This monograph discusses the use of the omeprazole; amoxicillin; rifabutin combination product. Clinicians may wish to consult the individual monographs for more information.
Omeprazole; amoxicillin; rifabutin is an oral 3-drug combination of a proton pump inhibitor (PPI), a penicillin antibacterial, and a rifamycin antibacterial indicated for the eradication of H. pylori infection in adults. H. pylori testing is recommended for patients with active peptic ulcer disease (PUD) and those with defined risk factors. Combination eradication therapy is recommended for patients found to be H. pylori positive. Eradication of H. pylori may decrease symptoms and reduce the risk of further disease development, including gastric cancer. Omeprazole and almost all antibacterial agents, including amoxicillin and rifabutin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with proton pump inhibitors (PPIs) and antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Also, treatment with PPIs may lead to a slightly increased risk of gastrointestinal infections due to other pathogens such as Salmonella sp. and Campylobacter sp.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer doses at least 4 hours apart (e.g. morning, mid-day, and evening) with food.
-Swallow capsules whole with a full glass of water (8 ounces). Do not crush or chew capsules.
-Missed dose: If a dose is missed and the next dose is not within 4 hours, administer the missed dose as soon as possible. If a dose is missed and the next dose is within 4 hours, administer the missed dose as soon as possible and delay the next dose to ensure there are at least 4 hours between doses.
This monograph discusses the use of the omeprazole; amoxicillin; rifabutin combination product. Clinicians may wish to consult the individual monographs for more information about each specific agent.
Gastrointestinal adverse events reported during clinical trials with omeprazole; amoxicillin; rifabutin include diarrhea (10.1% to 14.3%), nausea (3.9% to 4.8%), vomiting (1.3% to 2.2%), oropharyngeal pain (0.9% to 3.9%), upper and lower abdominal pain (3.5% to 3.9%), and dyspepsia, including epigastric discomfort, (1.3% to 2.2%). Flatulence, acid regurgitation (gastroesophageal reflux), and constipation have been reported in 1% or more of patients treated with omeprazole alone; flatulence, anorexia, and eructation have been reported in 1% or more of patients treated with rifabutin alone. Pancreatitis (including fatal cases), anorexia, irritable colon, mucosal atrophy of the tongue, stomatitis, abdominal swelling, and xerostomia have been reported postmarketing. Cases of microscopic colitis or fundic gland polyps (gastric polyps) have also been reported with PPIs such as omeprazole. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term PPI treatment and are generally associated with the underlying condition. Black hairy tongue was noted in postmarketing with amoxicillin.
Headache, including migraine, was reported in 7.5% to 15.6% of patients during clinical trials with omeprazole; amoxicillin; rifabutin. Dizziness was reported in 1% or more of patients receiving omeprazole alone. Insomnia was reported in 1% or more of patients receiving rifabutin alone. Other CNS or psychiatric adverse events noted in postmarketing with omeprazole include depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, drowsiness, anxiety, abnormal dreams, tremor, paresthesias, and vertigo. CNS or psychiatric adverse effects noted postmarketing with amoxicillin include hyperactivity, agitation, anxiety, insomnia, confusion, seizures, behavioral changes, and dizziness.
Microbial overgrowth and superinfection can occur with antibiotic use. The use of gastric acid suppressive therapy, such as PPIs, 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 omeprazole; amoxicillin; rifabutin. 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. Vulvovaginal candidiasis, including vulvovaginal mycotic infection, fungal infection, and vaginal discharge with vulvovaginal burning sensation and pruritus, was reported in 2.2% of patients during omeprazole; amoxicillin; rifabutin clinical trials. Also, upper respiratory tract infection has been reported in 1% or more of patients receiving omeprazole alone, and urinary tract infection was noted in postmarketing reports with omeprazole.
Uveitis has been reported rarely with rifabutin therapy. Due to the possible occurrence of uveitis, monitor patients carefully when rifabutin is given concurrently with macrolides or fluconazole and related compounds. If uveitis is suspected, refer the patients for an ophthalmologic evaluation. If necessary, consider suspending therapy. Other ocular adverse events have been noted in postmarketing with omeprazole and include optic atrophy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, and double vision.
Musculoskeletal adverse events reported in 1% or more of patients receiving omeprazole alone include asthenia and back pain; muscle weakness, myalgia, muscle cramps, joint pain, leg pain, and bone fractures have been observed in postmarketing with omeprazole. Asthenia and myalgia have been reported in 1% or more of patients receiving rifabutin alone, and arthralgia and myositis have been reported in less than 1% of patients treated with rifabutin.
Both new onset and an exacerbation of existing autoimmune disease, including cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), have been reported in patients taking proton pump inhibitors (PPIs), including omeprazole. The majority of PPI-induced lupus erythematous cases were CLE. If lupus-like symptoms develop, discontinue omeprazole; amoxicillin; rifabutin and evaluate as appropriate.
Acute tubulo-interstitial nephritis (AIN or TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). TIN has also been observed in patients taking penicillins, such as amoxicillin. Discontinue omeprazole; amoxicillin; rifabutin and evaluate patients with suspected acute TIN. Other renal or genitourinary (GU) adverse events noted during postmarketing with omeprazole include hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, glycosuria, increased urinary frequency, impotence (erectile dysfunction), and testicular pain. Crystalluria was reported in postmarketing with amoxicillin and after overdosage.
Cough has been reported in 1% or more of patients receiving omeprazole alone, and epistaxis has been reported in postmarketing with omeprazole. Dyspnea has been reported in less than 1% of patients receiving rifabutin alone.
General adverse events reported in 1% or more of patients receiving rifabutin alone include chest pain (unspecified), fever, and pain (unspecified).
There have been postmarketing reports of severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), associated with the components of omeprazole; amoxicillin; rifabutin. Additionally, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with rifabutin. If patients develop a skin rash, monitor them closely and discontinue rifabutin if lesions progress. For DRESS, a multi-system potentially life-threatening event, the time to onset of the first symptoms may be prolonged. DRESS is a clinical diagnosis, and its clinical presentation remains the basis for decision-making. An early withdrawal of rifabutin is essential due to the syndrome's mortality and visceral Involvement (e.g. liver, bone marrow, or kidney). Rash, including maculopapular rash, morbilliform rash, and urticaria, was reported in 2.6% to 5.2% of patients during clinical trials with omeprazole; amoxicillin; rifabutin. Skin-related adverse events reported with omeprazole alone in postmarketing include photosensitivity, urticaria, pruritus, petechiae, purpura, alopecia, xerosis, and hyperhidrosis.
Leukopenia and anemia have been reported in 1% or more of patients receiving rifabutin alone; hemolysis, thrombocytopenia, and pancytopenia have been reported in less than 1% of patients receiving rifabutin, and agranulocytosis and lymphopenia have been reported in postmarketing with rifabutin. Hematologic adverse events noted in postmarketing with omeprazole alone include agranulocytosis, anemia, hemolytic anemia, pancytopenia, neutropenia, thrombocytopenia, leukopenia, and leukocytosis. Anemia, hemolytic anemia, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), eosinophilia, leukopenia, and agranulocytosis have been reported in postmarketing with amoxicillin alone.
Taste perversion or dysgeusia has been reported in 1% or more of patients receiving rifabutin alone. Taste perversion and tinnitus have been reported in postmarketing with omeprazole alone.
Hepatitis and jaundice have been reported in less than 1% of patients receiving rifabutin alone. Hepatic adverse events reported in postmarketing with omeprazole alone include fatal hepatic failure or hepatic necrosis, hepatic encephalopathy, hepatocellular disease, cholestatic disease, mixed hepatitis, and jaundice. Hepatic dysfunction, cholestatic jaundice, cholestasis, and acute cytolytic hepatitis have been reported in postmarketing with amoxicillin alone.
Cardiovascular adverse events reported in postmarketing with omeprazole alone include angina, sinus tachycardia, bradycardia, palpitations, elevated blood pressure (hypertension), and peripheral edema.
Endocrine, metabolism, and nutritional adverse events reported in postmarketing with omeprazole alone include gynecomastia, hypoglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia, and weight gain.
Serious and fatal hypersensitivity reactions, including anaphylactoid reactions, angioedema, erythema multiforme, Stevens-Johnson Syndrome, exfoliative dermatitis, hypersensitivity vasculitis, interstitial nephritis, and serum sickness, have been reported with omeprazole, amoxicillin, and/or rifabutin. Signs and symptoms of these reactions may include hypotension, urticaria, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, or flu-like syndrome (i.e., weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, or palpitations). Discontinue omeprazole; amoxicillin; rifabutin and institute immediate therapy if hypersensitivity reactions occur.
Rifabutin can discolor (brown-orange) urine, feces, saliva, sputum, perspiration, tears, and skin. Permanent soft contact lens discoloration may occur. Chromaturia (urine discoloration) was reported in 13% of patients during omeprazole; amoxicillin; rifabutin clinical trials. Skin discoloration has been reported in less than 1% of patients receiving with rifabutin alone, and stool discoloration has been reported in postmarketing with omeprazole alone.
Omeprazole; amoxicillin; rifabutin is contraindicated in patients with a known hypersensitivity to amoxicillin or other beta-lactam antibiotics (i.e., penicillin hypersensitivity, cephalosporin hypersensitivity, and carbapenem hypersensitivity); hypersensitivity to omeprazole or other benzimidazoles (i.e., proton pump inhibitors (PPIs) hypersensitivity and anthelmintics hypersensitivity); or hypersensitivity to rifabutin or other rifamycin hypersensitivity. There has been evidence of PPI cross-sensitivity in some sensitive individuals in literature reports. Although rare, occasionally such reactions can be serious (i.e., result in anaphylaxis, angioedema, or acute interstitial nephritis). Acute tubulo-interstitial nephritis (TIN or AIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). There have been reports of patients who were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue omeprazole; amoxicillin; rifabutin and evaluate patients with suspected acute TIN.
Consider pseudomembranous colitis in patients presenting with diarrhea after omeprazole; amoxicillin; rifabutin 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. PPI therapy may also be associated with an increased risk of C. difficile-associated diarrhea (CDAD), especially in hospitalized patients.
Avoid omeprazole; amoxicillin; rifabutin in patients with mononucleosis. A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash.
Administration of omeprazole may result in laboratory test interference, specifically serum chromogranin A (CgA) tests for neuroendocrine tumors, urine tests for tetrahydrocannabinol (THC), secretin stimulation tests, and diagnostic tests for H. pylori. Gastric acid suppression may increase serum CgA. Increased CgA concentrations may cause false-positive results in diagnostic investigations for neuroendocrine tumors. To prevent this interference, temporarily stop omeprazole at least 14 days before assessing CgA concentrations and consider repeating the test if initial concentrations are high. If serial tests are performed, ensure the same commercial laboratory is used as reference ranges may vary. Reports have suggested use of proton pump inhibitors (PPIs) may cause false-positive urine screening tests for THC. If a PPI-induced false-positive urine screen is suspected, confirm the positive results using an alternative testing method. Omeprazole may cause a hyper-response in gastrin secretion to the secretin stimulation test, falsely suggesting gastrinoma. Health care providers are advised to temporarily stop omeprazole at least 14 days prior to performing a secretin stimulation test to allow gastrin concentrations to return to baseline. A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins, such as amoxicillin, and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, or Diastix). Patients with diabetes mellitus who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on amoxicillin treatment. Preparations that combine PPIs with antimicrobials and bismuth are known to suppress H. pylori; thus, ingestion of these preparations within 4 weeks of performing diagnostic tests for H. pylori may lead to false-negative results. At a minimum, instruct the patient to avoid the use of omeprazole in the 1 to 2 weeks prior to the test and the use of antimicrobials and bismuth preparations in the 4 weeks prior to the test.
Because geriatric adults are more likely to have decreased renal function, it may be useful to monitor renal function in older adults taking omeprazole; amoxicillin; rifabutin. Amoxicillin is known to be substantially excreted by the kidney, and the risk of toxic reactions to amoxicillin may be greater in those with impaired renal function. According to the Beers Criteria, proton pump inhibitors (PPIs) may be potentially inappropriate medications (PIMs) for use in geriatric patients due to the risk of C. difficile infection and bone loss/fractures, but the Beers criteria are not intended to apply to the appropriate use of PPI-containing regimens to address proper treatment of H.pylori infection.
Avoid omeprazole; amoxicillin; rifabutin in patients with renal failure or severe renal impairment (GFR less than 30 mL/minute). Amoxicillin is primarily eliminated by the kidney, and the risk of toxic reactions to amoxicillin may be greater in patients with impaired renal function.
Avoid omeprazole; amoxicillin; rifabutin in patients with hepatic impairment or hepatic disease. In patients with hepatic impairment (Child-Pugh A, B, or C), exposure to omeprazole substantially increased compared to healthy subjects.
Both new onset and an exacerbation of existing autoimmune disease, including cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), have been reported in patients taking proton pump inhibitors (PPIs), including omeprazole. If signs or symptoms consistent with CLE or SLE develop, discontinue omeprazole; amoxicillin; rifabutin and evaluate as appropriate.
Poor metabolizers of CYP2C19 are expected to have higher exposure to omeprazole than normal (extensive) metabolizers. Approximately 3% of White patients and 15% to 20% of Asian patients are CYP2C19 poor metabolizers. Asian patients exhibit a 4-fold increase in AUC of omeprazole compared to White patients.
Use omeprazole; amoxicillin; rifabutin in patients with or who have risk factors for osteoporosis cautiously. Proton pump inhibitors (PPIs) have been associated with a possible increased risk of bone fractures of the hip, wrist, and spine. The risk of fracture was increased in patients who received high-dose (defined as multiple daily doses or doses greater than those recommended in non-prescription use), and long-term PPI therapy (a year or longer); fractures were primarily observed in older adult and geriatric patients 50 years of age and older. Use the shortest duration of PPI therapy appropriate to the condition being treated. In patients with or at risk for osteopenia or osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.
Rifabutin can discolor (brown-orange) urine, feces, saliva, sputum, perspiration, tears, and skin. Advise patients to be treated with omeprazole; amoxicillin; rifabutin of these possibilities and to expect resolution after therapy is completed. Soft contact lenses may be permanently stained.
There have been reports of serious rash or severe cutaneous adverse reactions (SCAR) associated with rifabutin use. If patients develop a skin rash, monitor them closely and discontinue rifabutin if lesions progress.
Omeprazole; amoxicillin; rifabutin use is generally not recommended during pregnancy. If use is necessary, advise pregnant women of the potential risk to the fetus. Based on animal reproduction studies, omeprazole; amoxicillin; rifabutin may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies of omeprazole, amoxicillin, or rifabutin (used separately or together) in pregnant women. Available epidemiologic data do no demonstrate an increased risk of major congenital malformation or other adverse pregnancy outcomes with first trimester omeprazole use. Fetal malformations were not observed in animal reproduction studies with esomeprazole (an enantiomer of omeprazole). Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or more than approximately 11 times the oral human dose of 120 mg of omeprazole or esomeprazole; however, when maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. Available data from published epidemiologic studies and pharmacovigilance case reports over several decades with amoxicillin use have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No adverse developmental effects were observed in animal reproduction studies with amoxicillin administration to pregnant mice and at doses up to 3 to 6 times an oral human dose of 3 g. After administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. Small retrospective studies evaluated the use of rifabutin (in combination with other drugs) for the treatment of tuberculosis during pregnancy; available studies were inconclusive in determining whether rifabutin use during pregnancy was associated with adverse effects in the pregnant woman or neonates. In animals given rifabutin at doses about 6 to 13 times the recommended human daily dose (RHD) based on body surface area (BSA) comparisons, no fetal malformations were observed. However, in rats given rifabutin at about 6 times the RHD based on BSA comparisons, there was a decrease in fetal viability. In rats given rifabutin at a dose approximately equivalent to the RHD based BSA comparisons, rifabutin caused an increase in fetal skeletal variations. In rabbits given rifabutin at approximately 5 times the RHD based on BSA, rifabutin cause maternal toxicity and fetal skeletal anomalies.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for omeprazole; amoxicillin; rifabutin and any potential adverse effects on the breast-fed child from omeprazole; amoxicillin; rifabutin or from the underlying maternal condition. Limited data suggest omeprazole may be present in human milk. There are no clinical data on the effects of omeprazole on the breast-fed infant or on milk production. Potentially serious adverse reactions may occur with the use of omeprazole during breast-feeding, including suppression of gastric acid secretion in the nursing infant. Data from a clinical lactation study reports that amoxicillin is present in human milk. There are no data on the effects of amoxicillin on milk production. Unless the infant is allergic to penicillins, breast-feeding is generally safe during maternal penicillin therapy. Penicillins may cause diarrhea (due to disruption of GI flora), candidiasis, and skin rash in breast-feeding infants. Small studies assessing adverse events in breast-fed infants exposed to antibiotics have found adverse event rates of 7.5% to 8.3% after exposure to amoxicillin. The adverse events reported included diarrhea, rash, and somnolence. There are no data on the presence of rifabutin in human milk or the effects of rifabutin on the breast-fed infant or on milk production. Previous American Academy of Pediatrics (AAP) recommendations considered amoxicillin and another rifamycin, rifampin, as usually compatible with breast-feeding.
Omeprazole; amoxicillin; rifabutin may be associated with reproductive risk. Based on animal studies, omeprazole; amoxicillin; rifabutin may cause infertility in males of reproductive potential.
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: 40 mg omeprazole; 1,000 mg amoxicillin; 50 mg rifabutin PO 3 times daily for 14 days. Rifabutin-based triple therapy is recommended as a salvage regimen.
Maximum Dosage Limits:
-Adults
12 capsules/day (120 mg/day omeprazole; 3,000 mg/day amoxicillin; 150 mg/day rifabutin) PO.
-Geriatric
12 capsules/day (120 mg/day omeprazole; 3,000 mg/day amoxicillin; 150 mg/day rifabutin) 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
Avoid omeprazole; amoxicillin; rifabutin use in patients with hepatic impairment.
Patients with Renal Impairment Dosing
GFR 30 mL/minute or more: No dosage adjustment is needed.
GFR less than 30 mL/minute: Avoid omeprazole; amoxicillin; rifabutin use.
*non-FDA-approved indication
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Rifabutin may accelerate the metabolism of zidovudine. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifamycins, including rifampin, rifabutin and rifapentine.
Abemaciclib: (Major) Avoid coadministration of rifabutin with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Abemaciclib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with other moderate CYP3A inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 29% to 53%.
Abiraterone: (Moderate) Concomitant use of abiraterone with rifabutin may result in decreased serum concentrations of abiraterone. Abiraterone is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of this enzyme. Caution and close monitoring for decreased efficacy are advised if these drugs are used together.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib capsules and omeprazole; decreased acalabrutinib exposure occurred in a drug interaction study. Consider using the acalabrutinib tablet formlation or use an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib capsules and antacids by at least 2 hours; give acalabrutinib capsules 2 hours before a H2-blocker. Acalabrutinib capsuel solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib capsules were coadministered with omeprazole 40 mg/day for 5 days.
Acetaminophen: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (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: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (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: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (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: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with rifamycins is necessary; consider increasing the dose of dihydrocodeine as needed. If the rifamycin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Rifamycins are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with rifamycins can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Codeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer.
Acetaminophen; Dextromethorphan: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Diphenhydramine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Hydrocodone: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with rifabutin is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If rifabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Acetaminophen; Ibuprofen: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Oxycodone: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of oxycodone as needed. If rifabutin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Pseudoephedrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Adagrasib: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with adagrasib is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with CYP3A inhibitors may significantly increase the plasma concentration of rifabutin. (Moderate) Monitor for omeprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Albuterol; Budesonide: (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Alendronate: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Alendronate; Cholecalciferol: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with rifamycins is necessary. If the rifamycin is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of CYP3A4 inducers like rifamycins with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Allopurinol: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Alprazolam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the CYP450 system, such as alprazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin could induce the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as alprazolam.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and aminosalicylate sodium, aminosalicylic acid. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Amlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Amlodipine; Atorvastatin: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Amlodipine; Benazepril: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Amlodipine; Celecoxib: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Amlodipine; Olmesartan: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Amlodipine; Valsartan: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia. (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Amobarbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Amoxicillin; Clarithromycin; Omeprazole: (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.
Amphetamine: (Moderate) Use amphetamine; dextroamphetamine and proton pump inhibitors concomitantly with caution. Gastrointestinal alkalinizing agents may increase exposure to amphetamine; dextroamphetamine and exacerbate its actions.
Amphetamine; Dextroamphetamine Salts: (Moderate) Use amphetamine; dextroamphetamine and proton pump inhibitors concomitantly with caution. Gastrointestinal alkalinizing agents may increase exposure to amphetamine; dextroamphetamine and exacerbate its actions.
Amphetamine; Dextroamphetamine: (Moderate) Use amphetamine; dextroamphetamine and proton pump inhibitors concomitantly with caution. Gastrointestinal alkalinizing agents may increase exposure to amphetamine; dextroamphetamine and exacerbate its actions.
Ampicillin: (Major) Proton pump inhibitors (PPIs) have long-lasting effects on the secretion of gastric acid. For enteral ampicillin, whose bioavailability is influenced by gastric pH, the concomitant administration of PPIs can exert a significant effect on ampicillin absorption.
Ampicillin; Sulbactam: (Major) Proton pump inhibitors (PPIs) have long-lasting effects on the secretion of gastric acid. For enteral ampicillin, whose bioavailability is influenced by gastric pH, the concomitant administration of PPIs can exert a significant effect on ampicillin absorption.
Apalutamide: (Major) Avoid concomitant use of apalutamide with omeprazole as omeprazole plasma concentrations may be decreased, reducing its efficacy. Omeprazole is a CYP3A and CYP2C19 substrate. Apalutamide is a strong inducer of both CYP3A and CYP2C19. Coadministration with apalutamide has been observed to decrease the overall exposure of omeprazole by 85%. (Moderate) Monitor for decreased efficacy of rifabutin and potential issues of resistance if coadministration with apalutamide is necessary. Rifabutin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
Aprepitant, Fosaprepitant: (Major) Use caution if rifabutin and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant as well as an increase in rifabutin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Rifabutin is 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 and may increase plasma concentrations of rifabutin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Additionally, Rifabutin is a moderate CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers. (Minor) Use caution if omeprazole and aprepitant are used concurrently and monitor for an increase in omeprazole-related adverse effects for several days after administration of a multi-day aprepitant regimen. Omeprazole is 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 and may increase plasma concentrations of omeprazole. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, caution is advisable during coadministration of a CYP3A4 inducer, such as rifabutin. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. A dose adjustment of aripiprazole may be needed. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.
Armodafinil: (Moderate) Armodafinil is partially metabolized via CYP3A4/5 isoenzymes. Drugs that exhibit significant induction of the CYP3A4 isoenzyme, such as rifabutin, may potentially increase the metabolism of armodafinil. Decreased serum levels of armodafinil could potentially result in decreased efficacy of the drug. (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as omeprazole during coadministration with armodafinil. A 40% increase in exposure of omeprazole was observed during coadministration with armodafinil. The clinical significance of this interaction is unknown.
Artemether; Lumefantrine: (Major) Rifabutin is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
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 coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (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: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (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 rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as omeprazole, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects. (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) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of oxycodone as needed. If rifabutin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (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: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with atazanavir is necessary. Avoid concurrent use of rifabutin and atazanavir boosted with cobicistat. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with atazanavir boosted with ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with atazanavir/ritonavir increased the AUC of rifabutin by approximately 110%.
Atazanavir; Cobicistat: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with atazanavir is necessary. Avoid concurrent use of rifabutin and atazanavir boosted with cobicistat. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with atazanavir boosted with ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with atazanavir/ritonavir increased the AUC of rifabutin by approximately 110%. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Atenolol; Chlorthalidone: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Atogepant: (Major) Avoid use of atogepant and rifabutin when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with rifabutin. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Atovaquone: (Major) The administration of rifabutin with atovaquone is not recommended. Taking these drugs together reduces the average steady-state plasma concentrations of atovaquone and rifabutin by 34% and 19%, respectively. Dose adjustments have not been established. If these drugs are given together, instruct patient to take atovaquone with a fatty meal and monitor for decreased atovaquone efficacy.
Atovaquone; Proguanil: (Major) The administration of rifabutin with atovaquone is not recommended. Taking these drugs together reduces the average steady-state plasma concentrations of atovaquone and rifabutin by 34% and 19%, respectively. Dose adjustments have not been established. If these drugs are given together, instruct patient to take atovaquone with a fatty meal and monitor for decreased atovaquone efficacy.
Avacopan: (Major) Avoid concomitant use of avacopan and rifabutin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Avanafil: (Minor) Avanafil is a weak inhibitor of CYP2C19 isoenzymes. A single avanafil (200 mg) dose increased the AUC and Cmax of a single omeprazole (40 mg) dose, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively. (Minor) Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as rifabutin, may decrease avanafil plasma levels. Concomitant use is not recommended.
Avapritinib: (Major) Avoid coadministration of avapritinib with rifabutin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Axitinib: (Major) Avoid coadministration of axitinib with rifabutin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and rifabutin is a CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Azilsartan; Chlorthalidone: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Urinary concentrations of rifabutin could interfere with the therapeutic effectiveness of BCG. Postpone instillation of BCG if the patient is receiving antibiotics.
Barbiturates: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Bedaquiline: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
Belumosudil: (Major) Increase the dosage of belumosudil to 200 mg PO twice daily when coadministered with a proton pump inhibitor (PPI). Concomitant use may result in decreased belumosudil exposure and reduced belumosudil efficacy. Coadministration with other PPIs has decreased belumosudil exposure by 47% to 80% in healthy subjects.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of omeprazole 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 omeprazole is a CYP2C19 inhibitor.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Benzhydrocodone; Acetaminophen: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Concurrent use of benzhydrocodone with rifabutin may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of rifabutin may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If rifabutin is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Rifabutin is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Major) Concomitant use of bictegravir and rifabutin is not recommended as coadministration may result in decreased bictegravir plasma concentrations, which may result in the loss of therapeutic efficacy and development of resistance. Bictegravir is a substrate of CYP3A4; rifabutin is an inducer of CYP3A4.
Bisacodyl: (Minor) The concomitant use of bisacodyl oral tablets with drugs that raise gastric pH like proton pump inhibitors can cause the enteric coating of the bisacodyl tablets to dissolve prematurely, leading to possible gastric irritation or dyspepsia. When taking bisacodyl tablets, it is advisable to avoid PPIs within 1 hour before or after the bisacodyl dosage.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Coadministration of bismuth subcitrate potassium and omeprazole resulted in a significant increase in the systemic absorption of bismuth. However, when administered in the FDA-approved dosage regimen, bismuth subcitrate potassium; metronidazole; tetracycline capsules (Pylera) is administered with omeprazole for 10 days. The manufacturer does not feel that short-term exposure to bismuth concentrations > 50 mcg/L will increase the risk of neurotoxicity; health care practitioners should be aware of this potential adverse effect. (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: (Minor) Coadministration of bismuth subcitrate potassium and omeprazole resulted in a significant increase in the systemic absorption of bismuth. However, when administered in the FDA-approved dosage regimen, bismuth subcitrate potassium; metronidazole; tetracycline capsules (Pylera) is administered with omeprazole for 10 days. The manufacturer does not feel that short-term exposure to bismuth concentrations > 50 mcg/L will increase the risk of neurotoxicity; health care practitioners should be aware of this potential adverse effect.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Coadministration of bismuth subcitrate potassium and omeprazole resulted in a significant increase in the systemic absorption of bismuth. However, when administered in the FDA-approved dosage regimen, bismuth subcitrate potassium; metronidazole; tetracycline capsules (Pylera) is administered with omeprazole for 10 days. The manufacturer does not feel that short-term exposure to bismuth concentrations > 50 mcg/L will increase the risk of neurotoxicity; health care practitioners should be aware of this potential adverse effect. (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.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Bortezomib: (Minor) Agents that induce CYP3A4, such as rifabutin, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with CYP3A4 inducers is not known.
Bosutinib: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as omeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Brigatinib: (Major) Avoid coadministration of brigatinib with rifabutin due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with rifabutin, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of rifabutin, resume the brigatinib dose that was tolerated prior to initiation of rifabutin. Brigatinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and rifabutin are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; rifabutin is a moderate inducer of CYP3A4.
Budesonide: (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Formoterol: (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Glycopyrrolate; Formoterol: (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Bumetanide: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and loop diuretic use due to risk for hypomagnesemia.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Butalbital; Acetaminophen: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate 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.
Cabotegravir: (Major) Coadministration of rifabutin and cabotegravir; rilpivirine injection is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir and rilpivirine, which may result in potential loss of virologic response and development of resistance. Rifabutin may be coadministered with cabotegravir extended-release injection; however, dosage adjustments are needed. When rifabutin is started before or concomitantly with the first initiation injection of cabotegravir injection, the recommended dosing of cabotegravir injection is one 600-mg injection, followed 2 weeks later by a second 600-mg initiation injection and monthly thereafter while on rifabutin. When rifabutin is started at the time of the second initiation injection or later, the recommended dosing schedule of cabotegravir injection is 600 mg monthly while on rifabutin. After stopping rifabutin, the recommended dosing schedule of cabotegravir injection is 600 mg every 2 months. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifabutin is an inducer of UGT. Coadministration with rifabutin decreased cabotegravir exposure by 33%. Rifabutin may be coadministered with oral cabotegravir monotherapy.
Cabotegravir; Rilpivirine: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Coadministration of rifabutin and cabotegravir; rilpivirine injection is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir and rilpivirine, which may result in potential loss of virologic response and development of resistance. Rifabutin may be coadministered with cabotegravir extended-release injection; however, dosage adjustments are needed. When rifabutin is started before or concomitantly with the first initiation injection of cabotegravir injection, the recommended dosing of cabotegravir injection is one 600-mg injection, followed 2 weeks later by a second 600-mg initiation injection and monthly thereafter while on rifabutin. When rifabutin is started at the time of the second initiation injection or later, the recommended dosing schedule of cabotegravir injection is 600 mg monthly while on rifabutin. After stopping rifabutin, the recommended dosing schedule of cabotegravir injection is 600 mg every 2 months. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifabutin is an inducer of UGT. Coadministration with rifabutin decreased cabotegravir exposure by 33%. Rifabutin may be coadministered with oral cabotegravir monotherapy. (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Cabozantinib: (Major) Avoid coadministration of cabozantinib with rifabutin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with rifabutin 2 to 3 days after discontinuation of rifabutin. Cabozantinib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer.
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.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Cannabidiol: (Moderate) Consider a dose reduction of omeprazole when coadministered with cannabidiol due to the risk of omeprazole-associated adverse reactions. In vivo data shows cannabidiol is a CYP219 inhibitor; omeprazole is a sensitive 2C19 substrate.
Capivasertib: (Major) Avoid coadministration of capivasertib with rifabutin due to decreased capivasertib exposure and risk of decreased efficacy. Capivasertib is a CYP3A substrate; rifabutin is a moderate CYP3A inducer. Coadministration of another moderate CYP3A inducer is predicted to decrease the capivasertib overall exposure by 60%.
Capmatinib: (Major) Avoid coadministration of capmatinib and rifabutin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
Capreomycin: (Moderate) Adverse hepatic effects have been associated with capreomycin, especially with concurrent use of other antituberculosis drugs known to alter hepatic function. Theoretically, coadministration of capreomycin and any of the rifamycins could increase the risk of hepatotoxicity. Monitor patients for changes in liver function if these drugs are coadministered.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Carbamazepine: (Major) Avoid concomitant use of omeprazole and carbamazepine as omeprazole exposure may be decreased, reducing its efficacy. Omeprazole is a CYP3A substrate and carbamazepine is a strong CYP3A inducer. (Moderate) Inducers of the hepatic CYP3A4 isoenzyme, such as rifabutin, can increase the rate of carbamazepine metabolism, leading to subtherapeutic carbamazepine plasma concentrations.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as rifabutin or rifampin, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as omeprazole, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Carvedilol: (Moderate) Serum concentrations of carvedilol may be decreased if coadministered with rifabutin. Rifabutin is a known hepatic enzyme inducer, thus, it is not possible to stagger the administration times to avoid this interaction.
Caspofungin: (Moderate) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving rifabutin. Coadministration of CYP450 enzyme inducers, such as rifabutin, with caspofungin may reduce the plasma concentrations of caspofungin.
Cefpodoxime: (Moderate) Cefpodoxime proxetil requires a low gastric pH for dissolution; therefore, concurrent administration with medications that increase gastric pH, such as proton pump inhibitors (PPIs) may decrease the bioavailability of cefpodoxime. When cefpodoxime was administered with high doses of antacids and H2-blockers, peak plasma concentrations were reduced by 24% and 42% and the extent of absorption was reduced by 27% and 32%, respectively. The rate of absorption is not affected.
Cefuroxime: (Major) Avoid the concomitant use of proton pump inhibitors (PPIs) and cefuroxime. Drugs that reduce gastric acidity, such as PPIs, can interfere with the oral absorption of cefuroxime axetil and may result in reduced antibiotic efficacy.
Ceritinib: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with ceritinib is necessary; a dosage adjustment may be necessary. Ceritinib is a strong CYP3A4 inhibitor and rifabutin is primarily metabolized by CYP3A4. Concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin.
Chlordiazepoxide: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, including chlordiazepoxide, leading to lower benzodiazepine concentrations.
Chlordiazepoxide; Amitriptyline: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, including chlordiazepoxide, leading to lower benzodiazepine concentrations.
Chlordiazepoxide; Clidinium: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, including chlordiazepoxide, leading to lower benzodiazepine concentrations.
Chlorothiazide: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with rifabutin is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If rifabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Chlorpromazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Chlorthalidone: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
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) When significant CYP2C19 inhibitors, such as omeprazole, are administered concomitantly with cilostazol, the cilostazol dosage should be reduced by 50%. Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19. When given concurrently with omeprazole, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%.
Ciprofloxacin: (Minor) Concomitant use of ciprofloxacin and omeprazole may decrease the AUC and Cmax of ciprofloxacin, but the clinical significance of this interaction is unknown. Codministration of a single tablet dose of 500 mg ciprofloxacin and once-daily administration of 20 mg omeprazole pretreatment for 4 days resulted in a 16% reduction of mean Cmax and mean AUC of ciprofloxacin. A single 1000 mg oral dose of Cipro XR administered with omeprazole (40 mg once daily for 3 days) to 18 healthy volunteers resulted in a decrease in the ciprofloxacin mean AUC by 20% and Cmax by 23%. However, coadministration of a single 1000 mg oral dose of Proquin XR given 2 hours after the third dose of omeprazole (40 mg once daily for 3 days) to 27 healthy volunteers resulted in no changes in the ciprofloxacin AUC and Cmax. If ciprofloxacin is administered with omeprazole with magnesium, chelation of the ciprofloxacin would be expected; in general, it is recommended that ciprofloxacin be administered 2 hours before or 6 hours after any divalent cations like magnesium to help limit an interaction.
Cisapride: (Moderate) Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. Inducers of CYP3A4, such as rifabutin, may increase the clearance of cisapride.
Citalopram: (Moderate) Citalopram is metabolized by CYP2C19 and CYP3A4. Rifabutin can induce the metabolism of various CYP 450 isoenzymes, including those involved in citalopram metabolism. The possibility of an increase in the clearance of citalopram should be considered if coadministered with rifabutin. (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with omeprazole. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation. Citalopram is a sensitive CYP2C19 substrate; omeprazole is a weak inhibitor of CYP2C19.
Clarithromycin: (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.
Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and omeprazole is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Clomipramine: (Minor) Coadministration may result in increased clomipramine exposure. Omeprazole is a CYP2C19 inhibitor and clomipramine is a CYP2C19 substrate.
Clonazepam: (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, such as clonazepam, leading to lower benzodiazepine concentrations.
Clopidogrel: (Major) Avoid concomitant use of clopidogrel and omeprazole as it significantly reduces the antiplatelet activity of clopidogrel. If necessary, consider using an alternative proton pump inhibitor, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Omeprazole is an inhibitor of CYP2C19. In clinical studies, use of omeprazole significantly reduced the antiplatelet activity of clopidogrel when administered concomitantly or 12 hours apart.
Clorazepate: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as clorazepate. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin is a hepatic inducers and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, such as clorazepate, leading to lower benzodiazepine concentrations.
Clozapine: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with rifabutin. Consideration should be given to increasing the clozapine dose if necessary. When rifabutin is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Cobicistat: (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with rifabutin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and rifabutin is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Codeine: (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer.
Codeine; Phenylephrine; Promethazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin. (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer.
Codeine; Promethazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin. (Moderate) Concomitant use of codeine with rifabutin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifabutin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rifabutin is a moderate CYP3A4 inducer.
Conjugated Estrogens: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Bazedoxifene: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Medroxyprogesterone: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers.
Cysteamine: (Major) Monitor white blood cell (WBC) cystine concentration closely when administering delayed-release cysteamine (Procysbi) with proton pump inhibitors (PPIs). Drugs that increase the gastric pH may cause the premature release of cysteamine from delayed-release capsules, leading to an increase in WBC cystine concentration. Concomitant administration of omeprazole 20 mg did not alter the pharmacokinetics of delayed-release cysteamine when administered with orange juice; however, the effect of omeprazole on the pharmacokinetics of delayed-release cysteamine when administered with water have not been studied.
Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as rifabutin. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
Dacomitinib: (Major) Avoid coadministration of omeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with rifabutin is necessary. Dapsone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). In a study of 16 HIV-infected patients, rifabutin decreased dapsone exposure by 27% to 40%.
Daridorexant: (Major) Avoid concomitant use of daridorexant and rifabutin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Darunavir: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with darunavir is necessary. Avoid concurrent use of rifabutin and darunavir boosted with cobicistat. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with darunavir boosted with ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with darunavir increased the AUC of the active metabolite of rifabutin by 881%. (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day.
Darunavir; Cobicistat: (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with darunavir is necessary. Avoid concurrent use of rifabutin and darunavir boosted with cobicistat. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with darunavir boosted with ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with darunavir increased the AUC of the active metabolite of rifabutin by 881%. (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with darunavir is necessary. Avoid concurrent use of rifabutin and darunavir boosted with cobicistat. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with darunavir boosted with ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with darunavir increased the AUC of the active metabolite of rifabutin by 881%. (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Dasatinib: (Major) Do not administer proton pump inhibitors with dasatinib due to the potential for decreased dasatinib exposure and reduced efficacy. Consider using an antacid if acid suppression therapy is needed. Administer the antacid at least 2 hours prior to or 2 hours after the dose of dasatinib. Concurrent use of an proton pump inhibitor reduced the mean Cmax and AUC of dasatinib by 42% and 43%, respectively.
Deflazacort: (Major) Avoid concomitant use of deflazacort and rifabutin. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; rifabutin is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
Delavirdine: (Contraindicated) The coadministration of rifabutin and delavirdine is contraindicated. Concurrent administration results in a 230% increase in rifabutin AUC. However, rifabutin significantly decreases delavirdine plasma concentrations. Clinical pharmacokinetic studies have shown an 82% reduction in delavirdine AUC when rifabutin was given concurrently. (Major) Because proton pump inhibitors (PPIs) increase gastric pH, decreased delavirdine absorption may occur. However, since these agents affect gastric pH for an extended period, separation of doses may not eliminate the interaction. Chronic use of PPIs with delavirdine is not recommended.
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.
Desogestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Dextroamphetamine: (Moderate) Use amphetamine; dextroamphetamine and proton pump inhibitors concomitantly with caution. Gastrointestinal alkalinizing agents may increase exposure to amphetamine; dextroamphetamine and exacerbate its actions.
Dextromethorphan; Quinidine: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of quinidine.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with omeprazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor. (Moderate) Rifabutin induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as diazepam, may require dosage adjustments when administered concurrently with rifabutin.
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: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Digoxin: (Moderate) Omeprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Omeprazole increases the AUC of digoxin by about 10%. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Because, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement. (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.
Diltiazem: (Moderate) Diltiazem is a CYP3A4 substrate and inhibitor. Rifabutin is a CYP3A4 substrate and inducer. Coadministration of these drugs could lead to a complex interaction. Significant decreases in diltiazem concentrations could be seen, and significant increases in rifabutin concentrations could be seen. When possible, avoid coadministration of these drugs and consider alternative therapy. When an alternative therapy is not possible, patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure, as well as associated rifabutin side effects.
Disopyramide: (Moderate) Hepatic microsomal enzyme-inducing agents, such as rifabutin, have the potential to accelerate the hepatic metabolism of disopyramide, a CYP3A4 substrate. Patients should be monitored for loss of disopyramide activity if rifabutin is added.
Disulfiram: (Moderate) Monitor patients to determine if it is necessary to adjust the dose of disulfiram when taken concomitantly with omeprazole. In a single patient, the combined use of disulfiram and omeprazole caused disorientation, confusion, and nightmares. These reactions occurred on 2 separate challenges when omeprazole was added to disulfiram therapy.
Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Doravirine: (Major) Increase the doravirine dose to 100 mg PO twice daily (approximately 12 hours apart) if coadministered with rifabutin. Concurrent use decreases doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) Increase the doravirine dose to 100 mg PO twice daily (approximately 12 hours apart) if coadministered with rifabutin. Concurrent use decreases doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers, such as rifabutin, may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol. (Moderate) Cytochrome P450 enzyme inhibitors, such as omeprazole, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
Doxorubicin Liposomal: (Major) Rifabutin is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifabutin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxorubicin: (Major) Rifabutin is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifabutin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
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: (Moderate) Use caution if coadministration of dronabinol with rifabutin is necessary, and monitor for a decrease in the efficacy of dronabinol. Concomitant use may result in decreased plasma concentrations of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; rifabutin is a moderate inducer of CYP3A4.
Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Omeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
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.
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.
Drospirenone; Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Drospirenone; Ethinyl Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Duvelisib: (Major) Avoid concomitant use of duvelisib with rifabutin. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib; rifabutin exposure may also be increased. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily. Monitor for rifabutin-related adverse reactions. When rifabutin has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with rifabutin. Duvelisib is a CYP3A substrate and a moderate CYP3A4 inhibitor. Rifabutin is a CYP3A4 substrate and a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
Efavirenz: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer. (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer. (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer. (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
Elacestrant: (Major) Avoid concurrent use of elacestrant and rifabutin due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced elacestrant overall exposure by 55% to 73%.
Elagolix: (Moderate) Coadministration of elagolix with omeprazole may increase plasma concentrations of omeprazole. Consider dosage reduction of omeprazole when elagolix is used concomitantly with higher doses of omeprazole, e.g., in patients with Zollinger-Ellison syndrome; however, no dose adjustments are needed for omeprazole at doses of 40 mg once daily or lower. Elagolix is a weak CYP2C19 inhibitor and omeprazole is a CYP2C19 sensitive substrate.
Elagolix; Estradiol; Norethindrone acetate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (Moderate) Coadministration of elagolix with omeprazole may increase plasma concentrations of omeprazole. Consider dosage reduction of omeprazole when elagolix is used concomitantly with higher doses of omeprazole, e.g., in patients with Zollinger-Ellison syndrome; however, no dose adjustments are needed for omeprazole at doses of 40 mg once daily or lower. Elagolix is a weak CYP2C19 inhibitor and omeprazole is a CYP2C19 sensitive substrate. (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.
Elbasvir; Grazoprevir: (Major) If possible, avoid concurrent administration of elbasvir with rifabutin; consider use of an alternative hepatitis C treatment regimen. Rifabutin is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with rifabutin; consider use of an alternative hepatitis C treatment regimen. Rifabutin is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of rifabutin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Elexacaftor; tezacaftor; ivacaftor: (Major) Do not administer tezacaftor; ivacaftor and rifabutin together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of rifabutin, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inducers of CYP1A2, such as omeprazole, on the systemic exposure of eltrombopag has not been established. Monitor patients for a decrease in the efficacy of eltrombopag if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Major) Coadministration of rifabutin with elvitegravir may result in reduced elvitegravir concentrations and elevated rifabutin concentrations. If these drugs must be used concurrently, reduce the dose of rifabutin by at least 75% of the usual 300 mg/day dose (e.g., 150 mg every other day or 3x/week). If the rifabutin dose is reduced, no dose adjustment is required for elvitegravir. Monitor closely for rifabutin-associated adverse events. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Major) Coadministration of rifabutin with elvitegravir may result in reduced elvitegravir concentrations and elevated rifabutin concentrations. If these drugs must be used concurrently, reduce the dose of rifabutin by at least 75% of the usual 300 mg/day dose (e.g., 150 mg every other day or 3x/week). If the rifabutin dose is reduced, no dose adjustment is required for elvitegravir. Monitor closely for rifabutin-associated adverse events. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Empagliflozin; Linagliptin: (Moderate) Concomitant use of linagliptin with rifabutin may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
Empagliflozin; Linagliptin; Metformin: (Moderate) Concomitant use of linagliptin with rifabutin may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Emtricitabine; Tenofovir alafenamide: (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Encorafenib: (Major) Avoid concomitant use of omeprazole and encorafenib as omeprazole exposure may be decreased, reducing its efficacy. Omeprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Entrectinib: (Major) Avoid coadministration of entrectinib with rifabutin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Enzalutamide: (Major) Avoid concomitant use of enzalutamide, a strong CYP3A4 inducer and a moderate CYP2C19 inducer, and omeprazole, a CYP3A4 and CYP2C19 substrate, as omeprazole plasma exposure may be reduced. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC and Cmax of omeprazole was decreased following a single oral dose of omeprazole 20 mg administered after at least 55 days of oral enzalutamide 160 mg/day.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Erdafitinib: (Major) If coadministration of erdafitinib and rifabutin is necessary at the initiation of erdafitinib therapy, increase the dose of erdafitinib to 9 mg once daily. Erdafitinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced erdafitinib overall exposure by 45%.
Erlotinib: (Major) Avoid coadministration of erlotinib with omeprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with omeprazole decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%. (Major) Avoid the coadministration of erlotinib with rifabutin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib.
Erythromycin: (Moderate) Caution is warranted when erythromycin is administered with rifabutin as rifabutin concentrations may be elevated. Monitor for adverse events of rifabutin, such as neutropenia and rash. Erythromycin is an inhibitor of CYP3A4, and rifabutin is a substrate of CYP3A4.
Escitalopram: (Moderate) CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. Rifabutin can induce the metabolism of escitalopram via induction of CYP3A4. Given the enzyme-inducing properties rifabutin, the possibility that the drug may increase the clearance of escitalopram should be considered if the 2 drugs are coadministered. (Moderate) Monitor for an increase in escitalopram-related adverse effects, such as QT prolongation and serotonin syndrome, if concomitant use with omeprazole is necessary. An empiric escitalopram dosage reduction may be considered in patients with additional risk factors for adverse effects, such as age older than 60 years. Concomitant use has been observed to increase escitalopram concentrations by 51% to 94%, which may increase the risk for adverse effects.
Eslicarbazepine: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of omeprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
Estazolam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as estazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
Esterified Estrogens: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Esterified Estrogens; Methyltestosterone: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Estradiol; Levonorgestrel: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Estradiol; Norethindrone: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Estradiol; Norgestimate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Estradiol; Progesterone: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Estropipate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Ethacrynic Acid: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and loop diuretic use due to risk for hypomagnesemia. (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.
Ethambutol: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Ethinyl Estradiol; Norelgestromin: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Ethinyl Estradiol; Norgestrel: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Ethionamide: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Ethotoin: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Etonogestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Etravirine: (Moderate) If a patient's antiretroviral treatment regimen contains etravirine and a protease inhibitor boosted with ritonavir (i.e., either darunavir or saquinavir with ritonavir), then rifabutin should not be coadministered due to the potential for significant reductions in etravirine exposure. However, if the antiretroviral regimen does not contain a protease inhibitor boosted with ritonavir, then rifabutin may be used (at a dose of 300 mg daily).
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with rifabutin is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
Ezetimibe; Simvastatin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Fedratinib: (Major) Avoid coadministration of fedratinib with rifabutin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%. (Moderate) Monitor for increased omeprazole adverse effects as coadministration of omeprazole and fedratinib increased omeprazole exposure by 3-fold in a drug interaction study. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher omeprazole doses may require an adjustment in omeprazole dose. Omeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4; fedratinib is an inhibitor of CYP2C19 and CYP3A4.
Felodipine: (Moderate) Concomitant use of felodipine and rifabutin may decrease the exposure and therapeutic efficacy of felodipine. If used together, monitor blood pressure closely; the dosage requirements of felodipine may be increased. Felodipine is a CYP3A substrate. Rifabutin is a CYP3A inducer.
Fenofibrate: (Minor) At therapeutic concentrations, fenofibrate is a weak inhibitor of CYP2C19. Concomitant use of febofirbrate with CYP2C19 substrates, such as omeprazole, has not been formally studied. Fenofibrate may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of omeprazole during coadministration with fenofibrate.
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as omeprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of omeprazole during coadministration with fenofibric acid.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of rifabutin is necessary. If rifabutin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like rifabutin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Ferric Maltol: (Moderate) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
Fexinidazole: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with fexinidazole. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP2C19 substrate and fexinidazole is a moderate CYP2C19 inhibitor.
Finerenone: (Major) Avoid concurrent use of finerenone and rifabutin due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased overall exposure to finerenone by 80%.
Flibanserin: (Major) Coadministration of flibanserin with rifabutin is not recommended due to decreased plasma concentrations of flibanserin. Flibanserin is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased flibanserin exposure by approximately 21%. (Moderate) Use of omeprazole may increase flibanserin concentrations, potentially increasing the risk for severe hypotension, syncope, and/or CNS depression. Monitor for flibanserin-induced adverse reactions; consider if a different PPI would be a better choice for the patient. Omeprazole is a CYP2C19 inhibitor, and has been noted to cause clinically important drug interactions with certain CYP2C19 substrates. Flibanserin is a CYP2C19 substrate. Interactions may be especially significant for patients who are also known CYP2C19 poor metabolizers.
Fluconazole: (Moderate) Monitor for rifabutin-associated adverse effects with concomitant fluconazole use. Reduce the rifabutin dose or discontinue rifabutin if toxicity is suspected. Carefully monitor for uveitis when rifabutin is given concomitantly with fluconazole. If uveitis is suspected, refer the patient to an ophthalmologist, and if considered necessary, discontinue rifabutin. Coadministration of fluconazole increased the rifabutin AUC by 82% and Cmax by 88%.
Fluphenazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Flurazepam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as flurazepam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Several hepatic inducers, including rifabutin, can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Fluvastatin: (Moderate) Concomitant administration of omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%. (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors. To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
Fluvoxamine: (Moderate) Omeprazole is a primary substrate of CYP2C19 and CYP3A4. Reduced metabolism and resulting elevated plasma concentrations of omeprazole may occur if combined with fluvoxamine. Fluvoxamine is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Concomitant administration of omeprazole and a combined inhibitor of CYP2C19 and CYP3A4 resulted in more than doubling of the omeprazole exposure. No specific dose adjustments are recommended, unless the patient is receiving high doses of omeprazole, as for Zollinger-Ellison Syndrome; in such patients, omeprazole dose reduction might be necessary.
Fosamprenavir: (Major) Reduce rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use of fosamprenavir is necessary. Concomitant use may increase rifabutin exposure. There are no clinically significantly alterations in fosamprenavir pharmacokinetics. Rifabutin is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Coadministration with fosamprenavir/ritonavir significantly increased the AUC of the active metabolite of rifabutin.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Fosphenytoin: (Major) Avoid concomitant use of omeprazole and fosphenytoin as omeprazole exposure may be decreased, reducing its efficacy. Concomitant use may also increase phenytoin concentrations. Omeprazole is a CYP2C19 inhibitor and CYP3A substrate and fosphenytoin is a CYP2C19 substrate and strong CYP3A inducer. (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
Fruquintinib: (Major) Avoid coadministration of fruquintinib with rifabutin if possible due to decreased fruquintinib exposure and risk of decreased efficacy. If concomitant use of fruquintinib and rifabutin is necessary, monitor for decreased efficacy. Fruquintinib is a CYP3A substrate; rifabutin is a strong CYP3A inducer. Coadministration of a moderate CYP3A inducer is predicted to decrease fruquintinib exposure by 32%.
Furosemide: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and loop diuretic use due to risk for hypomagnesemia. (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.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and rifabutin due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Gefitinib: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Glasdegib: (Major) Avoid coadministration of glasdegib and rifabutin due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after rifabutin has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
Glecaprevir; Pibrentasvir: (Major) When possible, avoid concurrent administration of glecaprevir and rifabutin; consider use of an alternative hepatitis C treatment. Use of these drugs together may decrease the plasma concentration of glecaprevir. Use of another rifamycin with glecaprevir resulted in an 88% decrease in the plasma concentration of glecaprevir. (Major) When possible, avoid concurrent administration of pibrentasvir and rifabutin; consider use of an alternative hepatitis C treatment. Use of these drugs together may decrease the plasma concentration of pibrentasvir. Use of another rifamycin with pibrentasvir resulted in an 87% decrease in the plasma concentration of pibrentasvir.
Glimepiride: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
Glipizide: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
Glipizide; Metformin: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
Glyburide: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
Glyburide; Metformin: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
Guanfacine: (Major) Rifabutin may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if rifabutin is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If rifabutin is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and rifabutin is a moderate CYP3A4 inducer.
Haloperidol: (Major) Significant reductions in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and CYP3A4 enzyme-inducing drugs such as carbamazepine or rifampin. Rifabutin is an inducer and a substrate of CYP3A4. Haloperidol dosage adjustments should be made as needed when rifabutin is added or discontinued.
Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with rifabutin is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If rifabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Hydantoins: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with rifabutin is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If rifabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with rifabutin is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If rifabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with rifabutin. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Ibrutinib: (Moderate) Use ibrutinib and rifabutin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of oxycodone as needed. If rifabutin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with rifabutin, a CYP3A substrate, as rifabutin toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with omeprazole, a CYP3A substrate, as omeprazole toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with rifabutin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; rifabutin is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
Indinavir: (Major) Omeprazole has been reported to decrease the oral bioavailability of indinavir. In one study, indinavir plasma levels fell to below 95% of normal in roughly half of the patients receiving omeprazole concurrently. An increase in indinavir dosage resolved the interaction. It is unclear if other gastric acid-pump inhibitors would interact with indinavir in this manner. (Major) Reduce rifabutin dose to 150 mg PO once daily and increase indinavir dose from 800 mg to 1,000 mg 3 times daily if concomitant use is necessary. Monitor for decrease in indinavir efficacy and for rifabutin-related adverse effects, such as uveitis and neutropenia. Concomitant use may increase rifabutin exposure and decrease indinavir exposure. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; indinavir is a CYP3A substrate and strong CYP3A inhibitor. Coadministration increased rifabutin exposure by 173% and decreased indinavir exposure by 34%.
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 coadministration of infigratinib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease infigratinib exposure resulting in decreased efficacy. If necessary, infigratinib may be administered two hours before or ten hours after an H2-receptor antagonist or two hours before or after a locally acting antacid. Coadministration with a PPI decreased infigratinib exposure by 45%. (Major) Avoid concurrent use of infigratinib and rifabutin. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Iron Salts: (Moderate) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
Iron Salts: (Moderate) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
Iron: (Moderate) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
Isavuconazonium: (Major) Caution and close monitoring are warranted when isavuconazonium is administered with rifabutin as there is a potential for elevated rifabutin concentrations and decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Rifabutin is a substrate and inducer of the hepatic isoenzyme CYP3A4. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. (Moderate) Concomitant use of isavuconazonium with omeprazole may result in increased serum concentrations of omeprazole. Omeprazole is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of omeprazole with rifampin due to the risk of decreased omeprazole plasma concentrations which may decrease efficacy. Omeprazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of omeprazole with rifampin due to the risk of decreased omeprazole plasma concentrations which may decrease efficacy. Omeprazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Isradipine: (Moderate) Because isradipine is a substrate of CYP3A4, the concomitant use of drugs that induce CYP3A4 such as rifabutin, may cause a reduction in the bioavailability and thus decreased therapeutic effect of isradipine. Until more data are available, patients should be monitored for potential loss of therapeutic effect when hepatic enzyme inducers are added to isradipine therapy.
Itraconazole: (Moderate) When administering proton pump inhibitors with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when proton pump inhibitors are administered with the 65 mg itraconazole capsule. Administer proton pump inhibitors at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if proton pump inhibitors are administered with itraconazole 65 mg capsules.
Ketoconazole: (Major) Avoid use of proton pump inhibitors (PPIs) with ketoconazole. Medications that increase gastric pH may impair oral ketoconazole absorption. (Major) Concurrent use of ketoconzole with rifabutin is not recommended. Taking these drug together may result in increased exposure to rifabutin and decreased exposure to ketoconazole. Both drugs are substrates for CYP3A4, while rifabutin is also a CYP3A4 inducer and ketoconazole is a potent inhibitor of CYP3A4.
Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Rifabutin may accelerate the metabolism of zidovudine. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifamycins, including rifampin, rifabutin and rifapentine.
Lansoprazole; Amoxicillin; Clarithromycin: (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.
Larotrectinib: (Major) Avoid concurrent use of larotrectinib and rifabutin due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If rifabutin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifabutin. Larotrectinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with rifabutin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy. (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Lefamulin: (Major) Avoid coadministration of lefamulin with rifabutin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer.
Lemborexant: (Major) Avoid coadministration of lemborexant and rifabutin as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer.
Lenacapavir: (Major) Avoid concurrent use of lenacapavir and rifabutin due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced lenacapavir overall exposure by 56%.
Leniolisib: (Major) Avoid concomitant use of leniolisib and rifabutin. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced leniolisib overall exposure by 58%.
Letermovir: (Major) Concurrent administration of letermovir and rifabutin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, an increase in the plasma concentration of rifabutin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rifabutin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Monitor for reduced omeprazole efficacy and adjust the dose of omeprazole if needed during concurrent use of letermovir. Coadministration may result in a clinically relevant decrease in the plasma concentration of omeprazole. Omeprazole is a sensitive substrate of CYP2C19. Letermovir is a CYP2C19 inducer.
Leuprolide; 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.
Levamlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Levoketoconazole: (Major) Avoid use of proton pump inhibitors (PPIs) with ketoconazole. Medications that increase gastric pH may impair oral ketoconazole absorption. (Major) Concurrent use of ketoconzole with rifabutin is not recommended. Taking these drug together may result in increased exposure to rifabutin and decreased exposure to ketoconazole. Both drugs are substrates for CYP3A4, while rifabutin is also a CYP3A4 inducer and ketoconazole is a potent inhibitor of CYP3A4.
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.
Levonorgestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
Levothyroxine: (Moderate) Proton pump inhibitors (PPIs) may reduce the oral absorption of thyroid hormones and thus reduce efficacy; monitor for altered clinical response to thyroid hormone therapy if concomitant use is necessary. Alternatively, an oral liquid levothyroxine dosage form may be considered. Gastric acidity is an essential requirement for adequate absorption of levothyroxine tablets and capsules and other thyroid hormones. Gastric acidity may be less essential for the absorption of oral liquid dosage forms of levothyroxine; PPIs have been observed to have a minimal effect on the bioavailability of oral liquid levothyroxine.
Levothyroxine; Liothyronine (Porcine): (Moderate) Proton pump inhibitors (PPIs) may reduce the oral absorption of thyroid hormones and thus reduce efficacy; monitor for altered clinical response to thyroid hormone therapy if concomitant use is necessary. Alternatively, an oral liquid levothyroxine dosage form may be considered. Gastric acidity is an essential requirement for adequate absorption of levothyroxine tablets and capsules and other thyroid hormones. Gastric acidity may be less essential for the absorption of oral liquid dosage forms of levothyroxine; PPIs have been observed to have a minimal effect on the bioavailability of oral liquid levothyroxine.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Proton pump inhibitors (PPIs) may reduce the oral absorption of thyroid hormones and thus reduce efficacy; monitor for altered clinical response to thyroid hormone therapy if concomitant use is necessary. Alternatively, an oral liquid levothyroxine dosage form may be considered. Gastric acidity is an essential requirement for adequate absorption of levothyroxine tablets and capsules and other thyroid hormones. Gastric acidity may be less essential for the absorption of oral liquid dosage forms of levothyroxine; PPIs have been observed to have a minimal effect on the bioavailability of oral liquid levothyroxine.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
Linagliptin: (Moderate) Concomitant use of linagliptin with rifabutin may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
Linagliptin; Metformin: (Moderate) Concomitant use of linagliptin with rifabutin may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
Liothyronine: (Moderate) Proton pump inhibitors (PPIs) may reduce the oral absorption of thyroid hormones and thus reduce efficacy; monitor for altered clinical response to thyroid hormone therapy if concomitant use is necessary. Alternatively, an oral liquid levothyroxine dosage form may be considered. Gastric acidity is an essential requirement for adequate absorption of levothyroxine tablets and capsules and other thyroid hormones. Gastric acidity may be less essential for the absorption of oral liquid dosage forms of levothyroxine; PPIs have been observed to have a minimal effect on the bioavailability of oral liquid levothyroxine.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and rifabutin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Rifabutin exposure and the risk for rifabutin-related adverse effects may also be increased; rifabutin dosage adjustments may be required if concomitant use is necessary. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor and rifabutin is a CYP3A4 substrate and moderate CYP3A4 inducer. (Moderate) Monitor for omeprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Loop diuretics: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and loop diuretic use due to risk for hypomagnesemia.
Lopinavir; Ritonavir: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with lopinavir; ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with lopinavir; ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and lopinavir; ritonavir is a strong CYP3A inhibitor. Coadministration with lopinavir; ritonavir increased the AUC of rifabutin by approximately 200%. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with a ritonavir-boosted protease inhibitor and adjust dose accordingly. Rifabutin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ritonavir (alone) increased the AUC of rifabutin by 300%. (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times.
Lorlatinib: (Major) Avoid concomitant use of lorlatinib and rifabutin due to decreased plasma concentrations of lorlatinib, which may reduce its efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Lorlatinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Lovastatin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
Luliconazole: (Minor) Theoretically, luliconazole may increase the side effects of omeprazole, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of omeprazole. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
Lumacaftor; Ivacaftor: (Major) Concomitant use of rifabutin and lumacaftor; ivacaftor is not recommended. Rifabutin may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Lumacaftor; ivacaftor may also decrease the therapeutic effect of rifabutin. Rifabutin is a substrate and potent inducer (per FDA-approved labeling for lumacaftor; ivacaftor) of CYP3A. Ivacaftor is a substrate of CYP3A and lumacaftor is a potent inducer of CYP3A; although the enzyme induction effects of lumacaftor are already accounted for in fixed-combination dosing, ivacaftor exposure is further decreased when given together with other CYP3A inducers. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure (AUC) by 57%, with minimal effect on the exposure of lumacaftor. Rifabutin may be expected to have a similar effect on some drugs that are affected by coadministration with rifampin. Rifabutin appears to be a less potent hepatic enzyme inducer than rifampin; however, the clinical significance of this finding has not been determined. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of omeprazole by substantially decreasing its systemic exposure. If used together, an omeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Omeprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
Lumacaftor; Ivacaftor: (Major) Concomitant use of rifabutin and lumacaftor; ivacaftor is not recommended. Rifabutin may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Lumacaftor; ivacaftor may also decrease the therapeutic effect of rifabutin. Rifabutin is a substrate and potent inducer (per FDA-approved labeling for lumacaftor; ivacaftor) of CYP3A. Ivacaftor is a substrate of CYP3A and lumacaftor is a potent inducer of CYP3A; although the enzyme induction effects of lumacaftor are already accounted for in fixed-combination dosing, ivacaftor exposure is further decreased when given together with other CYP3A inducers. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure (AUC) by 57%, with minimal effect on the exposure of lumacaftor. Rifabutin may be expected to have a similar effect on some drugs that are affected by coadministration with rifampin. Rifabutin appears to be a less potent hepatic enzyme inducer than rifampin; however, the clinical significance of this finding has not been determined. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of omeprazole by substantially decreasing its systemic exposure. If used together, an omeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Omeprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
Lumateperone: (Major) Avoid coadministration of lumateperone and rifabutin as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer.
Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may occur when the drug is co-administered with inducers of CYP3A4. Concurrent use of lurasidone and CYP3A4 inducers, such as rifabutin, may lead to a decrease in efficacy of lurasidone. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more).
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.
Maraviroc: (Moderate) Use caution if coadministration of maraviroc with rifabutin is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and rifabutin is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
Maribavir: (Major) Avoid concomitant use of maribavir and rifabutin. Coadministration may decrease maribavir exposure resulting in reduced virologic response. Maribavir is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with rifabutin due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP3A substrate and rifabutin is a moderate 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 omeprazole therapy. Avoid initiation of omeprazole 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 omeprazole therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP2C19 substrate and omeprazole is a weak CYP2C19 inhibitor. Concomitant use of mavacamten 10 mg with omeprazole 20 mg once daily increased overall mavacamten exposure by 48% with no effect on peak exposure in healthy CYP2C19 normal and rapid metabolizers.
Mebendazole: (Moderate) Mebendazole is metabolized by hepatic cytochrome P450 enzymes and other enzymes. Rifamycins induce hepatic microsomal enzymes and may increase the metabolism of mebendazole if given concomitantly.
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Rifabutin is an inducer of CYP3A4, and may increase the metabolism of mefloquine and reduce mefloquine plasma concentrations if coadministered. (Moderate) Proton pump inhibitors (PPIs) may increase plasma concentrations of mefloquine. Patients on chronic mefloquine therapy might be at increased risk of adverse reactions, especially patients with a neurological or psychiatric history.
Metformin; Repaglinide: (Minor) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Patients taking repaglinide concomitantly with a CYP3A4 inducer, such as rifabutin, should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Methohexital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Methotrexate: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities. (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.
Metolazone: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Midazolam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as midazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin is an inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving rifabutin may require higher doses of midazolam to achieve the desired clinical effect.
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.
Mitapivat: (Major) Avoid coadministration of mitapivat with rifabutin, if possible, due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. If concomitant use is necessary, up-titration of mitapivat may be required. Monitor hemoglobin and titrate the mitapivat dose based on response; do not exceed 100 mg PO twice daily. Mitapivat is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased mitapivat overall exposure by 55% to 60%.
Mitotane: (Major) Use caution if mitotane and rifabutin are used concomitantly, and monitor for decreased efficacy of rifabutin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and rifabutin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rifabutin. (Moderate) Use caution if mitotane and omeprazole are used concomitantly, and monitor for decreased efficacy of omeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and omeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of omeprazole.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and rifabutin. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Use of a moderate CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 58%.
Modafinil: (Moderate) Drugs that exhibit significant induction of the hepatic microsomal CYP3A4 isoenzyme may potentially increase the metabolism of modafinil. These medications include rifabutin. Decreased serum levels of modafinil could potentially result in decreased efficacy of modafinil.
Mycophenolate: (Moderate) Concomitant administration of proton pump inhibitors (PPIs) with mycophenolate mofetil (Cellcept) appears to reduce MPA exposure AUC-12h (25.8 +/- 6.4 mg/L x h with omeprazole vs. 33.3 +/- 11.5 mg//L x h without omeprazole); however, the interaction does not appear to exist with mycophenolate sodium delayed-release tablets (Myfortic). Reduced systemic exposure of MPA after mycophenolate mofetil in the presence of a PPI appears to be due to impaired absorption of mycophenolate mofetil which may occur because of incomplete dissolution of mycophenolate mofetil in the stomach at elevated pH. The clinical significance of reduced MPA exposure is unknown; however patients should be evaluated periodically if mycophenolate mofetil is administered with a PPI. Of note, MPA concentrations appear to be reduced in the initial hours after mycophenolate mofetil receipt but increase later in the dosing interval because of enterohepatic recirculation. A second peak in the concentration-time profile of MPA is observed 612 hours after dosing due to enterohepatic recirculation. For example, the 12-hour plasma concentrations of MPA were similar among patients who received mycophenolate mofetil with or without omeprazole. The biphasic plasma concentration-time course of MPA due to extensive enterohepatic circulation hampers therapeutic drug monitoring of MPA. Drug exposure as measured by AUC-12h is the best estimator for the clinical effectiveness of mycophenolate, but measurement of full-dose interval MPA AUC-12h requires collection of multiple samples over a 12-hour period; MPA predose concentrations correlate poorly with MPA AUC-12h. The interaction does not appear to exist with Mycophenolate sodium (Myfortic). (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.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with rifabutin is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with rifabutin. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Nelfinavir: (Major) Reduce rifabutin dose to 150 mg PO once daily and increase nelfinavir dose to 1,250 mg PO every 12 hours if concomitant use is necessary. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; nelfinavir is a CYP3A substrate and strong CYP3A inhibitor. While coadministration of nelfinavir 750 mg every 8 hours with rifabutin 300 mg once daily resulted in a 32% decrease in nelfinavir exposure and a 207% increase in rifabutin exposure, the coadministration of nelfinavir 1,250 mg every 12 hours with rifabutin 150 mg once daily resulted in no alterations in nelfinavir exposure. (Major) Use of proton pump inhibitors with nelfinavir is not recommended. Coadministration may result in decreased nelfinavir exposure, subtherapeutic antiretroviral activity, and possibility resistant HIV mutations. In one study, concurrent use of nelfinavir with omeprazole resulted in decreased nelfinavir AUC, Cmax, and Cmin by 36%, 37%, and 39%, respectively.
Neratinib: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%. (Major) Avoid concomitant use of rifabutin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
Nicardipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as nicardipine and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent enzyme inducers.
NIFEdipine: (Major) Avoid coadministration of nifedipine with rifabutin and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. Nifedipine is a CYP3A substrate and rifabutin is a CYP3A inducer.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Nimodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as nimodipine and thereby reduce their oral bioavailability. The dosage requirements of nimodipine may be increased in patients receiving concurrent enzyme inducers.
Niraparib; Abiraterone: (Moderate) Concomitant use of abiraterone with rifabutin may result in decreased serum concentrations of abiraterone. Abiraterone is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of this enzyme. Caution and close monitoring for decreased efficacy are advised if these drugs are used together.
Nirmatrelvir; Ritonavir: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with a ritonavir-boosted protease inhibitor and adjust dose accordingly. Rifabutin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ritonavir (alone) increased the AUC of rifabutin by 300%. (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times. (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of rifabutin is necessary. Concomitant use of nirmatrelvir and rifabutin may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours. (Major) Avoid concomitant use of nirogacestat and rifabutin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with rifabutin due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
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.
Norethindrone; Ethinyl Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
Norgestimate; Ethinyl Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
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.
Octreotide: (Moderate) Coadministration of oral octreotide with proton pump inhibitors (PPIs) may require increased doses of octreotide. Coadministration of oral octreotide with drugs that alter the pH of the upper GI tract, including PPIs, may alter the absorption of octreotide and lead to a reduction in bioavailability. This interaction has been documented with esomeprazole and can occur with the other PPIs.
Olaparib: (Major) Avoid coadministration of olaparib with rifabutin due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and rifabutin is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia. (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and rifabutin due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
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 concurrent use of omaveloxolone and rifabutin. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxone is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Ondansetron: (Minor) Monitor for altered response to ondansetron during coadministration of rifabutin. Rifabutin may increase the clearance and decrease blood concentrations of ondansetron. However, no dosage adjustment for ondansetron is recommended during coadministration.
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.
Oritavancin: (Moderate) Administration of oritavancin, a weak inhibitor of CYP2C19, with omeprazole resulted in a 15% increase in the ratio of omeprazole to 5-OH-omeprazole concentrations in the plasma. Monitor patients for omeprazole toxicities, such as headache or gastrointestinal distress, if these drugs are administered concurrently. (Moderate) Rifabutin is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of rifabutin may be reduced if these drugs are administered concurrently.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of oxycodone as needed. If rifabutin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including rifabutin.
Pacritinib: (Major) Avoid concurrent use of pacritinib with rifabutin due to the risk of decreased pacritinib exposure which may impair efficacy. Pacritinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Palovarotene: (Major) Avoid concomitant use of palovarotene and rifabutin. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Pazopanib: (Major) Pazopanib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of pazopanib and proton pump inhibitors (PPIs) that elevate the gastric pH may reduce the bioavailability of pazopanib. In a study of patients with solid tumors, the AUC and Cmax of pazopanib were decreased by approximately 40% when coadministered with esomeprazole. If a drug is needed to raise the gastric pH, consider use of a short-acting antacid; separate antacid and pazopanib dosing by several hours.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and rifabutin due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
Pentobarbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with rifabutin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of rifabutin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Rifabutin is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
Perindopril; Amlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Perphenazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Perphenazine; Amitriptyline: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Pexidartinib: (Major) Avoid coadministration of pexidartinib with omeprazole as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. As an alternative to a proton pump inhibitor (PPI), use locally-acting antacids or H2-receptor antagonists. Coadministration of another PPI decreased pexidartinib exposure by 50%.
Phenobarbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Phenothiazines: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Phenytoin: (Major) Avoid concomitant use of omeprazole and phenytoin as omeprazole exposure may be decreased, reducing its efficacy. Concomitant use may also increase phenytoin concentrations. Omeprazole is a CYP2C19 inhibitor and CYP3A substrate and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as rifabutin. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
Pioglitazone; Glimepiride: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and rifabutin due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. If concomitant use is necessary, an empiric pirtobrutinib dosage increase is required. If the current dosage is 200 mg once daily, increase the dose to 300 mg; if the current dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg. Pirtobrutinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Polyethylene Glycol; Electrolytes; Bisacodyl: (Minor) The concomitant use of bisacodyl oral tablets with drugs that raise gastric pH like proton pump inhibitors can cause the enteric coating of the bisacodyl tablets to dissolve prematurely, leading to possible gastric irritation or dyspepsia. When taking bisacodyl tablets, it is advisable to avoid PPIs within 1 hour before or after the bisacodyl dosage.
Posaconazole: (Major) The concurrent use of posaconazole and rifabutin should be avoided, if possible, due to the potential for decreased posaconazole efficacy as well as increased risk of rifabutin related adverse events. If used in combination, closely monitor for breakthrough fungal infections and rifabutin adverse events, such as uveitis and leukopenia. Rifabutin induces UDP-glucuronidase resulting in decreased posaconazole plasma concentrations. When posaconazole (200 mg PO daily) was administered with rifabutin (300 mg PO daily), the mean reductions in Cmax were 43% and the mean reductions in AUC were 49% for posaconazole. Additionally, posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rifabutin. Coadministration of posaconazole (200 mg PO daily) with rifabutin (300 mg PO daily) increased the mean rifabutin Cmax (by 31%) and AUC (by 72%). The concomitant use of rifabutin with posaconazole should be avoided unless the benefits outweigh the risks; dosage adjustment recommendations are not available. (Major) The concurrent use of posaconazole immediate-release oral suspension and proton pump inhibitors (PPIs) should be avoided, if possible, due to the potential for decreased posaconazole efficacy. If used in combination, closely monitor for breakthrough fungal infections. PPIs increase gastric pH, resulting in decreased posaconazole absorption and lower posaconazole plasma concentrations. When a single 400 mg dose of posaconazole oral suspension was administered with esomeprazole (40 mg PO daily), the mean reductions in Cmax were 46% and the mean reductions in AUC were 32% for posaconazole. The pharmacokinetics of posaconazole delayed-release tablets and oral suspension are not significantly affected by PPIs. Additionally, posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many PPIs (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole). Coadministration may result in increased plasma concentration of the PPIs.
Pralsetinib: (Major) Avoid concurrent use of rifabutin and pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the current dose of pralsetinib (400 mg to 600 mg; 300 mg to 500 mg; 200 mg to 300 mg) starting on day 7 of coadministration. Pralsetinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased the pralsetinib overall exposure by 45%.
Pravastatin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
Praziquantel: (Major) Avoid concomitant use of praziquantel and rifabutin. Concurrent use may decrease praziquantel exposure which may reduce its efficacy. If concomitant use is necessary, monitor for reduced response to praziquantel. Praziquantel is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. When praziquantel was administered after 13 days of treatment with a moderate CYP3A inducer, the mean praziquantel AUC was 77% lower than when praziquantel was given alone.
Pretomanid: (Major) Avoid coadministration of pretomanid with rifabutin as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased pretomanid exposure by 35%.
Primidone: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
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: (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.
Prochlorperazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Promethazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Promethazine; Dextromethorphan: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Promethazine; Phenylephrine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Propafenone: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of propafenone.
Propranolol: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
Pyrazinamide, PZA: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Quazepam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as quazepam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Quetiapine: (Moderate) Increased doses of quetiapine may be required to maintain symptom control if rifabutin is used concomitantly. Rifabutin is a less potent inducer of CYP3A4 than rifampin, a potent inducer. However, increased doses of quetiapine up to 5 fold may be required to maintain control of symptoms in patients receiving quetiapine and known potent CYP3A4 inducers. There are no specific recommendations for moderate inducers. When rifabutin is discontinued, the dose of quetiapine should be reduced to the original level within 7 to 14 days.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Quinidine: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of quinidine.
Quinine: (Major) Rifabutin is an inducer of hepatic metabolism and may significantly accelerate quinine clearance and reduce its half-life. Higher doses of quinine may be required in patients receiving rifabutin.
Quizartinib: (Major) Avoid concomitant use of rifabutin with quizartinib due to the risk of decreased quizartinib exposure which may reduce its efficacy. Quizartinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased the quizartinib overall exposure by 90%.
Ramelteon: (Moderate) Administration of rifabutin, a CYP1A2 enzyme inducer, may theoretically result in decreased exposure to ramelteon. Monitor the patient closely if rifabutin therapy is initiated or stopped in patients receiving ramelteon.
Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifabutin. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inducers can theoretically reduce the effectiveness of HMG-CoA reductase activity via induction of CYP3A4 metabolism. Examples of CYP3A4 inducers include rifabutin.
Relugolix; Estradiol; Norethindrone acetate: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Repaglinide: (Minor) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Patients taking repaglinide concomitantly with a CYP3A4 inducer, such as rifabutin, should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with rifabutin due to decreased repotrectinib exposure and risk of decreased efficacy. Repotrectinib is a CYP3A substrate; rifabutin is a moderate CYP3A inducer.
Ribociclib: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin.
Rifampin: (Major) Avoid coadministration of omeprazole with rifampin due to the risk of decreased omeprazole plasma concentrations which may decrease efficacy. Omeprazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer.
Rifapentine: (Major) Avoid concomitant use of omeprazole and rifapentine as omeprazole exposure may be decreased, reducing its efficacy. Omeprazole is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
Rilpivirine: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Riluzole: (Moderate) Coadministration of riluzole with omeprazole may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and omeprazole is a CYP1A2 inducer.
Rimegepant: (Major) Avoid coadministration of rimegepant with rifabutin; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Ripretinib: (Major) Avoid coadministration of ripretinib with rifabutin. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of rifabutin. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and rifabutin is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Risedronate: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH 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. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use PPIs in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Ritonavir: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with a ritonavir-boosted protease inhibitor and adjust dose accordingly. Rifabutin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ritonavir (alone) increased the AUC of rifabutin by 300%. (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times.
Rivaroxaban: (Minor) Coadministration of rivaroxaban and rifabutin may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Rifabutin is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs lack of efficacy of rivaroxaban.
Roflumilast: (Major) Coadminister rifabutin and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Rifabutin is a CYP3A4 inducer and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide. Specific pharmacokinetic study of this potential interaction has not been conducted.
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: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with saquinavir/ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with saquinavir/ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and saquinavir/ritonavir is a strong CYP3A inhibitor. Coadministration with saquinavir/ritonavir increased the AUC of rifabutin by approximately 50%.
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.
Secobarbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Secretin: (Major) Discontinue use of proton pump inhibitors before administering secretin. Patients who are receiving proton pump inhibitors at the time of stimulation testing may be hyperresponsive to secretin stimulation, falsely suggesting gastrinoma. The time required for serum gastrin concentrations to return to baseline after discontinuation of a proton pump inhibitor is specific to the individual drug.
Segesterone Acetate; Ethinyl Estradiol: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (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.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and rifabutin due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease selpercatinib exposure by 40% to 70%. (Major) Avoid coadministration of selpercatinib with omeprazole due to the risk of decreased selpercatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, selpercatinib must be taken with food. Coadministration under fasting conditions with omeprazole decreased selpercatinib exposure by 69%; however, concomitant use increased selpercatinib exposure by 2% or less when it was administered with a meal.
Selumetinib: (Major) Avoid coadministration of selumetinib and rifabutin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Sildenafil: (Minor) Sildenafil is metabolized principally by cytochrome P450 3A4 and 2C9 enzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as rifabutin, will decrease plasma levels of sildenafil, however, no interaction studies have been performed.
Simvastatin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Siponimod: (Moderate) Concomitant use of siponimod and rifabutin is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of rifabutin. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
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) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
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.
Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of CYP3A4, such as rifabutin. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate. (Major) Coadministration of proton pump inhibitors (PPIs) with velpatasvir is not recommended. If it is considered medically necessary to coadminister, velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Other PPIs have not been studied; however, it may be prudent to separate the administration of the other PPIs similarly. 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.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of CYP3A4, such as rifabutin. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate. (Major) Avoid coadministration of voxilaprevir with moderate to potent inducers of CYP3A4, such as rifabutin. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. Voxilaprevir is metabolized by CYP3A4. (Major) Coadministration of proton pump inhibitors (PPIs) with velpatasvir is not recommended. If it is considered medically necessary to coadminister, velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Other PPIs have not been studied; however, it may be prudent to separate the administration of the other PPIs similarly. 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.
Solifenacin: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and rifabutin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Sorafenib: (Major) Avoid coadministration of sorafenib with rifabutin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
Sotorasib: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Sparsentan: (Major) Avoid concurrent use of sparsentan and proton pump inhibitors (PPIs) due to the risk for decreased sparsentan exposure which may reduce its efficacy. Medications that affect gastric pH may reduce sparsentan absorption.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Stiripentol: (Moderate) Consider a dose reduction of omeprazole when coadministered with stiripentol. Coadministration may increase plasma concentrations of omeprazole resulting in an increased risk of adverse reactions. Omeprazole is a sensitive CYP2C19 substrate. In vitro data predicts inhibition of CYP2C19 by stiripentol potentially resulting in clinically significant interactions.
Sucralfate: (Minor) Proton pump inhibitors should be taken at least 30 minutes prior to sucralfate. Sucralfate has been shown to delay absorption and reduce the bioavailability of omeprazole by about 16%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if rifabutin must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of sufentanil injection as needed. If rifabutin is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
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: (Moderate) Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. Sulfamethoxazole; trimethoprim, SMX-TMP did not alter the pharmacokinetics of rifabutin. (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) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
Tacrolimus: (Major) Increase tacrolimus dose and monitor tacrolimus serum concentrations if coadministration with rifabutin is necessary. Concurrent use may decrease tacrolimus serum concentrations and increase the risk of rejection. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rifabutin is a CYP3A inducer. (Moderate) Concomitant administration of omeprazole and tacrolimus may increase tacrolimus serum concentrations possibly leading to increased risk of serious adverse reactions (e.g., neurotoxicity, infection, QT prolongation), especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Monitor tacrolimus whole blood concentrations; reduce tacrolimus dose if needed to maintain therapeutic concentrations.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and rifabutin. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as rifabutin, may reduce the efficacy of tasimelteon.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with rifabutin as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Telmisartan; Amlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Temsirolimus: (Major) Avoid coadministration of temsirolimus with rifabutin due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If rifabutin is discontinued, decrease the dose of temsirolimus to the dose used before initiation of rifabutin. Temsirolimus is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
Tenofovir Alafenamide: (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
Tenofovir Alafenamide: (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
Terbinafine: (Moderate) Due to the risk for breakthrough fungal infections, caution is advised when administering terbinafine with rifabutin. 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 decrease 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; rifabutin induces this enzyme. Monitor patients for breakthrough fungal infections.
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) Do not administer tezacaftor; ivacaftor and rifabutin together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of rifabutin, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
Thiazide diuretics: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Thioridazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Thiothixene: (Major) Limited data suggest that rifampin can increase the metabolism or reduce the bioavailability of thiothixene. Dosage adjustments of thiothixene may be necessary following the addition of rifampin or another rifamycin (e.g., rifabutin, rifapentine).
Thyroid hormones: (Moderate) Proton pump inhibitors (PPIs) may reduce the oral absorption of thyroid hormones and thus reduce efficacy; monitor for altered clinical response to thyroid hormone therapy if concomitant use is necessary. Alternatively, an oral liquid levothyroxine dosage form may be considered. Gastric acidity is an essential requirement for adequate absorption of levothyroxine tablets and capsules and other thyroid hormones. Gastric acidity may be less essential for the absorption of oral liquid dosage forms of levothyroxine; PPIs have been observed to have a minimal effect on the bioavailability of oral liquid levothyroxine.
Tipranavir: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with tipranavir/ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with tipranavir/ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and tipranavir/ritonavir is a strong CYP3A inhibitor. Coadministration with tipranavir/ritonavir increased the AUC of rifabutin by approximately 2.9-fold. (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Tipranavir markedly induces the hepatic cytochrome P-450 enzyme CYP2C19, an enzyme responsible for the metabolism of PPIs. However, since tipranavir is not given unless it is co-prescribed with ritonavir, a known marked enzyme inhibitor, a reduction in PPI metabolism may be unlikely to occur. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If tipranavir and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
Tirofiban: (Minor) Patients who receive omeprazole concomitantly with tirofiban may have a higher rate of tirofiban clearance than patients who do not receive omeprazole. The clinical significance of this is unknown.
Tocilizumab: (Minor) Concomitant use of tocilizumab and omeprazole may lead to a decrease in the efficacy of omeprazole. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 12 to 28% decrease in omeprazole exposure occurred 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Omeprazole is a substrate of both CYP2C19 and CYP3A4.
Tolterodine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
Toremifene: (Major) Avoid coadministration of rifabutin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
Torsemide: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and loop diuretic use due to risk for hypomagnesemia.
Tramadol; Acetaminophen: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Trandolapril; Verapamil: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as verapamil and thereby reduce their oral bioavailability. The dosage requirements of verapamil may be increased in patients receiving concurrent enzyme inducers.
Tretinoin, ATRA: (Moderate) Rifabutin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifabutin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Triazolam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as triazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
Trifluoperazine: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
Trimethoprim: (Moderate) Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. Sulfamethoxazole; trimethoprim, SMX-TMP did not alter the pharmacokinetics of rifabutin.
Trospium: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
Tucatinib: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with tucatinib is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin. (Moderate) Monitor for omeprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
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: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with rifabutin as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer.
Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and rifabutin is a CYP3A4 inducer. Concomitant use is expected to decrease the plasma concentration of ulipristal and may decrease its effectiveness.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant omeprazole and thiazide diuretic use due to risk for hypomagnesemia.
Vemurafenib: (Major) Concomitant administration of rifabutin and vemurafenib may decrease concentrations of both agents. Both rifabutin and vemurafenib are CYP3A4 substrates and inducers. Avoid using these agents together if possible.
Venetoclax: (Major) Avoid coadministration of venetoclax with rifabutin as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Verapamil: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as verapamil and thereby reduce their oral bioavailability. The dosage requirements of verapamil may be increased in patients receiving concurrent enzyme inducers.
Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including rifabutin. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including rifabutin. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
Voclosporin: (Major) Avoid coadministration of voclosporin with rifabutin. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%.
Vonoprazan: (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.
Vonoprazan; Amoxicillin: (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.
Vonoprazan; Amoxicillin; Clarithromycin: (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.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and rifabutin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with rifabutin, a CYP3A inducer.
Voriconazole: (Contraindicated) Concurrent administration of rifabutin and voriconazole is contraindicated. In one study, the maximum plasma concentration (Cmax) and systemic exposure (AUC) of voriconazole were decreased by an average of 67% and 79%, respectively, when given with rifabutin. Another study, found concurrent administration caused the Cmax and AUC of rifabutin to be increased by an average of 3-times and 4-times, respectively. Rifabutin induces the CYP2C9, CYP2C19 and CYP3A4 metabolism of voriconazole. Voriconazole inhibits the CYP3A4 metabolism of rifabutin. (Moderate) Reduce the omeprazole dose by one-half when initiating voriconazole therapy in patients who are currently receiving omeprazole at doses of 40 mg/day or greater. Levels of omeprazole may increase by up to 2-fold due to CYP2C19 and CYP3A4 inhibition by voriconazole.
Voxelotor: (Major) Avoid coadministration of voxelotor and rifabutin as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,000 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; rifabutin is a moderate CYP3A inducer. Coadministration of voxelotor with a moderate CYP3A inducer is predicted to decrease voxelotor exposure by up to 24%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with rifamycins is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Rifamycins may induce the hepatic metabolism of warfarin through induction of CYP3A4, CYP2C9, and CYP1A2. A 2- to 3-fold increase in the daily dose of warfarin may be needed within a week of starting rifamycins to maintain appropriate anticoagulation. Once the rifamycin is discontinued, the dose of warfarin will need to be decreased. (Moderate) Monitor the INR in patients receiving warfarin with proton pump inhibitors. Increases in INR may lead to abnormal bleeding. Adjust the warfarin dose to maintain the target INR. (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.
Zanubrutinib: (Major) Avoid concurrent use of zanubrutinib and rifabutin due to the risk of decreased zanubrutinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the zanubrutinib dose to 320 mg twice daily and monitor response. Resume the previous dose of zanubrutinib if rifabutin is discontinued. Zanubrutinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with rifabutin decreased zanubrutinib exposure by 44%.
Zidovudine, ZDV: (Minor) Rifabutin may accelerate the metabolism of zidovudine. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifamycins, including rifampin, rifabutin and rifapentine.
Ziprasidone: (Moderate) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4, such as rifabutin. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone.
Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as rifabutin. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
Omeprazole; amoxicillin; rifabutin is active against most clinical isolates of H. pylori. Omeprazole inhibits gastric acid secretion which is believed to enhance the effect of antimicrobial agents eradicating H. pylori. It is a substituted benzimidazole, proton pump inhibitor (PPI), which suppresses gastric acid secretion by inhibiting the H+/K+ ATPase enzyme system of gastric parietal cells. A significant increase in gastric pH and decrease in basal acid output follow oral administration. In hypersecretory conditions, it has a marked effect on gastric acid secretion, both basal- and pentagastrin-stimulated. Omeprazole exerts an inhibitory effect on gastric acid for at least 24 hours. It does not antagonize H2 or cholinergic receptors. 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. PBPs 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. PBPs 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. Rifabutin inhibits DNA-dependent RNA polymerase in susceptible microorganisms, but not mammalian cells.
Resistance to amoxicillin is mediated primarily through beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive. Resistance to rifabutin occurs through mutations in the DNA-dependent RNA polymerase.
Omeprazole; amoxicillin; rifabutin is administered orally. The systemic pharmacokinetic information for the individual components is listed below.
Omeprazole: Omeprazole is 95% protein-bound. Extensive hepatic metabolism occurs, and the metabolites (hydroxyomeprazole and omeprazole-sulphone) have very little or no antisecretory activity. Approximately 77% of a dose is excreted renally as metabolites, and the remainder of the dose is excreted in the feces. The mean elimination half-life is 1 hour.
Amoxicillin: Approximately 20% of circulating amoxicillin is protein-bound. Amoxicillin is widely distributed into most body tissues and fluids, excluding the brain and spinal fluid except when meninges are inflamed. Amoxicillin is not significantly metabolized. The unchanged drug and its metabolites are excreted into the urine primarily via tubular secretion and glomerular filtration. Approximately 60% of an orally administered dose is excreted in the urine (mostly as unchanged drug), primarily via tubular secretion and glomerular filtration, within 6 to 8 hours. The mean elimination half-life is 1.4 hours.
Rifabutin: Rifabutin is 85% protein-bound. Of the 5 metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant with a plasma metabolite:parent AUC ratio of 0.1 and 0.07, respectively. The 25-O-desacetylrifabutin metabolite has an activity equal to the parent drug with up to 10% to the total antimicrobial activity. Approximately 53% of the oral dose is excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces. Renal and biliary clearance of unchanged drug each contribute approximately 5% to apparent oral clearance. The mean elimination half-life is 34 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP2C19, CYP3A4
Omeprazole is metabolized by CYP2C19 (primary) and by CYP3A4 (secondary). It inhibits CYP2C19 in vitro and in vivo and CYP2C9 in vitro. Omeprazole is a time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of coadministered drugs that are CYP2C19 substrates. Omeprazole does not appear to inhibit CYP3A4. In vitro, omeprazole induces CYP1A2. Rifabutin may be expected to have a similar effect on some drugs that are affected by coadministration with rifampin. Rifabutin is an inducer and a substrate of the CYP3A4 isoenzyme. Rifabutin appears to be a less potent hepatic enzyme inducer than rifampin; however, the clinical significance of this finding has not been determined. Unlike with rifampin, acetylation of isoniazid by rifabutin is not affected. The overall potency of rifabutin induction is variable among substrates and rifabutin may alter drug metabolizing enzymes in a dose-dependent manner. Additionally, plasma concentrations at standard doses of rifabutin are lower compared to other rifamycins which may explain the lower induction potential clinically.
-Route-Specific Pharmacokinetics
Oral Route
Omeprazole; amoxicillin; rifabutin is a delayed-release capsule.
Omeprazole: Peak plasma concentrations are achieved 1.25 hours after administration. The Cmax is 1,281 ng/mL and the AUC24 is 7,161 ng x hour/mL. Administration with a high-fat meal decreases the Cmax by 92% and the AUC by 83% while increasing the Tmax by 3 hours relative to fasting. After oral administration, the onset of secretory effect of omeprazole occurs within 1 hour, with the maximum effect occurring within 2 hours. The inhibitory effect of omeprazole on acid secretion increases with repeated daily dosing. Secretory activity returns gradually, over 3 to 5 days, after discontinuation due to prolonged binding to the parietal H+/K+ ATPase enzyme.
Amoxicillin: Peak plasma concentrations are achieved 2 hours after administration. The Cmax is 15,860 ng/mL and the AUC24 is 145,788 ng x hour/mL. Administration with a high-fat meal decreases the Cmax by 30% while increasing the Tmax by 1.5 hours relative to fasting; AUC is not influenced.
Rifabutin: Peak plasma concentrations are achieved 3 hours after administration. The Cmax is 88 ng/mL and the AUC24 is 1,320 ng x hour/mL. Administration with a high-fat meal increases the Cmax by 14% and the AUC by 23% while increasing the Tmax by 2 hours relative to fasting.
-Special Populations
Hepatic Impairment
The pharmacokinetics of amoxicillin and rifabutin in patients with moderate and severe hepatic impairment are not known. In patients with chronic hepatic disease classified as Child-Pugh Class A (n = 3), B (n = 4), and C (n = 1), the bioavailability of omeprazole increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect. The plasma half-life of omeprazole increased to nearly 3 hours compared with the half-life in healthy subjects of 0.5 to 1 hour. Plasma clearance averaged 70 mL/minute, compared to 500 to 600 mL/minute in healthy subjects.
Renal Impairment
For omeprazole, no clinically meaningful change in bioavailability was reported in patients with chronic renal impairment (CrCl 10 to 62 mL/minute/1.73 m2). Amoxicillin is primarily eliminated by the kidney. 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. Rifabutin disposition was studied after a 300 mg dose in 18 patients with varying degrees of renal function. The rifabutin AUC increased by about 41% in patients with mild to moderate renal impairment (CrCl 30 to 61 mL/minute) and by about 71% in patients with severe renal impairment (CrCl less than 30 mL/minute) as compared to patients with a CrCl between 61 and 74 mL/minute.