itraconazole 100 mg capsules. Monitor for increased itraconazole-related adverse effects if vonoprazan is administered with itraconazole 65 mg capsules; a dose reduction may be needed. Drugs that reduce gastric acidity, such as vonoprazan, may decrease the systemic exposure of the 100 mg itraconazole capsule formulation. Conversely, exposure to itraconazole is increased when gastric acid reducers are administered with the 65 mg itraconazole capsule.
Ivabradine: (Contraindicated) Coadministration of ivabradine and clarithromycin is contraindicated. Ivabradine is primarily metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with clarithromycin due to increased plasma concentrations of ivosidenib and additive QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If clarithromycin is discontinued, wait at least 5 half-lives of clarithromycin before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and clarithromycin due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%. (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of vonoprazan is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and clarithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both ketoconazole and clarithromycin are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid concomitant use of ketoconazole and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ketoconazole reducing its efficacy.
Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Lapatinib: (Major) Avoid coadministration of lapatinib with clarithromycin due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities prior to treatment. If clarithromycin is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and TdP. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Ledipasvir; Sofosbuvir: (Major) Avoid concomitant use of ledipasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ledipasvir reducing its efficacy.
Lefamulin: (Major) Avoid coadministration of lefamulin with clarithromycin as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Clarithromycin is a P-gp and strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lemborexant: (Major) Avoid coadministration of lemborexant and clarithromycin as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold. (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with vonoprazan as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; vonoprazan is a weak CYP3A inhibitor. Coadministration with a weak CYP3A inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and clarithromycin due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
Letermovir: (Moderate) Administering clarithromycin concurrently with letermovir may result in elevated concentrations of both drugs. The impact on the serum concentration of clarithromycin may be increased in patients receiving letermovir with cyclosporine. Closely monitor for adverse events including tachycardia, atrial fibrillation, gastrointestinal events, dizziness, or confusion. Clarithromycin is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent use with another CYP3A inhibitor increased clarithromycin exposure (AUC) by 94%, and decreased AUC of 14-OH clarithromycin by 70%.
Leuprolide: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Levamlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Levofloxacin: (Major) Concomitant use of levofloxacin and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and clarithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both ketoconazole and clarithromycin are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid concomitant use of ketoconazole and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ketoconazole reducing its efficacy.
Levomilnacipran: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as clarithromycin. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Levonorgestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Levothyroxine: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Levothyroxine; Liothyronine (Porcine): (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4. (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4. (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4. (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Linagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Linagliptin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Liothyronine: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Liraglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Lithium: (Major) Concomitant use of lithium and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lixisenatide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with clarithromycin due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Lomitapide: (Contraindicated) Concomitant use of clarithromycin and lomitapide is contraindicated. If treatment with clarithromycin is unavoidable, lomitapide should be stopped during the course of treatment. Markedly increased transaminases have been reported with coadministration. Clarithromycin is a strong CYP3A4 inhibitor and lomitapide is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lomitapide exposure approximately 27-fold. (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with vonoprazan is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Vonoprazan is a weak CYP3A inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A inhibitors.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and clarithromycin is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Major) Avoid coadministration of lonafarnib and vonoprazan; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing vonoprazan. Lonafarnib is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Loperamide: (Major) Concomitant use of loperamide and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A4 and P-gp substrate and clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Loperamide; Simethicone: (Major) Concomitant use of loperamide and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A4 and P-gp substrate and clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with clarithromycin due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with clarithromycin due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of clarithromycin may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If clarithromycin is discontinued, resume the original dose of lorlatinib after 3 plasma half-lives of clarithromycin. Lorlatinib is a CYP3A4 substrate and moderate CYP3A4 inducer. Clarithromycin is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. (Major) Avoid concomitant use of vonoprazan and lorlatinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Lovastatin: (Contraindicated) The concurrent use of lovastatin and clarithromycin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of treatment with clarithromycin therapy is available, lovastatin use must be suspended during clarithromycin treatment. Lovastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration if possible; lumacaftor; ivacaftor may decrease the therapeutic efficacy of clarithromycin. If concomitant use is necessary, monitor microbiological activity and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when clarithromycin is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking clarithromycin, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking clarithromycin. Clarithromycin is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Increasing the metabolism of clarithromycin decreases plasma concentrations of clarithromycin, but increases plasma concentrations of 14-OH-clarithromycin (active metabolite); the microbiological activity of each is different for different bacteria. In addition, the inhibitory effects of clarithromycin may increase the systemic exposure of ivacaftor. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A inhibitor, increased ivacaftor exposure by 4.3-fold. However, because lumacaftor is a strong inducer of CYP3A, the net exposure of ivacaftor at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours). (Major) Avoid concomitant use of vonoprazan and lumacaftor; ivacaftor due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration if possible; lumacaftor; ivacaftor may decrease the therapeutic efficacy of clarithromycin. If concomitant use is necessary, monitor microbiological activity and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when clarithromycin is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking clarithromycin, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking clarithromycin. Clarithromycin is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Increasing the metabolism of clarithromycin decreases plasma concentrations of clarithromycin, but increases plasma concentrations of 14-OH-clarithromycin (active metabolite); the microbiological activity of each is different for different bacteria. In addition, the inhibitory effects of clarithromycin may increase the systemic exposure of ivacaftor. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A inhibitor, increased ivacaftor exposure by 4.3-fold. However, because lumacaftor is a strong inducer of CYP3A, the net exposure of ivacaftor at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours). (Major) Avoid concomitant use of vonoprazan and lumacaftor; ivacaftor due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of clarithromycin is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inhibitors, such as clarithromycin, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and clarithromycin due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as clarithromycin. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Macitentan; Tadalafil: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Mafenide: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
Maprotiline: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with maprotiline. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, such as clarithromycin.
Maraviroc: (Major) Coadministration of maraviroc (a substrate of CYP3A, P-gp, and OATP1B1) with clarithromycin (a strong CYP3A4 inhibitor and P-gp/OATP1B1 inhibitor) may result in increased maraviroc concentrations. Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with clarithromycin (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with clarithromycin due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease efficacy of clarithromycin. Mavacamten is a substrate and moderate inducer of CYP3A and clarithromycin is a substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A inducer. (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting vonoprazan therapy. Avoid initiation of vonoprazan in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable vonoprazan therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP2C19 substrate and vonoprazan is a weak CYP2C19 inhibitor. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%.
Mefloquine: (Major) There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as clarithromycin. In addition, mefloquine is metabolized by CYP3A4 and P-glycoprotein (P-gp). Clarithromycin is an inhibitor of these enzymes and may decrease the clearance of mefloquine and further increasing the risk for QT prolongation. (Moderate) Use mefloquine with caution if coadministration with vonoprazan is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A and vonoprazan is a weak CYP3A inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and vonoprazan is a weak CYP3A inhibitor. Concomitant use with vonoprazan can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Metformin; Repaglinide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Dosage reduction of repaglinide may be needed. Careful monitoring of glucose is recommended.
Metformin; Saxagliptin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Metformin; Sitagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as clarithromycin, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with clarithromycin, an inhibitor of CYP3A4 and P-gp, may result in increased serum concentrations of methadone. (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; vonoprazan is a weak CYP3A and CYP2C19 inhibitor. Concomitant use with vonoprazan can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Methohexital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Methotrexate: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Methylergonovine: (Major) Avoid concomitant use of methylergonovine with clarithromycin. Concomitant use may increase methylergonovine exposure and the risk for vasospasm which may lead to cerebral or peripheral ischemia. Methylergonovine is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Methylprednisolone: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and methylprednisolone have been noted. Clarithromycin is a CYP3A4 inhibitor and may decrease the clearance of methylprednisolone if coadministered.
Metronidazole: (Major) Concomitant use of metronidazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Major) Dose adjustments of oral midazolam may be necessary when coadministered with clarithromycin. Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as clarithromycin, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent. (Moderate) Use caution when midazolam is coadministered with vonoprazan. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and clarithromycin due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mifepristone: (Major) Avoid coadministration of mifepristone with clarithromycin due to the risk of additive QT prolongation and torsade de pointes (TdP); the exposure of both drugs may also be increased. If concomitant use of mifepristone is necessary for the treatment of Cushing's syndrome in a patient already receiving clarithromycin, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with clarithromycin is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with clarithromycin is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with clarithromycin is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with clarithromycin is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and clarithromycin are substrates and strong inhibitors of CYP3A4 that are associated with QT prolongation.
Miglitol: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Minocycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Mirtazapine: (Major) Concomitant use of mirtazapine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of clarithromycin is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with clarithromycin due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Major) Avoid concomitant use of vonoprazan and mitotane due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Coadministration of mitotane and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and clarithromycin. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Major) Coadministration of modafinil and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, clarithromycin is a significant inhibitor of CYP3A4, which may increase serum concentrations of modafinil.
Momelotinib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; clarithromycin is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Mometasone: (Moderate) Concomitant administration of clarithromycin and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with clarithromycin long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Moxifloxacin: (Major) Concurrent use of clarithromycin and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin; therefore, the recommended dose or infusion rate should not be exceeded.
Mycophenolate: (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear. (Moderate) Monitor for altered mycophenolate efficacy when coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of mycophenolate reducing its efficacy.
Nafcillin: (Major) Avoid concomitant use of vonoprazan and nafcillin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with clarithromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; clarithromycin is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with strong CYP3A4 inhibitors is contraindicated. Naloxegol is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inhibitors, such as clarithromycin, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with clarithromycin is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and clarithromycin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Nateglinide: (Moderate) The use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, inhibition of CYP3A by clarithromycin may occur, and dose adjustment of nateglinide may be needed. Careful monitoring of glucose is recommended.
Nelfinavir: (Major) Avoid concomitant use of nelfinavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of nelfinavir reducing its efficacy.
Neratinib: (Major) Avoid concomitant use of clarithromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of neratinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of neratinib reducing its efficacy.
Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Clarithromycin is partially metabolized by CYP3A4, and increased concentrations may lead to an increased risk for side effects, including QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as clarithromycin can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Nevirapine: (Major) Avoid coadministration of nevirapine and clarithromycin. Coadministration of nevirapine and clarithromycin significantly decreases clarithromycin serum concentrations. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Additionally, the exposure of nevirapine may also be increased, leading to increased toxicity. Nevirapine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
Nicardipine: (Major) Avoid coadministration of clarithromycin and nicardipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nicardipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nicardipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
NIFEdipine: (Major) Avoid coadministration of clarithromycin and nifedipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nifedipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nifedipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Nilotinib: (Major) Avoid concomitant use of nilotinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of nilotinib reducing its efficacy. (Major) Avoid the concomitant use of nilotinib and clarithromycin; significant prolongation of the QT interval and torsade de pointes (TdP) may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Clarithromycin is associated with an established risk for QT prolongation and TdP. If therapy with clarithromycin is necessary, interrupt nilotinib therapy if possible. Monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If clarithromycin is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and clarithromycin is a strong inhibitor of CYP3A4.
Nimodipine: (Major) Avoid coadministration of clarithromycin and nimodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nimodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nimodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with vonoprazan is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as clarithromycin, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Clarithromycin is a moderate P-gp inhibitor and a potent inhibitor of CYP3A4; nintedanib is a P-gp substrate, and a minor CYP3A4 substrate. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and clarithromycin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 3.46-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with clarithromycin, particularly in geriatric patients, due to increased plasma concentrations of nisoldipine. If the use of a macrolide antibiotic is necessary in a patient receiving nisoldipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and clarithromycin is a CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Major) Avoid coadministration of nisoldipine with vonoprazan due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and vonoprazan is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Norethindrone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Norgestimate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Octreotide: (Moderate) Concomitant use of oral octreotide with vonoprazan may require increased doses of octreotide. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral octreotide reducing its efficacy.
Ofloxacin: (Major) Concomitant use of ofloxacin and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Olanzapine; Fluoxetine: (Major) Concomitant use of clarithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Olanzapine; Samidorphan: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Olaparib: (Major) Avoid coadministration of olaparib with clarithromycin due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after clarithromycin is discontinued. Olaparib is a CYP3A substrate and clarithromycin is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and clarithromycin is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and clarithromycin may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If clarithromycin is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Olopatadine; Mometasone: (Moderate) Concomitant administration of clarithromycin and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with clarithromycin long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Omadacycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and clarithromycin. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of vonoprazan and rifabutin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) The combination of rifabutin and clarithromycin should be avoided. Clarithromycin is a substrate and inhibitor of CYP3A4, and rifabutin is a substrate and inducer of CYP3A4. The metabolism of rifabutin is inhibited by clarithromycin, possibly through inhibition of CYP3A4. Inhibition of rifabutin metabolism results in significant increases in rifabutin serum concentrations and adverse reactions. Also, rifabutin increases the metabolism of clarithromycin resulting in significant decreases in clarithromycin concentrations thereby reducing the antimicrobial efficacy of clarithromycin. As compared with the plasma concentration obtained with clarithromycin monotherapy, the clarithromycin plasma concentration was reduced by 63% when rifabutin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 2 +/- 1.5 mcg/ml when given in combination with rifabutin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups.
Ondansetron: (Major) Concomitant use of ondansetron and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Oritavancin: (Moderate) Clarithromycin is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of clarithromycin may be reduced if these drugs are administered concurrently.
Osilodrostat: (Major) Avoid coadministration of clarithromycin with osilodrostat due to the risk of QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of clarithromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Ospemifene: (Moderate) Coadministration of clarithromycin and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase the systemic exposure of ospemifene by approximately1.4-fold.
Oxaliplatin: (Major) Avoid coadministration of clarithromycin with oxaliplatin due to the risk of QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
Oxcarbazepine: (Major) Coadministration of oxcarbazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Serum concentrations of oxybutynin may be increased when administered with inhibitors of the CYP3A4 enzyme system, including clarithromycin.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking clarithromycin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Paclitaxel: (Minor) Paclitaxel is partially metabolized by CYP3A4. The systemic clearance of paclitaxel may be decreased if coadministered with clarithromycin, an inhibitor of CYP3A4.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with clarithromycin is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with clarithromycin 500 mg twice a day for 5 days increased pacritinib exposure by 80%.
Palbociclib: (Major) Avoid coadministration of clarithromycin with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If clarithromycin is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of clarithromycin. Palbociclib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clarithromycin. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Palovarotene: (Major) Avoid concomitant use of palovarotene and clarithromycin due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) The co-administration of panobinostat with clarithromycin is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Clarithromycin is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. This interaction may be relevant to combination products containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole (Prevpac) and amoxicillin; clarithromycin; omeprazole (Omeclamox-Pak) triple therapy packs.
Paricalcitol: (Moderate) Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as clarithromycin. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Pasireotide: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Cautious use of pasireotide and clarithromycin is needed, as coadministration may have additive effects on the prolongation of the QT interval.
Pazopanib: (Major) Avoid concomitant use of pazopanib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of pazopanib reducing its efficacy. (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and clarithromycin have been reported to prolong the QT interval. If pazopanib and clarithromycin must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a substrate for CYP3A4 and P-glycoprotein (P-gp) and weak inhibitor of CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4, an inhibitor of P-gp, and substrate of CYP3A4. Concurrent administration of clarithromycin and pazopanib may result in increased pazopanib and/or clarithromycin concentrations; avoid use of these agents together if possible. If co-administration of pazopanib and clarithromycin is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and clarithromycin due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If clarithromycin is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of clarithromycin. Pemigatinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Pentamidine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with clarithromycin include intravenous pentamidine.
Pentobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Perampanel: (Moderate) Concurrent use of perampanel with clarithromycin may increase exposure to perampanel and increase plasma concentrations. Clarithromycin is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
Perindopril; Amlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Perphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with perphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while perphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with perphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while perphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and clarithromycin due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease clarithromycin plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If clarithromycin is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of clarithromycin. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; clarithromycin is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. (Major) Avoid concomitant use of vonoprazan and pexidartinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of pexidartinib reducing its efficacy. Vonoprazan is a CYP3A substrate and pexidartinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Phenobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) There have been spontaneous and/or published reports of interactions between clarithromycin and phenobarbital. Inducers of CYP3A enzymes, such as phenobarbital will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OHclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. Clinicians should observe patients closely for infection resolution if these drugs are administered concurrently.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) There have been spontaneous and/or published reports of interactions between clarithromycin and phenobarbital. Inducers of CYP3A enzymes, such as phenobarbital will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OHclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. Clinicians should observe patients closely for infection resolution if these drugs are administered concurrently.
Phenytoin: (Major) Avoid concomitant use of vonoprazan and phenytoin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase phenytoin concentrations. Vonoprazan is a CYP3A substrate and CYP2C19 inhibitor and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Coadministration of phenytoin and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. Additionally, there have been postmarketing reports of interactions of clarithromycin and phenytoin. The clarithromycin manufacturer recommends caution if coadministered.
Pimavanserin: (Major) Coadministration of pimavanserin and clarithromycin should be avoided if possible. Clarithromycin is associated with a risk for QT prolongation and torsade de pointes (TdP); pimavanserin may also cause QT prolongation. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5. Concurrent use of a strong inhibitor of CYP3A4, such as clarithromycin, is expected to increase pimavanserin exposure. If coadministration cannot be avoided, reduce the pimavanserin dose to 10 mg/day PO and closely monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of macrolide antibiotics with pimozide is contraindicated. (Major) Avoid concomitant use of pimozide and vonoprazan. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Pioglitazone: (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Pioglitazone; Glimepiride: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Pioglitazone; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and clarithromycin due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of clarithromycin use. Resume the previous dose of pirtobrutinib after clarithromycin is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pitolisant: (Major) Avoid coadministration of pitolisant with clarithromycin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of clarithromycin due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Polysaccharide-Iron Complex: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Ponatinib: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking clarithromycin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and clarithromycin is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Consider use of azithromycin in place of clarithromycin. Both posaconazole and clarithromycin are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of clarithromycin. Further, clarithromycin is an inhibitor of the drug efflux protein, P-glycoprotein, for which posaconazole is a substrate and an inhibitor. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and clarithromycin and an increased risk for serious adverse events. Additionally, both drugs have been associated with prolongation of the QT interval as well as rare cases of torsade de pointes.
Pralsetinib: (Major) Avoid concomitant use of clarithromycin and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and clarithromycin is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%.
Pramlintide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Pravastatin: (Major) Do not exceed 40 mg per day of pravastatin if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Coadministration of clarithromycin increased the AUC and Cmax of pravastatin by 110% and 128%, respectively.
Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include clarithromycin.
Primidone: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Coadministration of primidone and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. Primidone is metabolized in the liver to produce phenobarbital and PEMA. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Probenecid: (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and clarithromycin due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and clarithromycin is a dual strong CYP3A and P-gp inhibitor. Concomitant use has been observed to increase colchicine overall exposure by 3.8-fold. (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
Procainamide: (Major) Clarithromycin should be used cautiously with procainamide. Procainamide and clarithromycin are both associated with a well-established risk of QT prolongation and torsades de pointes (TdP).
Prochlorperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with prochlorperazine. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Phenothiazines, like prochlorperazine, have been reported to prolong the QT interval, while clarithromycin is associated with an established risk for QT prolongation and TdP.
Progesterone: (Moderate) Use caution if coadministration of clarithromycin with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Promethazine: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Monitor for increased propafenone toxicity if coadministered with vonoprazan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and vonoprazan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate and vonoprazan is a weak CYP3A inhibitor.
Quazepam: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
Quetiapine: (Major) Avoid concurrent use of quetiapine and clarithromycin due to the potential for additive effects on the QT interval and torsade de pointes (TdP) and the potential for greatly increased quetiapine exposure. Clarithromycin is a potent inhibitor of CYP3A4 that is expected to signficantly reduce metabolism of quetiapine. If administration of clarithromycin is required in a patient taking quetiapine, reduce the quetiapine dose to one sixth of the current dose. Monitor for quetiapine-related side effects. If clarithromycin is discontinued, increase the quetiapine dose by 6-fold. Clarithromycin has an established causal association with QT prolongation and TdP (torsade de pointes). Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
Quinidine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Quinidine (including dextromethorphan; quinidine) and disopyramide are also associated with QT prolongation and TdP. There have been post-marketing reports of TdP occurring with the coadministration of clarithromycin and quinidine or disopyramide. If used concomitantly, monitor ECGs for QT prolongation and consider monitoring serum concentrations of quinidine or disopyramide.
Quinine: (Major) Concurrent use of quinine with clarithromycin should be avoided due to the risk for QT prolongation and torsade de pointes (TdP). Both quinine and clarithromycin have been associated with prolongation of the QT interval. In addition, because both clarithromycin and quinine are substrates and inhibitors of CYP3A4; coadministration may result in elevated plasma concentration of both drugs, causing an increased risk for adverse events.
Quizartinib: (Major) Avoid concomitant use of clarithromycin with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. Concomitant use may also increase the risk for torsade de pointes (TdP) and QT/QTc prolongation. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quizartinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Ramelteon: (Moderate) Use caution with concurrent use of ramelteon and strong inhibitors of CYP3A4, such as clarithromycin. Because ramelteon is partially metabolized via CYP3A4, an increase in exposure of ramelteon is expected. An increase in ramelteon AUC by approximately 84% and Cmax by 36% was noted when coadministered with a strong CYP3A4 inhibitor (ketoconazole). Similar increases were noted in M-II pharmacokinetics. Patients should be monitored for increased ramelteon side effects. Also use caution with concurrent use of combinations containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole or amoxicillin; clarithromycin; omeprazole.
Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
Red Yeast Rice: (Contraindicated) Clarithromycin potently inhibits the metabolism of certain HMG Co-A reductase inhibitors ('statins') via the CYP3A4 isoenzyme and increase the risk of myopathy and rhabdomyolysis. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, it should not be used in combination with clarithromycin.
Regorafenib: (Major) Avoid coadministration of regorafenib with clarithromycin due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Regular Insulin: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Regular Insulin; Isophane Insulin (NPH): (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Relugolix: (Major) Avoid coadministration of clarithromycin with relugolix. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Also, concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. Relugolix therapy may be interrupted for up to 14 days if a short course of clarithromycin is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of clarithromycin with relugolix. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Also, concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. Relugolix therapy may be interrupted for up to 14 days if a short course of clarithromycin is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Repaglinide: (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Dosage reduction of repaglinide may be needed. Careful monitoring of glucose is recommended.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with clarithromycin. Concomitant use may increase repotrectinib exposure and the risk for repotrectinib-related adverse effects and decrease clarithromycin exposure and efficacy. Repotrectinib is a CYP3A and P-gp substrate and moderate CYP3A inducer; clarithromycin is a CYP3A substrate and strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A and P-gp inhibitor increased repotrectinib exposure by 5.9-fold. CYP3A inducers decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Clarithromycin and 14-OH-clarithromycin have a different spectrum of microbiologic activity. (Major) Avoid concomitant use of vonoprazan and repotrectinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A inducer.
Resmetirom: (Major) Avoid concomitant use of resmetirom and clarithromycin due to the risk for increased resmetirom exposure which may increase the risk for resmetirom-related adverse effects. Resmetirom is an OATP1B1/3 substrate and clarithromycin is an OATP1B1/3 inhibitor.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as clarithromycin, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with clarithromycin because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increase in potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; clarithromycin is an inhibitor of OATP1B1 and OATP1B3.
Ribociclib: (Major) Avoid coadministration of ribociclib with clarithromycin due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib. Ribociclib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that has an established risk for QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with clarithromycin due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib. Ribociclib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that has an established risk for QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
Rifabutin: (Major) Avoid concomitant use of vonoprazan and rifabutin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) The combination of rifabutin and clarithromycin should be avoided. Clarithromycin is a substrate and inhibitor of CYP3A4, and rifabutin is a substrate and inducer of CYP3A4. The metabolism of rifabutin is inhibited by clarithromycin, possibly through inhibition of CYP3A4. Inhibition of rifabutin metabolism results in significant increases in rifabutin serum concentrations and adverse reactions. Also, rifabutin increases the metabolism of clarithromycin resulting in significant decreases in clarithromycin concentrations thereby reducing the antimicrobial efficacy of clarithromycin. As compared with the plasma concentration obtained with clarithromycin monotherapy, the clarithromycin plasma concentration was reduced by 63% when rifabutin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 2 +/- 1.5 mcg/ml when given in combination with rifabutin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups.
Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Clarithromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. As compared with the plasma concentration obtained with clarithromycin 500 mg twice daily as monotherapy, the clarithromycin plasma concentration was reduced by 87% when rifampin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 0.7 +/- 0.6 mcg/ml when given in combination with rifampin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Rifapentine: (Major) Avoid concomitant use of vonoprazan and rifapentine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Consider alternatives to clarithromycin if treatment with rifapentine is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and clarithromycin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Rimegepant: (Major) Avoid coadministration of rimegepant with clarithromycin; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; clarithromycin is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with clarithromycin. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Risedronate: (Major) Avoid concomitant use of vonoprazan with delayed-release risedronate tablets (Atelvia). Concomitant use of drugs that raise gastric pH, such as vonoprazan, increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Risperidone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with risperidone. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Clarithromycin is associated with an established risk for QT prolongation and TdP. Risperidone has been associated with a possible risk for QT prolongation and/or TdP; however, data are currently lacking to establish causality in association with TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
Ritonavir: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria.
Rivaroxaban: (Moderate) Pharmacokinetic data suggests coadministration of rivaroxaban with clarithromycin is unlikely to affect bleeding risk. However, coadministration of rivaroxaban with other combined P-gp and strong CYP3A4 inhibitors has resulted in increased rivaroxaban exposure and is not recommended. Educate patients about the signs and symptoms of bleeding if concurrent use of clarithromycin with rivaroxaban is necessary; patients with renal impairment may be at greater risk with this combination.
Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and clarithromycin, a strong CYP3A4 inhibitor and a P-gp inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. In addition, romidepsin has been reported to prolong the QT interval. Clarithromycin may also prolong the QT interval. If romidepsin and the clarithromycin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
Rosiglitazone: (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clarithromycin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and clarithromycin is an OATP1B1/3 inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clarithromycin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and clarithromycin is an OATP1B1/3 inhibitor.
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with clarithromycin in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of clarithromycin in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily; alternatively, ruxolitinib therapy may be interrupted for the duration of clarithromycin use. Ruxolitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Salmeterol: (Major) Avoid concomitant use of salmeterol with clarithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Salsalate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites or could displace other highly protein-bound drugs such as penicillins. An enhanced effect of the displaced drug may occur.
Saquinavir: (Contraindicated) Concurrent administration of saquinavir boosted with ritonavir and clarithromycin is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as clarithromycin. In addition to the potential for arrhythmias, because saquinavir and clarithromycin are both CYP3A4 inhibitors and substrates, clinically significant increases in the plasma concentrations of both drugs are seen with concurrent use. Coadministration of clarithromycin (500 mg twice daily) with saquinavir (Fortovase and Invirase; 1200mg three times daily) resulted in a 177% increase in saquinavir AUC, a 45% increase in clarithromycin AUC, and a 24% decrease in the clarithromycin 14-OH metabolite AUC.
Sarecycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Saxagliptin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended.
Secobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. (Minor) Coadministration of segesterone and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and clarithromycin due to the risk of additive QT prolongation and increased selpercatinib exposure resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If clarithromycin is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of clarithromycin. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%. (Major) Avoid concomitant use of selpercatinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of selpercatinib reducing its efficacy.
Selumetinib: (Major) Avoid coadministration of selumetinib and clarithromycin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If clarithromycin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of clarithromycin. Selumetinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Semaglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sertraline: (Major) Concomitant use of sertraline and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
SGLT2 Inhibitors: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sildenafil: (Major) Coadministration of clarithromycin is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving clarithromycin. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Clarithromycin is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
Silodosin: (Contraindicated) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. Clarithromycin inhibits CYP3A4 and may cause significant increases in silodosin plasma concentrations. Concurrent use is contraindicated.
Simvastatin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving clarithromycin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Clarithromycin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and clarithromycin may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Major) Avoid concomitant use of sirolimus and clarithromycin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Sitagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sodium Benzoate; Sodium Phenylacetate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and clarithromycin. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and clarithromycin is an OATP1B3 inhibitor.
Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir: (Major) Avoid concomitant use of velpatasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of velpatasvir reducing its efficacy. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy. (Moderate) Use caution when administering velpatasvir with clarithromycin. Taking these medications together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of P-glycoprotein (P-gp) and CYP3A4. Clarithromycin is a CYP3A4 and P-gp inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of velpatasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of velpatasvir reducing its efficacy. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy. (Major) Avoid concurrent administration of voxilaprevir and clarithromycin due to the potential for increased voxilaprevir exposure. Voxilaprevir is a substrate for the drug transporter Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3); clarithromycin is an OATP1B1/1B3 inhibitor. (Moderate) Use caution when administering velpatasvir with clarithromycin. Taking these medications together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of P-glycoprotein (P-gp) and CYP3A4. Clarithromycin is a CYP3A4 and P-gp inhibitor.
Solifenacin: (Major) Avoid coadministration of clarithromycin with solifenacin if possible due to the risk of QT prolongation; plasma concentrations of solifenacin may also increase. If concomitant use is unavoidable, do not administer more than than solifenacin 5 mg per day in adults; do not exceed the initial starting dose in pediatric patients. Periodically monitor ECGs and electrolytes; an interruption of clarithromycin therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Solifenacin is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold. Both drugs have been associated with dose- or concentration-dependent QT prolongation, and torsade de pointes (TdP) was reported in postmarketing experience with solifenacin although causality was not determined.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and clarithromycin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Clarithromycin is a strong CYP3A4 inhibitor; sonidegib is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Sorafenib: (Major) Avoid coadministration of sorafenib with clarithromycin due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Sotagliflozin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sotalol: (Major) Concomitant use of sotalol and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Major) Avoid concomitant use of vonoprazan and sotorasib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of sotorasib reducing its efficacy. Vonoprazan is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Consider alternatives to clarithromycin if treatment with sotorasib is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Sparsentan: (Major) Avoid concomitant use of sparsentan and clarithromycin. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of vonoprazan and St. John's Wort due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Moderate) St. John's Wort appears to induce CYP3A4 and may lead to increased systemic clearance of clarithromycin, a CYP3A4 substrate. Additionally, clarithromycin may increase serum concentrations of St. John's Wort due to CYP3A4 inhibition. Postmarketing reports of interactions have been noted.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if clarithromycin must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If clarithromycin is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil. (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if vonoprazan must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a weak CYP3A inhibitor like vonoprazan can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If vonoprazan is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfadiazine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfasalazine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfonamides: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfonylureas: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sunitinib: (Major) Avoid coadministration of clarithromycin with sunitinib due to increased sunitinib exposure as well as the risk of QT prolongation and torsade de pointes (TdP). Sunitinib is a CYP3A4 substrate that can cause QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and TdP. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and clarithromycin is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with clarithromycin as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Additional tacrolimus dosage reductions may be required. Despite an initial reduction in tacrolimus dose, a rapid, sharp increase in tacrolimus levels has been reported during coadministration with clarithromycin. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; clarithromycin is a strong CYP3A4 inhibitor. Both tacrolimus and clarithromycin are associated with an established risk of QT prolongation and torsade de pointes (TdP). Use this combination with caution. (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with vonoprazan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; vonoprazan is a weak CYP3A inhibitor.
Tadalafil: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Talazoparib: (Major) Avoid coadministration of clarithromycin with talazoparib when used for the treatment of breast cancer due to increased talazoparib exposure. If concomitant use is unavoidable, reduce the dose of talazoparib to 0.75 mg PO once daily. If clarithromycin is discontinued, wait at least 3 to 5 half-lives of clarithromycin before increasing the dose of talazoparib to the prior dose used before clarithromycin therapy. A talazoparib dose reduction is not necessary for patients with prostate cancer; monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a P-gp substrate and clarithromycin is a P-gp inhibitor. In clinical trials, coadministration with clarithromycin increased talazoparib exposure by 45%.
Tamoxifen: (Major) Concomitant use of tamoxifen and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of clarithromycin. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as clarithromycin, should be avoided.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as clarithromycin, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with clarithromycin as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with telavancin. Both telavancin and clarithromycin are associated with QT prolongation, while clarithromycin is also associated with an established risk for TdP.
Telmisartan; Amlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Temsirolimus: (Major) Avoid coadministration of clarithromycin with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of clarithromycin before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
Tenofovir Alafenamide: (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering clarithromycin. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; clarithromycin is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
Tetrabenazine: (Major) Concurrent use of tetrabenazine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tetrabenazine causes a small increase in the corrected QT interval (QTc), while clarithromycin is associated with an established risk for QT prolongation and TdP.
Tetracycline: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Tetracyclines: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Tezacaftor; Ivacaftor: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with clarithromycin; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); clarithromycin is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Theophylline, Aminophylline: (Major) Clarithromycin can inhibit aminophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for aminophylline products states that aminophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when aminophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered. (Major) Clarithromycin can inhibit theophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for theophylline products states that theophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when theophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline or theophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered.
Thiazolidinediones: (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with clarithromycin which, when combined with a thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and clarithromycin if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; clarithromycin is a strong CYP3A4 inhibitor.
Thyroid hormones: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as clarithromycin. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with clarithromycin substantially increases ticagrelor exposure which may increase the bleeding risk.
Tipranavir: (Major) The coadministration of tipranavir and ritonavir with clarithromycin results in increased tipranavir and clarithromycin concentrations, and a decreased concentration of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance 30-60 ml/min, the dose of clarithromycin should be reduced by 50 percent; for patients with CrCl less than 30 ml/min, the dose of clarithromycin should be reduced by 75 percent.
Tirzepatide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with clarithromycin is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with clarithromycin. Concurrent use may increase tolterodine exposure. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and clarithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
Topotecan: (Major) Avoid coadministration of clarithromycin with oral topotecan due to increased topotecan exposure; clarithromycin may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and clarithromycin is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Avoid coadministration of clarithromycin with toremifene if possible due to the risk of increased toremifene exposure resulting in additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to the risk of increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Major) Avoid coadministration of clarithromycin and verapamil, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving verapamil therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Verapamil is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension.
Trazodone: (Major) Avoid coadministration of trazodone with clarithromycin due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
Triamcinolone: (Moderate) Clarithromycin may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Triazolam: (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Clarithromycin is considered a strong inhibitor of this isoenzyme. Concurrent use is expected to produce large increases in systemic exposure to triazolam, with the potential for serious adverse effects. (Moderate) Monitor for signs of triazolam toxicity during coadministration with vonoprazan. Coadministration may increase the exposure of triazolam. Consider appropriate dose reduction of triazolam when coadministered with weak CYP3A inhibitors, as clinically indicated. Triazolam is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Triclabendazole: (Major) Concomitant use of triclabendazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with trifluoperazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while trifluoperazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Triptorelin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
Typhoid Vaccine: (Major) Antibiotics which possess bacterial activity against salmonella typhi organisms may interfere with the immunological response to the live typhoid vaccine. Allow 24 hours or more to elapse between the administration of the last dose of the antibiotic and the live typhoid vaccine.
Ubrogepant: (Contraindicated) Coadministration of ubrogepant and clarithromycin is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant. (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with vonoprazan. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and clarithromycin is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
Upadacitinib: (Major) During concomitant use of upadacitinib and clarithromycin reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Valbenazine: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as clarithromycin. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Valproic Acid, Divalproex Sodium: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered.
Vamorolone: (Major) Decrease the vamorolone dose to 4 mg/kg once daily (max: 200 mg) and monitor for adverse effects if concomitant use with clarithromycin is necessary. Concomitant use may increase vamorolone exposure and the risk for vamorolone-related adverse effects. Vamorolone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased vamorolone overall exposure by 44%.
Vandetanib: (Major) Avoid coadministration of vandetanib with clarithromycin due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with clarithromycin due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; clarithromycin is a strong CYP3A4 inhibitor. Use of vardenafil with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to16-fold. Use of these drugs together may increase the risk for QT prolongation or vardenafil-related side effects. Clarithromycin has an established risk of QT prolongation and torsade de pointes. Vardenafil may produce an increase in QTc interval at both therapeutic and supratherapeutic doses.
Vemurafenib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as clarithromycin. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of clarithromycin with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of clarithromycin. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; clarithromycin is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Major) Concomitant use of venlafaxine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Major) Avoid coadministration of clarithromycin and verapamil, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving verapamil therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Verapamil is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension.
Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as clarithromycin. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with clarithromycin is necessary. Vinblastine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Postmarketing reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
Vincristine: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Postmarketing reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
Vinorelbine: (Moderate) Consider if an alternative to clarithromycin is appropriate in patients who will undergo vinorelbine therapy. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Increased concentrations of vinorelbine are likely. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vinorelbine is a CYP3A4 and P-gp substrate. Reports of interactions, including serious toxicity, between clarithromycin and vinca alkaloids have been noted. (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with vonoprazan is necessary. Vinorelbine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and clarithromycin is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Additive QT prolongation may also occur. Voclosporin is a sensitive CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor that has been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vorapaxar: (Major) Avoid coadministration of vorapaxar and clarithromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with clarithromycin, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. If these drugs are given together, closely monitor for prolongation of the QT interval and other adverse effects such as drowsiness, fatigue, dry mouth, nausea, or insomnia. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorinostat: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin should be used cautiously with other medications which may prolong the QT interval including vorinostat.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with clarithromycin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Clarithromycin is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Closely monitor the INR if coadministration of warfarin with vonoprazan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Zafirlukast: (Moderate) Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
Zaleplon: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as clarithromycin, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with clarithromycin. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of clarithromycin, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 183% when coadministered with clarithromycin.
Zavegepant: (Major) Avoid concomitant use of zavegepant and clarithromycin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and clarithromycin is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Zidovudine, ZDV: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Ziprasidone: (Major) Concomitant use of ziprasidone and clarithromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with clarithromycin is necessary. Zolpidem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and clarithromycin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
Zuranolone: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with clarithromycin is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Vonoprazan, amoxicillin and clarithromycin are used together to eradicate Helicobacter pylori infection. Amoxicillin has demonstrated in vitro activity against most susceptible strains of H. pylori. Vonoprazan appears to have some in vitro activity against H. pylori but the clinical significance of this finding has not been established. A combination therapy regimen is necessary for successful eradication of H. pylori and to avoid the development of resistance. The relative contribution of systemic versus local antimicrobial activity against H. pylori for the components of vonoprazan; amoxicillin; clarithromycin triple pack therapy has not been established. Acid suppression enhances the replication of H. pylori bacteria and the stability and effectiveness of antimicrobials in the treatment of H. pylori infection.
-Vonoprazan: Vonoprazan is a potassium-competitive acid blocker (PCAB). Vonoprazan suppresses basal and stimulated gastric acid secretion at the secretory surface of the gastric parietal cell through inhibition of the H+, K+-ATPase enzyme system in a potassium competitive manner. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, vonoprazan has been characterized as a type of gastric proton-pump inhibitor, in that it blocks the final step of acid production. Vonoprazan does not require activation by acid. Vonoprazan may selectively concentrate in the parietal cells in both the resting and stimulated states. Vonoprazan binds to the active proton pumps in a noncovalent and reversible manner. Following a single 20 mg dose of vonoprazan, the onset of the antisecretory effect as measured by intragastric pH occurs within 2 to 3 hours. The elevated intragastric pH compared to placebo is maintained for over 24-hours after dosing. At a dose 6 times the maximum recommended dose, vonoprazan does not prolong the QT interval to any clinically relevant extent.
-Amoxicillin: Amoxicillin is a penicillin class antibacterial drug. It is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of active multiplication. It acts through the inhibition of cell wall biosynthesis that leads to the death of the bacteria. Resistance to amoxicillin is mediated primarily through enzymes called beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive. Beta-lactam antibiotics such as amoxicillin are mainly bactericidal. Like other penicillins, amoxicillin inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinsic activity of amoxicillin, as well as the other penicillins, against a particular organism depends on their ability to gain access to and bind with the necessary PBP. The aminopenicillins are able to penetrate gram-negative bacteria more readily than are the natural penicillins or penicillinase-resistant penicillins due to the presence of a free amino group within the structure. Like all beta-lactam antibiotics, the ability of amoxicillin to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.
-Clarithromycin: Clarithromycin binds to the 50 S subunit of the 70 S ribosome, thereby blocking RNA-mediated bacterial protein synthesis. Clarithromycin can be bacteriostatic or bactericidal in action, depending on the concentration as well as the particular organism and its inoculum. In addition, it appears that an alkaline pH facilitates bacterial cell penetration, since clarithromycin exists in an unionized state in this environment. H. pylori resistance can develop during clarithromycin therapy; therefore combination antimicrobial therapy is necessary. H. pylori resistance to clarithromycin in the U.S. ranges from about 7% to 11%. The major mechanisms of microbial resistance to macrolides are modification of the 23S rRNA in the 50S ribosomal subunit to alter binding or by active drug efflux.
The components of the product (vonoprazan tablets, amoxicillin capsules and clarithromycin immediate-release tablets) are administered orally. The pharmacokinetics of the individual drugs when coadministered have not been studied. Studies have shown no clinically significant interactions of vonoprazan and amoxicillin or vonoprazan and clarithromycin when administered together. The systemic pharmacokinetic information below is based on administration of each agent alone.
-Vonoprazan: Plasma-protein binding of vonoprazan ranged from 85% to 88% in healthy subjects and was independent of concentration from 0.1 to 10 mcg/mL. Vonoprazan is metabolized in the liver to inactive metabolites via multiple pathways by a combination of cytochrome P450 (CYP) isoenzymes (CYP3A4/5, CYP2B6, CYP2C19, CYP2C9 and CYP2D6) along with sulfo- and glucuronosyl-transferases. CYP2C19 polymorphisms have been evaluated in clinical studies and there were no considerable differences in the pharmacokinetics of vonoprazan based on CYP2C19 metabolizer status. Following oral administration of radiolabeled vonoprazan, approximately 67% of the radiolabeled dose (8% as unchanged vonoprazan) was recovered in urine and 31% (1.4% as unchanged vonoprazan) was recovered in feces.
-Amoxicillin: Amoxicillin diffuses readily into most body tissues and fluids, except for brain and spinal fluid, where the drug only passes if meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound. Following a 1-gram dose and utilizing a special skin window technique to determine levels of the antibacterial, it was noted that therapeutic levels were found in the interstitial fluid. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine unchanged within 6 to 8 hours. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Since most of the amoxicillin is excreted unchanged in the urine, its excretion can be delayed by concurrent administration of probenecid. In patients with normal renal function, the elimination half-life of amoxicillin is 61.3 minutes.
-Clarithromycin: Protein binding is approximately 42% to 70%. Both clarithromycin and the 14-OH metabolite distribute readily into body tissues and fluids. There are no data on CSF penetration. Due to high intracellular concentrations, tissue concentrations are higher than serum concentrations. Clarithromycin is metabolized to 14-OH clarithromycin. The elimination half-life of clarithromycin was 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 500 mg every 12 hours. At steady-state the half-life of the metabolite 14-OH clarithromycin is about 7 to 9 hours. Roughly 30% of the dose is excreted in the urine as clarithromycin after a 500 mg dose every 12 hours. The renal clearance is relatively independent of the dosage given and approximates the glomerular filtration rate. 14-OH clarithromycin accounts for an additional 10% to 15% of the dose in urine after 500 mg PO every 12 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP3A4/5, CYP2B6, MATE1, OCT1, and P-glycoprotein (P-gp)
-Vonoprazan: In vitro studies have shown that vonoprazan directly and time-dependently inhibits CYP2C19, CYP3A4/5, and CYP2B6. Vonoprazan is a CYP2C19 inhibitor that can produce clinically significant interactions with medications metabolized or activated by this enzyme. Vonoprazan is a weak CYP3A inhibitor and may increase exposure to sensitive CYP3A4 substrates of narrow therapeutic index. Vonoprazan also inhibits multidrug and toxin extrusion protein 1 (MATE1) and organic cation transporter 1 (OCT1), but only at concentrations higher than clinically relevant. Strong or moderate CYP3A inducers may decrease vonoprazan exposure. While not related to enzyme activities, vonoprazan may also exhibit clinically significant drug interactions by reducing intragastric acidity, which may alter the absorption of certain drugs leading to changes in their safety and/or effectiveness.
-Clarithromycin: Clarithromycin is a strong inhibitor of CYP3A4 and P-gp and may have significant interactions with drugs metabolized or affected by this enzyme and/or drug transporter. It is a substrate of CYP3A4. It is also potentially a substrate of P-gp, but data are in vitro only. Clarithromycin does not have any significant inhibitory effects on CYP1A2, CYP2C9, and CYP2D6.
-Route-Specific Pharmacokinetics
Oral Route
-Vonoprazan: Vonoprazan exhibits time independent pharmacokinetics and steady-state concentrations are achieved by Day 3 to 4. After multiple doses of vonoprazan ranging from 10 mg to 40 mg once daily for 7 days in healthy subjects, the Cmax and AUC values for vonoprazan increased in an approximately dose-proportional manner. Steady-state mean plasma exposure of vonoprazan following 20 mg twice daily dosing was approximately 1.8-fold higher compared to Day 1. Administration with a high-fat meal resulted in a 5% increase in Cmax, a 15% increase in AUC, and a delay in median time to maximum concentration (Tmax) of 2 hours. These changes are not considered to be clinically significant.
-Amoxicillin: Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. Doses of 500-mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 5.5 mcg/mL to 7.5 mcg/mL.
-Clarithromycin: Clarithromycin immediate-release tablets are rapidly absorbed from the GI tract. Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were 3 mcg/mL to 4 mcg/mL with a 500 mg dose administered every 8 to 12 hours. The peak steady-state concentration of the metabolite 14-OH clarithromycin is slightly higher (up to 1 mcg/mL). For a single 500 mg dose, food slightly delays absorption and increases the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of absorption. Food does not affect the formation of the active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly increase the extent of metabolite formation; this is indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin may be given without regard to food.
-Special Populations
Hepatic Impairment
-Vonoprazan: Vonoprazan serum concentrations are increased in patients with hepatic impairment. In patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, there was an approximate 1.2-, 2.4- and 2.6-times greater respectively in mean AUC compared to normal subjects. Protein binding of vonoprazan is not affected by impaired hepatic function.
-Amoxicillin: Amoxicillin pharmacokinetics are not altered by hepatic impairment.
-Clarithromycin: The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. However, in trials the decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in subjects with impaired hepatic function when compared to healthy subjects.
Renal Impairment
-Vonoprazan: Vonoprazan systemic exposure (AUC) increased by 1.7 times, 1.3-times, and 2.4-times in patients with mild, moderate, and severe renal impairment when compared to patients with normal renal function. The AUC estimates were 1.3-fold greater when compared to patients with normal renal function for patients requiring dialysis. Protein binding of vonoprazan is not affected by impaired renal function. Vonoprazan was present in the dialysate and represented 0.94% of the dose administered in patients requiring dialysis. The use of vonoprazan should be avoided in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).
-Amoxicillin: Amoxicillin is mostly eliminated unchanged by the kidneys and elimination half-life increases as renal function declines. Studies in adult patients have shown that the elimination half-life of amoxicillin is prolonged to approximately 10 to 13 hours in patients with end-stage renal disease. Dosage adjustments are recommended in patients with severe renal impairment, and thus, the fixed-dose co-packaged vonoprazan; amoxicillin; clarithromycin pack should be avoided in patients with an eGFR less than 30 mL/min/1.73 m2.
-Clarithromycin: The renal clearance of clarithromycin is relatively independent of the dosage given and approximates the normal glomerular filtration rate (GFR). The pharmacokinetics of clarithromycin are altered in subjects with impaired renal function. In the presence of severe renal impairment (CrCl less than 30 mL/minute), with or without coexisting hepatic impairment, the dose or interval of administration should be altered. Avoid use of vonoprazan; amoxicillin; clarithromycin pack in these patients since dosages cannot be readily adjusted.
Gender Differences
There were no clinically significant differences in the pharmacokinetics of vonoprazan based on sex or gender.
Ethnic Differences
There were no clinically significant differences in the pharmacokinetics of vonoprazan based on race or ethnicity.