Lefamulin is a first-in-class oral and injectable pleuromutilin antibiotic indicated for the treatment of community-acquired pneumonia. Lefamulin may maintain activity against some bacterial isolates that may be resistant to other antibiotic classes. Lefamulin may cause QT prolongation, and the oral formulation is contraindicated for use with CYP3A4 substrates that also prolong the QT interval. Based on animal data, lefamulin may cause fetal harm when administered during pregnancy; therefore, effective contraception use is recommended for women of reproductive potential.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-If a dose is missed, administer the dose as soon as possible and anytime up to 8 hours before the next scheduled dose. If less than 8 hours remain before the next scheduled dose, do not administer the missed dose, and resume dosing at the next scheduled dose.
Route-Specific Administration
Oral Administration
-Administer at least 1 hour before a meal or 2 hours after a meal.
Oral Solid Formulations
-Swallow tablet whole with 6 to 8 ounces of water. Do not crush or divide tablets.
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Dilution:
-Dilute the entire 15 mL vial of lefamulin injection into the supplied diluent bag that contains 250 mL of 10 mM citrate buffered 0.9% Sodium Chloride Injection.
-Mix thoroughly.
-Do not use the diluent bag in series connections.
-Do not add other additives to the diluent bag.
-Storage: The diluted solution can be stored up to 24 hours at room temperature and up to 48 hours when refrigerated at 2 to 8 degrees C (36 to 46 degrees F).
Intermittent IV infusion:
-Infuse over 60 minutes.
Elevated hepatic enzymes, including increased AST and ALT, were reported in 2% to 3% of lefamulin-treated patients during clinical trials. Increased alkaline phosphatase and gamma-glutamyl transferase were reported in less than 2% of patients.
QT prolongation, atrial fibrillation, and palpitations were all reported in less than 2% of lefamulin-treated patients during clinical trials.
Gastrointestinal adverse events reported in lefamulin-treated patients during clinical trials include diarrhea (12%), nausea (3% to 5%), and vomiting (3%). Abdominal pain, constipation, dyspepsia, epigastric discomfort, and erosive gastritis were reported in less than 2% of patients.
Laboratory abnormalities reported in lefamulin-treated patients during clinical trials include hypokalemia (3%) and increased creatine phosphokinase (less than 2%).
Central nervous system or psychiatric adverse events reported in lefamulin-treated patients during clinical trials include insomnia (3%), headache (2%), somnolence or drowsiness (less than 2%), and anxiety (less than 2%).
Anemia and thrombocytopenia were reported in less than 2% of lefamulin-treated patients during clinical trials.
Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis (less than 2%) has been reported with lefamulin. 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. Oropharyngeal and vulvovaginal candidiasis have been reported in less than 2% of patients during clinical trials.
Urinary retention was reported in less than 2% of lefamulin-treated patients during clinical trials.
Administration site reactions (7%), including infusion site pain, infusion site phlebitis, and injection site reaction, were reported with intravenous lefamulin during clinical trials.
Lefamulin is contraindicated in patients with known pleuromutilin hypersensitivity or hypersensitivity to lefamulin or any of the components.
Lefamulin may cause QT prolongation. Avoid lefamulin use in patients with known prolongation of the QT interval, patients with ventricular arrhythmias (including torsade de pointes), and in patients receiving other medications known to prolong the QT interval. In patients with hepatic impairment or renal failure who require dialysis, metabolic disturbances may lead to QT prolongation. If lefamulin cannot be avoided in these populations, ECG monitoring is recommended during treatment. The magnitude of QT prolongation may increase with increasing concentrations of lefamulin or increasing rates of infusion of the intravenous formulation; therefore, do not exceed the recommended dose or infusion rate. Use lefamulin with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric adults 65 years of age and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial 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, including lefamulin, 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.
Monitor patients with hepatic disease for adverse reactions associated with lefamulin. Dosage reduction of lefamulin injection is necessary for patients with severe hepatic impairment. Oral lefamulin has not been studied in patients hepatic impairment, and lefamulin tablets are not recommended for use in patients with moderate or severe hepatic impairment. In patients with severe hepatic impairment, metabolic disturbances may lead to QT prolongation; lefamulin may also cause QT prolongation.
There are no available data on the use of lefamulin in human pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women. Animal studies indicate that intravenous administration of lefamulin during organogenesis resulted in increased incidence of prenatal mortality, decreased fetal body weights, apparent delay in sexual maturation, and malformations. Decreased ossification was seen in fetuses at all doses in a dose-related manner. There is a pregnancy pharmacovigilance program for lefamulin. If lefamulin is inadvertently administered during pregnancy or if a patient becomes pregnant while receiving lefamulin, report exposure by calling 1-855-5NABRIVA to enroll.
There are no data on the presence of lefamulin in human milk, its effects on the breast-fed infant, or its effects on milk production. Animal studies indicate that lefamulin was concentrated in the milk of lactating rats. Because of the potential for serious adverse reactions, including QT prolongation, advise a breast-feeding woman to pump and discard human milk for the duration of treatment with lefamulin and for 2 days after the final dose.
Lefamulin may be associated with reproductive risk. Verify pregnancy status in females of reproductive potential with pregnancy testing. Discuss contraception requirements with the patient. Advise females of reproductive potential to use effective contraception during treatment with lefamulin and for 2 days after the final dose.
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: Chlamydophila pneumoniae, Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus (MRSA), Staphylococcus aureus (MSSA), Streptococcus agalactiae (group B streptococci), Streptococcus anginosus, Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci), Streptococcus salivarius
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 the treatment of community-acquired pneumonia:
Oral dosage:
Adults: 600 mg PO every 12 hours for 5 days.
Intravenous dosage:
Adults: 150 mg IV every 12 hours for 5 to 7 days. May switch to oral therapy to complete treatment course.
Maximum Dosage Limits:
-Adults
1,200 mg/day PO and 300 mg/day IV.
-Geriatric
1,200 mg/day PO and 300 mg/day IV.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (Child-Pugh Class A): No dosage adjustment needed.
Moderate hepatic impairment (Child-Pugh Class B): Oral therapy is not recommended. No dosage adjustment needed for intravenous therapy.
Severe hepatic impairment (Child-Pugh Class C): Oral therapy is not recommended. Reduce the intravenous dose to 150 mg IV every 24 hours.
Patients with Renal Impairment Dosing
No dosage adjustment needed, including those on hemodialysis.
*non-FDA-approved indication
Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with oral lefamulin is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Abrocitinib: (Major) Avoid coadministration of abrocitinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; abrocitinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and abrocitinib is a P-gp inhibitor.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with oral lefamulin. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with oral lefamulin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oral lefamulin is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine; an interaction is not expected with intravenous lefamulin.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. An interaction is not expected with intravenous lefamulin. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If oral lefamulin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. If oral lefamulin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like oral lefamulin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone; an interaction is not expected with intravenous lefamulin. If oral lefamulin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid coadministration of adagrasib with lefamulin. Concomitant use may produce additive risk for QT/QTc prolongation and torsade de pointes (TdP) and may increase oral lefamulin exposure. Concentrations of intravenous lefamulin may be less affected. Lefamulin is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of a strong CYP3A inhibitor increased the exposure of oral lefamulin by 165%; the exposure to intravenous lefamulin was increased by 31%.
Albuterol; Budesonide: (Moderate) Avoid coadministration of systemic budesonide with oral lefamulin due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. If oral lefamulin is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. An interaction is not expected with intravenous lefamulin. If oral lefamulin is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Major) Avoid coadministration of lefamulin with alfuzosin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Alfuzosin may prolong the QT interval in a dose-dependent manner.
Alprazolam: (Major) Avoid coadministration of alprazolam and oral lefamulin due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. An interaction is not expected with intravenous lefamulin. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with lefamulin, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and lefamulin is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Amiodarone: (Major) Avoid coadministration of lefamulin with amiodarone as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Amiodarone is a P-gp inhibitor that is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Amisulpride: (Major) Avoid coadministration of lefamulin with amisulpride as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amobarbital: (Major) Avoid coadministration of lefamulin with amobarbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; amobarbital is a moderate CYP3A4 inducer.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of lefamulin with clarithromycin as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Clarithromycin is a P-gp and strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Anagrelide: (Major) Avoid coadministration of lefamulin with anagrelide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
Apalutamide: (Major) Avoid coadministration of lefamulin with apalutamide unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; apalutamide is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Apomorphine: (Major) Avoid coadministration of lefamulin with apomorphine since concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of oral lefamulin and aprepitant/fosaprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Additionally, oral lefamulin exposure and adverse effects may be increased. Aprepitant is a CYP3A4 substrate and moderate inhibitor of CYP3A4 when administered as a 3 day oral regimen; oral lefamulin is a CYP3A4 substrate and moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Administration of a moderate CYP3A4 inhibitor increased the aprepitant AUC by 2-fold.
Aripiprazole: (Major) Concomitant use of aripiprazole and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, monitor for aripiprazole-related adverse reactions during concomitant use of oral lefamulin. Patients receiving both a CYP2D6 inhibitor plus oral lefamulin may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Aripiprazole is CYP3A and CYP2D6 substrate, oral lefamulin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation.
Arsenic Trioxide: (Major) Avoid coadministration of lefamulin with arsenic trioxide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
Artemether; Lumefantrine: (Major) Avoid coadministration of lefamulin with artemether; lumefantrine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Artemether; lumefantrine is associated with prolongation of the QT interval.
Asenapine: (Major) Avoid coadministration of lefamulin with asenapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Asenapine has been associated with QT prolongation.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of lefamulin with butalbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. If oral lefamulin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like oral lefamulin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone; an interaction is not expected with intravenous lefamulin. If oral lefamulin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid coadministration of atazanavir with oral lefamulin due to increased lefamulin exposure; atazanavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir with oral lefamulin due to increased lefamulin exposure; atazanavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively. (Major) Avoid coadministration of cobicistat with oral lefamulin due to increased lefamulin exposure; cobicistat may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Atomoxetine: (Major) Avoid coadministration of lefamulin with atomoxetine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving oral lefamulin. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Avapritinib: (Major) Avoid coadministration of avapritinib with oral lefamulin due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Azithromycin: (Major) Avoid coadministration of azithromycin with lefamulin as concurrent use may increase the risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
Bedaquiline: (Major) Avoid coadministration of lefamulin with bedaquiline as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Bedaquiline prolongs the QT interval.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor patients for respiratory depression and sedation at frequent intervals if benzhydrocodone is administered with lefamulin. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Concurrent use may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Discontinuation of lefamulin in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4; lefamulin is a moderate inhibitor of CYP3A4.
Berotralstat: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with berotralstat as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A substrate; berotralstat is a moderate CYP3A inhibitor.
Bexarotene: (Major) Avoid coadministration of lefamulin with bexarotene unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bosentan: (Major) Avoid coadministration of lefamulin with bosentan unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer.
Bosutinib: (Major) Avoid concomitant use of bosutinib and oral lefamulin as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Brexpiprazole: (Moderate) Use caution if coadministration of oral lefamulin with brexpiprazole is necessary, as the systemic exposure of brexpiprazole may be increased resulting in an increase in brexpiprazole-related adverse reactions. Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and oral lefamulin are coadministered with a moderate to strong inhibitor of CYP2D6 or if the patient is a poor metabolizer of CYP2D6. If oral lefamulin is discontinued, adjust the brexpiprazole dosage to its original level. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Brexpiprazole is a CYP3A4 and CYP2D6 substrate. Concomitant use of moderate CYP3A4 inhibitors with a strong or moderate CYP2D6 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
Brigatinib: (Major) Avoid coadministration of brigatinib with oral lefamulin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of oral lefamulin, resume the brigatinib dose that was tolerated prior to initiation of oral lefamulin. Brigatinib is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of oral lefamulin. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A4 inhibitor increased bromocriptine exposure by 2.8-fold.
Budesonide: (Moderate) Avoid coadministration of systemic budesonide with oral lefamulin due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Budesonide; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with oral lefamulin due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with oral lefamulin due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Buprenorphine: (Major) Avoid coadministration of lefamulin with buprenorphine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Buprenorphine; Naloxone: (Major) Avoid coadministration of lefamulin with buprenorphine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with oral lefamulin is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and oral lefamulin is added or removed from therapy. Buspirone is a sensitive CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with other moderate CYP3A4 inhibitors increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
Butalbital; Acetaminophen: (Major) Avoid coadministration of lefamulin with butalbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of lefamulin with butalbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of lefamulin with butalbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of lefamulin with butalbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Cabotegravir; Rilpivirine: (Major) Avoid coadministration of lefamulin with rilpivirine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Cabozantinib: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with cabozantinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and cabozantinib is a P-gp inhibitor.
Cannabidiol: (Major) Avoid coadministration of cannabidiol with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; cannabidiol may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and cannabidiol is a P-gp inhibitor.
Capivasertib: (Major) Reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off if coadministration with oral lefamulin is necessary; monitor for adverse reactions. Concomitant use may increase capivasertib exposure which may increase the risk for capivasertib-related adverse effects. Capivasertib is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.5-fold.
Capmatinib: (Major) Avoid coadministration of capmatinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; capmatinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and capmatinib is a P-gp inhibitor.
Carbamazepine: (Major) Avoid coadministration of lefamulin with carbamazepine unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; carbamazepine is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Carvedilol: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with carvedilol as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and carvedilol is a P-gp inhibitor.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with oral lefamulin is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of oral lefamulin, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. An interaction is not expected with intravenous lefamulin.
Cenobamate: (Major) Avoid coadministration of lefamulin with cenobamate unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Major) Avoid coadministration of lefamulin with ceritinib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ceritinib is a strong CYP3A4 that can cause concentration-dependent QT prolongation. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Chloramphenicol: (Major) Avoid coadministration of chloramphenicol with oral lefamulin due to increased lefamulin exposure; chloramphenicol may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Chloroquine: (Major) Avoid coadministration of chloroquine with lefamulin due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Lefamulin has a concentration dependent QTc prolongation effect. The potential to prolong the QT interval of the ECG between lefamulin and other drugs that effect cardiac conduction is unknown.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. An interaction is not expected with intravenous lefamulin. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If oral lefamulin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpromazine: (Major) Avoid coadministration of lefamulin with chlorpromazine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with oral lefamulin, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
Ciprofloxacin: (Major) Avoid coadministration of lefamulin with ciprofloxacin as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ciprofloxacin is a moderate CYP3A4 inhibitor that has been associated with rare cases of QT prolongation and torsade de pointes (TdP) in postmarketing surveillance.
Cisapride: (Contraindicated) Coadministration of cisapride with lefamulin is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Citalopram: (Major) Avoid coadministration of lefamulin with citalopram as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Citalopram causes dose-dependent QT interval prolongation.
Clarithromycin: (Major) Avoid coadministration of lefamulin with clarithromycin as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Clarithromycin is a P-gp and strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Clofazimine: (Major) Concomitant use of clofazimine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with oral lefamulin; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Clozapine: (Major) Avoid coadministration of lefamulin with clozapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Cobicistat: (Major) Avoid coadministration of cobicistat with oral lefamulin due to increased lefamulin exposure; cobicistat may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Cobimetinib: (Major) Reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily if concurrent use of oral lefamulin is necessary; after discontinuation of oral lefamulin, resume cobimetinib at the previous dose. Use an alternative to oral lefamulin in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Codeine: (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Codeine; Promethazine: (Major) Concomitant use of promethazine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with oral lefamulin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of oral lefamulin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If oral lefamulin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Colchicine: (Major) Avoid concomitant use of colchicine and oral lefamulin due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Conivaptan: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with conivaptan as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A and P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of oral lefamulin with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
Crizotinib: (Major) Avoid coadministration of lefamulin with crizotinib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG and electrolytes during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Crizotinib is a moderate CYP3A4 that can cause concentration-dependent QT prolongation.
Cyclosporine: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with cyclosporine as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cyclosporine is a P-gp and moderate CYP3A4 inhibitor.
Dabrafenib: (Major) Avoid coadministration of lefamulin with dabrafenib unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer.
Daclatasvir: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with daclatasvir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and daclatasvir is a P-gp inhibitor.
Danazol: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with danazol as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor.
Daridorexant: (Major) Avoid coadministration of daridorexant with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; concomitant use may also increase daridorexant exposure. Daridorexant may be administered with intravenous lefamulin. If concomitant use with oral lefamulin is necessary, limit the daridorexant dose to 25 mg. Lefamulin is a P-gp substrate and oral lefamulin is a moderate CYP3A inhibitor and daridorexant is a CYP3A substrate and P-gp inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darifenacin: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with oral lefamulin. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Darunavir: (Major) Avoid coadministration of darunavir with oral lefamulin due to increased lefamulin exposure; darunavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat with oral lefamulin due to increased lefamulin exposure; cobicistat may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively. (Major) Avoid coadministration of darunavir with oral lefamulin due to increased lefamulin exposure; darunavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat with oral lefamulin due to increased lefamulin exposure; cobicistat may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively. (Major) Avoid coadministration of darunavir with oral lefamulin due to increased lefamulin exposure; darunavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Dasatinib: (Major) Coadministration of lefamulin tablets is contraindicated with dasatinib due to increased dasatinib exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with dasatinib. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Dasatinib is a sensitive CYP3A4 substrate that has the potential to prolong the QT interval. Lefamulin is a CYP3A4 inhibitor that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Deflazacort: (Major) Decrease deflazacort dose to one-third of the recommended dosage when coadministered with oral lefamulin. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Degarelix: (Major) Avoid coadministration of lefamulin with degarelix as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Avoid coadministration of delavirdine with oral lefamulin due to increased lefamulin exposure; delavirdine may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Desflurane: (Major) Avoid coadministration of lefamulin with halogenated anesthetics as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Halogenated anesthetics can prolong the QT interval.
Desogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Deutetrabenazine: (Major) Avoid coadministration of lefamulin with deutetrabenazine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Major) Avoid coadministration of lefamulin with quinidine as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Quinidine is a P-gp inhibitor that is associated with QT prolongation and torsade de pointes (TdP).
Dienogest; Estradiol valerate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Dihydroergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and lefamulin. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor.
Diltiazem: (Moderate) Monitor for lefamulin- or diltiazem-related adverse effects if oral lefamulin is administered with diltiazem as concurrent use may increase exposure from both drugs; an interaction is not expected with intravenous lefamulin. Both drugs are substrates and moderate inhibitors of CYP3A4.
Disopyramide: (Major) Avoid coadministration of lefamulin with disopyramide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP).
Dofetilide: (Major) Avoid coadministration of lefamulin with dofetilide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
Dolasetron: (Major) Avoid coadministration of lefamulin with dolasetron as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Major) Avoid coadministration of lefamulin with rilpivirine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Major) Avoid coadministration of lefamulin with donepezil as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Donepezil; Memantine: (Major) Avoid coadministration of lefamulin with donepezil as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Doxorubicin Liposomal: (Major) Avoid coadministration of oral lefamulin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP3A4 and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of oral lefamulin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP3A4 and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with oral lefamulin. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Dronedarone: (Contraindicated) Coadministration of dronedarone with lefamulin is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Avoid coadministration of lefamulin with droperidol as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Use extreme caution and initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
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: (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: (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: (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.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of oral lefamulin with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. The effects of concomitant administration of a moderate CYP3A4 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 inhibition.
Duvelisib: (Moderate) Monitor for increased toxicity if duvelisib is coadministered with oral lefamulin. Coadministration may increase the exposure of both drugs. Both drugs are CYP3A4 substrates and moderate CYP3A4 inhibitors; an interaction is not expected with intravenous lefamulin.
Efavirenz: (Major) Avoid coadministration of lefamulin with efavirenz as concurrent use may increase the risk of QT prolongation and decrease lefamulin exposure and efficacy. If coadministration cannot be avoided, monitor for decreased efficacy and ECG during treatment. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lefamulin with efavirenz as concurrent use may increase the risk of QT prolongation and decrease lefamulin exposure and efficacy. If coadministration cannot be avoided, monitor for decreased efficacy and ECG during treatment. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lefamulin with efavirenz as concurrent use may increase the risk of QT prolongation and decrease lefamulin exposure and efficacy. If coadministration cannot be avoided, monitor for decreased efficacy and ECG during treatment. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation.
Elacestrant: (Major) Avoid concomitant use of elacestrant and lefamulin due to the risk of increased exposure of both drugs which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and P-gp inhibitor; lefamulin is a P-gp substrate and moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Elagolix: (Major) Avoid coadministration of lefamulin with elagolix unless the benefits outweigh the risks due to unpredictable lefamulin exposure. Lefamulin is a CYP3A4 and P-gp substrate; elagolix is both an inducer of CYP3A4 as well as a P-gp inhibitor. The net effect on lefamulin concentrations is unclear.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of lefamulin with elagolix unless the benefits outweigh the risks due to unpredictable lefamulin exposure. Lefamulin is a CYP3A4 and P-gp substrate; elagolix is both an inducer of CYP3A4 as well as a P-gp inhibitor. The net effect on lefamulin concentrations is unclear. (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.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with oral lefamulin. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with oral lefamulin; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) Avoid coadministration of ivacaftor with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; ivacaftor may be administered with intravenous lefamulin. If lefamulin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Lefamulin is a P-gp substrate and a moderate CYP3A inhibitor, and ivacaftor is a P-gp inhibitor and a CYP3A substrate. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with lefamulin; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; lefamulin is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Eliglustat: (Major) Avoid coadministration of lefamulin with eliglustat as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets and eliglustat which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Concurrent use is contraindicated in EMs and IMs also receiving a strong or moderate CYP2D6 inhibitor. Lefamulin is a moderate CYP3A4 inhibitor and CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Eliglustat is CYP3A4 and CYP2D6 substrate and P-gp inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat with oral lefamulin due to increased lefamulin exposure; cobicistat may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat with oral lefamulin due to increased lefamulin exposure; cobicistat may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of lefamulin with rilpivirine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lefamulin with rilpivirine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Enasidenib: (Major) Avoid coadministration of enasidenib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; enasidenib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and enasidenib is a P-gp inhibitor.
Encorafenib: (Major) Avoid concomitant use of encorafenib and lefamulin due to the risk for decreased lefamulin exposure and efficacy, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use of oral lefamulin is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. An encorafenib dosage reduction is not required with intravenous lefamulin. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Lefamulin is a CYP3A substrate, oral lefamulin is a moderate CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold. Coadministration of a strong CYP3A inducer decreased the mean AUC of lefamulin oral tablets by 72% and the mean AUC of lefamulin injection by 28%.
Entrectinib: (Major) Avoid concomitant use of entrectinib with oral lefamulin due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, oral lefamulin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Enzalutamide: (Major) Avoid coadministration of lefamulin with enzalutamide unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with oral lefamulin in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving oral lefamulin, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating oral lefamulin and periodically thereafter. Eplerenone is a CYP3A4 substrate. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Erdafitinib: (Major) Avoid coadministration of erdafitinib with oral lefamulin as concurrent use may increase lefamulin exposure and adverse effects. If coadministration of erdafitinib with oral lefamulin is unavoidable, separate erdafitinib and lefamulin doses by at least 6 hours. Erdafitinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and erdafitinib is a P-gp inhibitor.
Ergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and lefamulin. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and lefamulin. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor.
Eribulin: (Major) Avoid coadministration of lefamulin with eribulin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Eribulin has been associated with QT prolongation.
Erythromycin: (Major) Avoid coadministration of lefamulin with erythromycin as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Erythromycin is a P-gp and moderate CYP3A4 that is associated with QT prolongation and torsade de pointes (TdP). The effect of moderate inhibitors on lefamulin has not been studied; however, coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Escitalopram: (Major) Avoid coadministration of lefamulin with escitalopram as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP).
Eslicarbazepine: (Major) Avoid coadministration of lefamulin with eslicarbazepine unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer.
Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethinyl Estradiol; Norelgestromin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethinyl Estradiol; Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Etonogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Etrasimod: (Major) Avoid concomitant use of etrasimod and oral lefamulin in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Etrasimod is a CYP2C9 and CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Etravirine: (Major) Avoid coadministration of lefamulin with etravirine unless the benefits outweigh the risks due to unpredictable lefamulin exposure. Lefamulin is a CYP3A4 and P-gp substrate; etravirine is both a moderate inducer of CYP3A4 as well as a P-gp inhibitor. The net effect on lefamulin concentrations is unclear.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with lefamulin is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Lefamulin is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oral lefamulin is necessary. Simvastatin is a sensitive CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin.
Fedratinib: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with fedratinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. The effect of moderate inhibitors on lefamulin has not been studied; however, use of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Felodipine: (Moderate) Concurrent use of felodipine and oral lefamulin should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Concurrent use of another moderate CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. If oral lefamulin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. An interaction is not expected with intravenous lefamulin. If oral lefamulin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fexinidazole: (Major) Concomitant use of fexinidazole and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, monitor for decreased fexinidazole efficacy if coadministration with oral lefamulin is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and oral lefamulin is a moderate CYP3A inhibitor; this inhibition is not expected with intravenous lefamulin.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or oral lefamulin; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Fingolimod: (Major) Avoid coadministration of lefamulin with fingolimod as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Avoid coadministration of lefamulin with flecainide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Flibanserin: (Major) The concomitant use of flibanserin and oral lefamulin is contraindicated due to increased flibanserin exposure, which can result in severe hypotension and syncope. If initiating flibanserin following use of oral lefamulin, start flibanserin at least 2 weeks after the last dose of oral lefamulin. If initiating oral lefamulin following flibanserin use, start oral lefamulin at least 2 days after the last dose of flibanserin. Flibanserin is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Fluconazole: (Major) Avoid coadministration of lefamulin with fluconazole as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Fluconazole is a moderate CYP3A4 that has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Fluoxetine: (Major) Avoid coadministration of lefamulin with fluoxetine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
Fluphenazine: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as lefamulin.
Fluvoxamine: (Major) Avoid coadministration of lefamulin with fluvoxamine as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Fluvoxamine is a moderate CYP3A4 that has been associated with QT prolongation and torsade de pointes (TdP) during postmarketing use.
Fosamprenavir: (Moderate) Monitor for an increase in adverse reactions from both drugs if oral lefamulin is administered with fosamprenavir. Concomitant use may increase the exposure of both drugs. An interaction is not expected with intravenous lefamulin. Lefamulin and fosamprenavir are both CYP3A substrates and moderate CYP3A inhibitors.
Foscarnet: (Major) Avoid coadministration of lefamulin with foscarnet as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
Fosphenytoin: (Major) Avoid coadministration of lefamulin with fosphenytoin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; fosphenytoin is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Fostamatinib: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with fostamatinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and fostamatinib is a P-gp inhibitor.
Fostemsavir: (Major) Avoid coadministration of lefamulin with fostemsavir as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that affect cardiac conduction is unknown. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Futibatinib: (Major) Avoid coadministration of futibatinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; futibatinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and futibatinib is a P-gp inhibitor.
Gemifloxacin: (Major) Avoid coadministration of lefamulin with gemifloxacin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of lefamulin with gemtuzumab as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG and electrolytes prior to and during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Avoid coadministration of lefamulin with gilteritinib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Gilteritinib has been associated with QT prolongation. The concurrent use of gilteritinib with oral lefamulin may increase lefamulin exposure and adverse effects; gilteritinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and gilteritinib is a P-gp inhibitor.
Glasdegib: (Major) Avoid coadministration of lefamulin with glasdegib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with glecaprevir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and glecaprevir is a P-gp inhibitor. (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with pibrentasvir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and pibrentasvir is a P-gp inhibitor.
Goserelin: (Major) Avoid coadministration of lefamulin with goserelin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
Granisetron: (Major) Avoid coadministration of lefamulin with granisetron as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Granisetron has been associated with QT prolongation.
Grapefruit juice: (Major) Advise patients to avoid grapefruit juice or grapefruit-containing foods while taking oral lefamulin due to increased lefamulin exposure; grapefruit juice may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; grapefruit juice is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. An interaction is not expected with intravenous lefamulin. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If oral lefamulin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Halogenated Anesthetics: (Major) Avoid coadministration of lefamulin with halogenated anesthetics as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Halogenated anesthetics can prolong the QT interval.
Haloperidol: (Major) Avoid coadministration of lefamulin with haloperidol as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Major) Avoid coadministration of lefamulin with histrelin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. An interaction is not expected with intravenous lefamulin. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If oral lefamulin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. An interaction is not expected with intravenous lefamulin. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If oral lefamulin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. An interaction is not expected with intravenous lefamulin. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If oral lefamulin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. An interaction is not expected with intravenous lefamulin. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If oral lefamulin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydroxychloroquine: (Major) Avoid coadministration of lefamulin and hydroxychloroquine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Hydroxyzine: (Major) Avoid coadministration of lefamulin with hydroxyzine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
Ibrutinib: (Major) If ibrutinib is coadministered with oral lefamulin, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if oral lefamulin is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. If oral lefamulin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like oral lefamulin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone; an interaction is not expected with intravenous lefamulin. If oral lefamulin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) Avoid coadministration of lefamulin with ibutilide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Major) Avoid coadministration of idelalisib with oral lefamulin due to increased lefamulin exposure; idelalisib may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with oral lefamulin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid coadministration of lefamulin with iloperidone as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Iloperidone has been associated with QT prolongation.
Imatinib: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with imatinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. The effect of moderate inhibitors on lefamulin has not been studied; however, use of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Indinavir: (Major) Avoid coadministration of indinavir with oral lefamulin due to increased lefamulin exposure; indinavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Infigratinib: (Major) Avoid concomitant use of infigratinib and lefamulin. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and lefamulin is a moderate CYP3A4 inhibitor.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of lefamulin with inotuzumab as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG before and during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Inotuzumab has been associated with QT interval prolongation.
Isavuconazonium: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with isavuconazonium as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; isavuconazonium is a P-gp and moderate CYP3A4 inhibitor. The effect of moderate inhibitors on lefamulin has not been studied; however, coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Isoflurane: (Major) Avoid coadministration of lefamulin with halogenated anesthetics as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Halogenated anesthetics can prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of lefamulin with rifampin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; rifampin is a P-gp and strong CYP3A4 inducer. Coadministration of rifampin decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of lefamulin with rifampin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; rifampin is a P-gp and strong CYP3A4 inducer. Coadministration of rifampin decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with oral lefamulin is necessary. Isradipine is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin.
Istradefylline: (Major) Avoid coadministration of istradefylline with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; istradefylline may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and istradefylline is a P-gp inhibitor. Istradefylline administered as 40 mg daily is also a weak CYP3A4 inhibitor.
Itraconazole: (Major) Avoid coadministration of lefamulin with itraconazole as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Itraconazole is a P-gp and strong CYP3A4 inhibitor that is also associated with QT prolongation. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Ivabradine: (Major) Avoid coadministration of ivabradine and oral lefamulin as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4 and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with other moderate CYP3A4 inhibitors increased the AUC of ivabradine by 2- to 3-fold.
Ivacaftor: (Major) Avoid coadministration of ivacaftor with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; ivacaftor may be administered with intravenous lefamulin. If lefamulin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Lefamulin is a P-gp substrate and a moderate CYP3A inhibitor, and ivacaftor is a P-gp inhibitor and a CYP3A substrate. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of lefamulin with ivosidenib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs and electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of oral lefamulin is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and oral lefamulin is a weak CYP3A inhibitor; an interaction is not expected with intravenous lefamulin.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and lefamulin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of lefamulin, further increasing the risk for adverse effects. Lefamulin is a CYP3A4 and P-gp substrate and ketoconazole is a P-gp and strong CYP3A inhibitor. Coadministration of ketoconazole increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of lefamulin with clarithromycin as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Clarithromycin is a P-gp and strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lapatinib: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with lapatinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and lapatinib is a P-gp inhibitor.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with lefamulin is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lasmiditan: (Major) Avoid coadministration of lasmiditan with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; lasmiditan may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with ledipasvir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and ledipasvir is a P-gp inhibitor.
Lemborexant: (Major) Avoid coadministration of lemborexant and lefamulin as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; lefamulin is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Major) Avoid coadministration of lenacapavir with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; lenacapavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A and P-gp substrate and lenacapavir is a moderate CYP3A and P-gp inhibitor.
Lenvatinib: (Major) Avoid coadministration of lefamulin with lenvatinib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Prolongation of the QT interval has been reported with lenvatinib therapy.
Letermovir: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with letermovir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Avoid coadministration in patients also receiving cyclosporine. Lefamulin is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. If the regimen also contains cyclosporine, the inhibitory effect is expected to be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Avoid coadministration of lefamulin with leuprolide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of lefamulin with leuprolide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levofloxacin: (Major) Concomitant use of levofloxacin and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and lefamulin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of lefamulin, further increasing the risk for adverse effects. Lefamulin is a CYP3A4 and P-gp substrate and ketoconazole is a P-gp and strong CYP3A inhibitor. Coadministration of ketoconazole increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
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: (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: (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 Fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Lithium: (Major) Avoid coadministration of lefamulin with lithium as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Lithium has been associated with QT prolongation.
Lofexidine: (Major) Avoid coadministration of lefamulin with lofexidine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Lofexidine also prolongs the QT interval.
Lomitapide: (Major) Concomitant use of oral lefamulin and lomitapide is contraindicated due to increased lomitapide exposure. If treatment with oral lefamulin is unavoidable, lomitapide should be stopped during the course of treatment. Lomitapide is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use based on the 27-fold increase in exposure observed with coadministration of a strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and oral lefamulin is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. An interaction is not expected with intravenous lefamulin. Lonafarnib is a sensitive CYP3A4 substrate and P-gp and strong CYP3A4 inhibitor; oral lefamulin is a CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor.
Loperamide: (Major) Avoid coadministration of lefamulin with loperamide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Major) Avoid coadministration of lefamulin with loperamide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with lefamulin due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. (Major) Avoid coadministration of ritonavir with oral lefamulin due to increased lefamulin exposure; ritonavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and ritonavir is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lorlatinib: (Major) Avoid coadministration of lefamulin with lorlatinib unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Lorlatinib is a moderate CYP3A inducer as well as a P-gp inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of lefamulin oral tablets by 72% and the mean AUC of lefamulin injection by 28%.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oral lefamulin is necessary. Coadministration may increase the exposure of lovastatin. Lovastatin is a sensitive substrate of CYP3A4 and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ivacaftor with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; ivacaftor may be administered with intravenous lefamulin. If lefamulin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Lefamulin is a P-gp substrate and a moderate CYP3A inhibitor, and ivacaftor is a P-gp inhibitor and a CYP3A substrate. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Avoid coadministration of lefamulin with lumacaftor; ivacaftor unless the benefits outweigh the risks due to unpredictable lefamulin exposure. Lefamulin is a CYP3A4 and P-gp substrate; lumacaftor; ivacaftor is both a strong inducer of CYP3A4 as well as a P-gp inhibitor and inducer. The net effect on lefamulin concentrations is unclear.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lefamulin with lumacaftor; ivacaftor unless the benefits outweigh the risks due to unpredictable lefamulin exposure. Lefamulin is a CYP3A4 and P-gp substrate; lumacaftor; ivacaftor is both a strong inducer of CYP3A4 as well as a P-gp inhibitor and inducer. The net effect on lefamulin concentrations is unclear.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of oral lefamulin is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; lefamulin is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Major) The recommended starting dose of lurasidone is 20 mg daily (maximum, 80 mg daily) if coadministration with oral lefamulin is necessary. Reduce the lurasidone dose to half of its original dose level if oral lefamulin is added to existing lurasidone therapy. Lurasidone is a sensitive CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A4 inhibitor increased lurasidone exposure by 116%.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and lefamulen due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. Lurbinectedin is a CYP3A substrate and lefamulen is a moderate CYP3A inhibitor.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as macimorelin. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Maprotiline: (Major) Avoid coadministration of lefamulin with maprotiline as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Maribavir: (Major) Avoid coadministration of maribavir with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; maribavir may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and maribavir is a P-gp inhibitor.
Mavacamten: (Major) Avoid coadministration of lefamulin with mavacamten unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. 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 lefamulin therapy. Avoid initiation of lefamulin 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 lefamulin therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP3A substrate and moderate CYP3A inducer and lefamulin is a CYP3A substrate and moderate CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Medroxyprogesterone: (Moderate) Use caution if coadministration of oral lefamulin with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
Mefloquine: (Major) Avoid coadministration of lefamulin with mefloquine as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Mefloquine is a P-gp inhibitor. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
Meropenem: (Major) Avoid coadministration of lefamulin with meropenem unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a P-gp substrate; meropenem is a P-gp inducer. Coadministration of a combined P-gp and strong CYP3A inducer decreased the mean AUC of lefamulin oral tablets by 72% and the mean AUC of lefamulin injection by 28%.
Meropenem; Vaborbactam: (Major) Avoid coadministration of lefamulin with meropenem unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a P-gp substrate; meropenem is a P-gp inducer. Coadministration of a combined P-gp and strong CYP3A inducer decreased the mean AUC of lefamulin oral tablets by 72% and the mean AUC of lefamulin injection by 28%.
Methadone: (Major) Avoid coadministration of lefamulin with methadone as concurrent use may increase the risk of QT prolongation; use of oral lefamulin may increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If coadministration cannot be avoided, monitor ECG during treatment. Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. Lefamulin has a concentration dependent QTc prolongation effect; oral lefamulin is a moderate CYP3A4 inhibitor. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Methadone is a CYP3A4 substrate considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Methohexital: (Major) Avoid coadministration of lefamulin with methohexital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; methohexital is a moderate CYP3A4 inducer.
Methylergonovine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of methylergonovine and oral lefamulin. Concomitant use may increase methylergonovine exposure. Methylergonovine is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor.
Metronidazole: (Major) Concomitant use of metronidazole and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Moderate) Monitor for signs of midazolam toxicity during coadministration with oral lefamulin. In drug interaction studies, coadministration of oral lefamulin and midazolam increased the AUC of midazolam by 200%. No clinically significant differences in midazolam pharmacokinetics were observed when midazolam was administered with lefamulin injection. Oral lefamulin is a moderate CYP3A inhibitor and midazolam is a sensitive CYP3A substrate.
Midostaurin: (Major) Coadministration of lefamulin tablets is contraindicated with midostaurin due to increased midostaurin exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with midostaurin. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Midostaurin is a sensitive CYP3A4 substrate that has been associated with QT prolongation in clinical trials. Lefamulin is a CYP3A4 inhibitor that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Mifepristone: (Major) Avoid coadministration of lefamulin with mifepristone as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Mifepristone is a P-gp and strong CYP3A4 inhibitor that is also associated with QT prolongation. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Mirtazapine: (Major) Concomitant use of lefamulin and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mitapivat: (Major) Avoid coadministration of mitapivat with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects. Do not exceed mitapivat 20 mg PO twice daily during coadministration with lefamulin and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Lefamulin is a P-gp substrate and a moderate CYP3A inhibitor and mitapivat is a CYP3A substrate and P-gp inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mitotane: (Major) Avoid coadministration of lefamulin with mitotane unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and lefamulin; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Modafinil: (Major) Avoid coadministration of lefamulin with modafinil unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer.
Moxifloxacin: (Major) Avoid coadministration of lefamulin with moxifloxacin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Nafcillin: (Major) Avoid coadministration of lefamulin with nafcillin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer.
Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with oral lefamulin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and oral lefamulin due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with oral lefamulin is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of lefamulin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor.
Nefazodone: (Major) Avoid coadministration of nefazodone with oral lefamulin due to increased lefamulin exposure; nefazodone may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Nelfinavir: (Major) Avoid coadministration of nelfinavir with oral lefamulin due to increased lefamulin exposure; nelfinavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; nelfinavir is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Neratinib: (Major) Avoid coadministration of neratinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; neratinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and neratinib is a P-gp inhibitor.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with netupitant as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. The effect of moderate inhibitors on lefamulin has not been studied; however, use of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
NIFEdipine: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with oral lefamulin as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Nilotinib: (Major) Avoid coadministration of lefamulin with nilotinib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Nilotinib is a moderate CYP3A4 inhibitor that has been associated with sudden death and QT interval prolongation in patients who received therapy.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with oral lefamulin is necessary. Nimodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of ritonavir with oral lefamulin due to increased lefamulin exposure; ritonavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and ritonavir is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and oral lefamulin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase exposure from oral lefamulin tablets and the risk for lefamulin-related adverse effects. An interaction is not expected with intravenous lefamulin. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; oral lefamulin is a CYP3A substrate and moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with oral lefamulin due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and oral lefamulin is a CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
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: (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: (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.
Norgestimate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
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.
Ofloxacin: (Major) Concomitant use of ofloxacin and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Avoid coadministration of lefamulin with olanzapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of lefamulin with fluoxetine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of lefamulin with olanzapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Major) Avoid coadministration of lefamulin with olanzapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olaparib: (Major) Avoid coadministration of olaparib with oral lefamulin due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after lefamulin is discontinued. Olaparib is a CYP3A substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Concomitant use may increase olaparib exposure. Coadministration with another moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and oral lefamulin is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and oral lefamulin may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If oral lefamulin is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with IV lefamulin.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and lefamulin. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Omeprazole; Amoxicillin; Rifabutin: (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.
Ondansetron: (Major) Concomitant use of ondansetron and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Osilodrostat: (Major) Avoid coadministration of lefamulin with osilodrostat as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of lefamulin with osimertinib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG and electrolytes during treatment; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Osimertinib is a P-gp inhibitor that has been associated with concentration-dependent QTc prolongation.
Oxaliplatin: (Major) Avoid coadministration of lefamulin with oxaliplatin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs and electrolytes during treatment; correct electrolyte abnormalities prior to administration of oxaliplatin. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation and ventricular arrhythmias, including fatal torsade de pointes, have been reported with oxaliplatin use in postmarketing experience.
Oxybutynin: (Minor) Monitor for oxybutynin-related adverse reactions if coadministration with oral lefamulin is necessary. Oxybutynin is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. Concomitant use with moderate CYP3A4 inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. If oral lefamulin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like oral lefamulin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone; an interaction is not expected with intravenous lefamulin. If oral lefamulin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) Avoid coadministration of lefamulin with ozanimod as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with torsade de pointes in patients with bradycardia.
Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with oral lefamulin is necessary. Coadministration may increase the exposure of paclitaxel. Paclitaxel is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Pacritinib: (Major) Avoid concurrent use of pacritinib with lefamulin due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Lefamulin exposure may also increase in patients taking the oral dosage form, increasing the risk of adverse reactions; lefamulin exposure should not increase if pacritinib is given with the IV formulation. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and P-gp inhibitor; lefamulin is a moderate CYP3A inhibitor and a P-gp substrate.
Paliperidone: (Major) Avoid coadministration of lefamulin with paliperidone as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Palovarotene: (Major) Avoid concomitant use of palovarotene and oral lefamulin due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Panobinostat: (Major) Avoid coadministration of lefamulin with panobinostat as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation has been reported with panobinostat.
Pasireotide: (Major) Avoid coadministration of lefamulin with pasireotide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of lefamulin with pazopanib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Pazopanib has been reported to prolong the QT interval.
Pentamidine: (Major) Avoid coadministration of lefamulin with pentamidine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Systemic pentamidine has been associated with QT prolongation.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Perphenazine: (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as lefamulin.
Perphenazine; Amitriptyline: (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as lefamulin.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and lefamulin due to the risk of increased pexidartinib exposure and decreased lefamulin exposure. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If lefamulin is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of lefamulin. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; lefamulin is a CYP3A substrate and moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenobarbital: (Major) Avoid coadministration of lefamulin with phenobarbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; phenobarbital is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of lefamulin with phenobarbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; phenobarbital is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Phenytoin: (Major) Avoid coadministration of lefamulin with phenytoin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; phenytoin is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Pimavanserin: (Major) Avoid coadministration of lefamulin with pimavanserin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Pimavanserin also prolongs the QT interval.
Pimozide: (Contraindicated) Coadministration of pimozide with lefamulin is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Pimozide is associated with a well-established risk of QT prolongation and TdP. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Pirtobrutinib: (Major) Avoid coadministration of pirtobrutinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; pirtobrutinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and pirtobrutinib is a P-gp inhibitor.
Pitolisant: (Major) Avoid coadministration of lefamulin with pitolisant as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Pitolisant prolongs the QT interval.
Ponesimod: (Major) Avoid coadministration of lefamulin with ponesimod as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with torsade de pointes in patients with bradycardia.
Posaconazole: (Major) Avoid coadministration of lefamulin with posaconazole as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Posaconazole is a P-gp and strong CYP3A4 that has been associated with prolongation of the QT interval. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Pralsetinib: (Major) Avoid concomitant use of oral lefamulin with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with injectable forms of lefamulin. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 71%.
Pretomanid: (Major) Avoid coadministration of pretomanid with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; pretomanid may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and pretomanid is a P-gp inhibitor.
Primaquine: (Major) Avoid coadministration of lefamulin with primaquine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Primaquine has also been associated with QT interval prolongation.
Primidone: (Major) Avoid coadministration of lefamulin with primidone unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; primidone is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and oral lefamulin due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Procainamide: (Major) Avoid coadministration of lefamulin with procainamide as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Prochlorperazine: (Minor) Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as lefamulin.
Promethazine: (Major) Concomitant use of promethazine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Avoid coadministration of lefamulin with propafenone as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Propafenone is a P-gp inhibitor that increases the QT interval, but largely due to prolongation of the QRS interval.
Quetiapine: (Major) Coadministration of lefamulin tablets is contraindicated with quetiapine due to increased quetiapine exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with quetiapine. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Quetiapine is a sensitive CYP3A4 substrate that may be associated with a significant prolongation of the QTc interval in rare instances. Lefamulin is a CYP3A4 inhibitor that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Quinidine: (Major) Avoid coadministration of lefamulin with quinidine as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Quinidine is a P-gp inhibitor that is associated with QT prolongation and torsade de pointes (TdP).
Quinine: (Major) Avoid coadministration of lefamulin with quinine as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Quinine is a P-gp and moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Quizartinib: (Major) Concomitant use of quizartinib and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with oral lefamulin is necessary. Coadministration may increase the exposure of ranolazine. Additionally, monitor for lefamulin-related adverse effects as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Ranolazine is a CYP3A4 substrate and P-gp inhibitor and oral lefamulin is CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased plasma levels of ranolazine by 50% to 130%.
Relugolix: (Major) Avoid coadministration of lefamulin with relugolix as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that affect cardiac conduction is unknown. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of lefamulin with relugolix as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that affect cardiac conduction is unknown. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Repotrectinib: (Major) Avoid coadministration of lefamulin with repotrectinib as concurrent use may decrease lefamulin exposure and efficacy. Oral lefamulin may also increase repotrectinib exposure and the risk for repotrectinib-related adverse effects. Lefamulin is a CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor; repotrectinib is a CYP3A substrate and moderate CYP3A inducer.
Ribociclib: (Major) Avoid coadministration of lefamulin with ribociclib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Ribociclib; Letrozole: (Major) Avoid coadministration of lefamulin with ribociclib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Rifabutin: (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.
Rifampin: (Major) Avoid coadministration of lefamulin with rifampin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; rifampin is a P-gp and strong CYP3A4 inducer. Coadministration of rifampin decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Rifapentine: (Major) Avoid coadministration of lefamulin with rifapentine unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the mean AUC of lefamulin oral tablets by 72% and the mean AUC of lefamulin injection by 28%.
Rilpivirine: (Major) Avoid coadministration of lefamulin with rilpivirine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with oral lefamulin; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor. An interaction is not expected with intravenous lefamulin.
Risperidone: (Major) Avoid coadministration of lefamulin with risperidone as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
Ritlecitinib: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with ritlecitinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A substrate; ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Major) Avoid coadministration of ritonavir with oral lefamulin due to increased lefamulin exposure; ritonavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and ritonavir is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with oral lefamulin is necessary; carefully weigh the risks and benefits of treatment. Roflumilast is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
Romidepsin: (Major) Avoid coadministration of lefamulin with romidepsin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs and electrolytes at baseline and periodically during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Romidepsin has been reported to prolong the QT interval.
Saquinavir: (Major) Coadministration of lefamulin tablets is contraindicated with saquinavir due to increased saquinavir exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with saquinavir. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Saquinavir is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor that is associated with concentration-dependent QT prolongation, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Lefamulin is a CYP3A4 substrate and CYP3A4 inhibitor that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Sarecycline: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with sarecycline as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and sarecycline is a P-gp inhibitor.
Secobarbital: (Major) Avoid coadministration of lefamulin with secobarbital unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; secobarbital is a moderate CYP3A4 inducer.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Selpercatinib: (Major) Avoid coadministration of lefamulin with selpercatinib as concurrent use may increase the risk of QT prolongation; concurrent use of oral lefamulin may also increase exposure from selpercatinib which may increase the risk of adverse effects; an interaction is not expected with intravenous lefamulin. If coadministration of oral lefamulin is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If oral lefamulin is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of lefamulin. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; lefamulin is a moderate CYP3A4 inhibitor that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Additionally, coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and oral lefamulin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If oral lefamulin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of oral lefamulin. Selumetinib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor. An interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Sertraline: (Major) Concomitant use of sertraline and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Avoid coadministration of lefamulin with halogenated anesthetics as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Halogenated anesthetics can prolong the QT interval.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with oral lefamulin is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
Silodosin: (Moderate) Monitor for silodosin-related adverse reactions if coadministration with oral lefamulin is necessary. Silodosin is a substrate of CYP3A4. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. The effect of moderate CYP3A4 inhibitors has not been evaluated; however, plasma concentrations of silodosin may increase based on its interaction with strong CYP3A4 inhibitors.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oral lefamulin is necessary. Simvastatin is a sensitive CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin.
Siponimod: (Major) Avoid coadministration of lefamulin with siponimod as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lefamulin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of taurursodiol with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; taurursodiol may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and taurursodiol is a P-gp inhibitor.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with velpatasvir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and velpatasvir is a P-gp inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with velpatasvir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and velpatasvir is a P-gp inhibitor. (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with voxilaprevir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and voxilaprevir is a P-gp inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Solifenacin: (Major) Avoid coadministration of lefamulin with solifenacin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and oral lefamulin; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sorafenib: (Major) Avoid coadministration of sorafenib with lefamulin due to the risk of additive QT prolongation. The risk of lefamulin-related adverse reactions may also increase if lefamulin is administered orally; an interaction is not expected with intravenous lefamulin. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is a P-glycoprotein (P-gp) inhibitor that is associated with QTc prolongation. Lefamulin is a P-gp substrate has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Sotalol: (Major) Concomitant use of sotalol and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Major) Avoid coadministration of lefamulin with sotorasib unless the benefits outweigh the risks as concurrent use may alter lefamulin exposure, which may lead to increased toxicity or decreased efficacy. Lefamulin is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Sparsentan: (Major) Avoid coadministration of sparsentan with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; sparsentan may be administered with intravenous lefamulin. Additionally, monitor for an increase in sparsentan-related adverse effects as concomitant use may also increase sparsentan exposure. Lefamulin is a P-gp substrate and moderate CYP3A inhibitor and sparsentan is a CYP3A substrate and P-gp inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of lefamulin with St. John's Wort unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; St. John's Wort is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Stiripentol: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with stiripentol as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and stiripentol is a P-gp inhibitor.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if oral lefamulin must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. If oral lefamulin is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong/moderate/weak CYP3A4 inhibitor like oral lefamulin can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil; an interaction is not expected with intravenous lefamulin. If oral lefamulin is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Major) Avoid coadministration of lefamulin with sunitinib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Sunitinib can prolong the QT interval.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with oral lefamulin. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
Tacrolimus: (Major) Coadministration of lefamulin tablets is contraindicated with tacrolimus due to increased tacrolimus exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with tacrolimus. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Tacrolimus is a sensitive CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Lefamulin is a CYP3A4 inhibitor that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Tamoxifen: (Major) Concomitant use of tamoxifen and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tamsulosin: (Moderate) Use caution if coadministration of oral lefamulin with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. The effects of concomitant administration of a moderate CYP3A4 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 inhibition.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with oral lefamulin as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If lefamulin is discontinued, wait at least 3 half-lives of lefamulin before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Major) Avoid coadministration of lefamulin with telavancin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Telavancin has been associated with QT prolongation.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Temsirolimus: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with temsirolimus as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and temsirolimus is a P-gp inhibitor.
Tepotinib: (Major) Avoid coadministration of tepotinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; tepotinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and tepotinib is a P-gp inhibitor.
Tetrabenazine: (Major) Avoid coadministration of lefamulin with tetrabenazine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with oral lefamulin; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) Avoid coadministration of ivacaftor with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; ivacaftor may be administered with intravenous lefamulin. If lefamulin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Lefamulin is a P-gp substrate and a moderate CYP3A inhibitor, and ivacaftor is a P-gp inhibitor and a CYP3A substrate. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Thioridazine: (Contraindicated) Coadministration of thioridazine with lefamulin is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Thioridazine is associated with a well-established risk of QT prolongation and TdP. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Ticagrelor: (Moderate) Monitor for increased bleeding and lefamulin-related adverse effects if oral lefamulin is administered with ticagrelor as concurrent use may increase exposure from both drugs; an interaction is not expected with intravenous lefamulin. Ticagrelor is a sensitive substrate of CYP3A and a P-gp inhibitor; lefamulin is a CYP3A4 and P-gp substrate and CYP3A4 moderate inhibitor.
Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with oral lefamulin is necessary. Concurrent use may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma concentrations of tinidazole. Tinidazole is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin.
Tipranavir: (Major) Avoid coadministration of lefamulin with tipranavir/ritonavir due to unpredictable lefamulin exposure. Lefamulin is a CYP3A4 and P-gp substrate; tipranavir boosted with ritonavir is both a strong inhibitor of CYP3A4 and P-gp inducer. The net effect on lefamulin concentrations is unclear.
Tolterodine: (Major) Avoid coadministration of lefamulin with tolterodine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Tolvaptan: (Major) Avoid coadministration of oral lefamulin when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with oral lefamulin. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Toremifene: (Major) Avoid coadministration of lefamulin with toremifene as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs and electrolytes during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with oral lefamulin is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of oral lefamulin, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. An interaction is not expected with intravenous lefamulin.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with oral lefamulin is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of oral lefamulin, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. An interaction is not expected with intravenous lefamulin.
Trandolapril; Verapamil: (Moderate) Monitor for increased toxicity of verapamil as well as lefamulin-related adverse effects if oral lefamulin is administered with verapamil as concurrent use may increase exposure from both drugs; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor; verapamil is a CYP3A4 substrate and P-gp and moderate CYP3A4 inhibitor.
Trazodone: (Major) Concomitant use of trazodone and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with oral lefamulin and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and oral lefamulin is a moderate CYP3A inhibitor. An interaction is not expected with intravenous lefamulin.
Triclabendazole: (Major) Concomitant use of triclabendazole and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as lefamulin.
Triptorelin: (Major) Avoid coadministration of lefamulin with triptorelin as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Tucatinib: (Major) Avoid coadministration of tucatinib with oral lefamulin due to increased lefamulin exposure; tucatinib may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral lefamulin by 165%; the exposure to intravenous lefamulin was increased by 31%.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with oral lefamulin. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate, and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Vandetanib: (Major) Avoid coadministration of vandetanib with lefamulin due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Vardenafil: (Major) Coadministration of lefamulin tablets is contraindicated with vardenafil due to increased vardenafil exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with vardenafil; however, if coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Vardenafil is a primary CYP3A4 substrate that is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. Lefamulin is a moderate CYP3A4 inhibitor that has a concentration-dependent QTc prolongation effect. Coadministration of vardenafil with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
Vemurafenib: (Major) Avoid coadministration of lefamulin with vemurafenib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Vemurafenib is a P-gp inhibitor that has been associated with QT prolongation.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with oral lefamulin due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of oral lefamulin. Venetoclax is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Venlafaxine: (Major) Concomitant use of venlafaxine and lefamulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Moderate) Monitor for increased toxicity of verapamil as well as lefamulin-related adverse effects if oral lefamulin is administered with verapamil as concurrent use may increase exposure from both drugs; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor; verapamil is a CYP3A4 substrate and P-gp and moderate CYP3A4 inhibitor.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with oral lefamulin is necessary. Vinblastine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with oral lefamulin is necessary. Vinorelbine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and oral lefamulin is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Voclosporin exposure and the risk for voclosporin-related adverse effects may also be increased. Avoid use of lefamulin injection with voclosporin. If concurrent use of lefamulin injection is necessary, monitor ECG and reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening. Voclosporin is a sensitive CYP3A4 substrate and P-gp inhibitor that is associated with QT prolongation at supratherapeutic doses. Oral lefamulin is a P-gp substrate and moderate CYP3A4 inhibitor that is associated with concentration dependent QTc prolongation. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of lefamulin with clarithromycin as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Clarithromycin is a P-gp and strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Voriconazole: (Major) Avoid coadministration of lefamulin with voriconazole as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Voriconazole is a strong CYP3A inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Vorinostat: (Major) Avoid coadministration of lefamulin with vorinostat as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Vorinostat therapy is associated with a risk of QT prolongation.
Voxelotor: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with voxelotor as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A substrate; voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with lefamulin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Lefamulin is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with oral lefamulin. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of oral lefamulin, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Ziprasidone: (Major) Avoid coadministration of lefamulin with ziprasidone as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
Zolpidem: (Moderate) Monitor for an increase in zolpidem-related adverse reactions, including excess sedation, if coadministration with oral lefamulin is necessary. A dose reduction of zolpidem may be necessary. Zolpidem is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during coadministration with some potent inhibitors of CYP3A4.
Zonisamide: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with zonisamide as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and zonisamide is a P-gp inhibitor.
Lefamulin is a systemic pleuromutilin antibacterial that may be bacteriostatic or bactericidal depending upon the organism. It inhibits bacterial protein synthesis through interactions (i.e., hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P-sites of the peptidyl transferase center (PTC) in domain V of the 23s rRNA of the 50S subunit. The binding pocket of the bacterial ribosome closes around the mutilin core for an induced fit that prevents correct positioning of tRNA.
The 24-hour free-drug AUC to minimal inhibitory concentration ratio (AUC/MIC) has been shown to be the best pharmacokinetic-pharmacodynamic (PK-PD) index for antibacterial activity of lefamulin in animal models.
The susceptibility interpretive criteria for lefamulin are delineated by pathogen. The MICs are defined for S. aureus as susceptible at 0.25 mcg/mL or less. The Clinical and Laboratory Standards Institute (CLSI) and the FDA differ on which isolates are included in MIC interpretation. The CLSI includes methicillin-resistant S. aureus; however, the FDA includes only methicillin-susceptible isolates. The MICs are defined for S. pneumoniae as susceptible at 0.5 mcg/mL or less. The MICs are defined for H. influenzae as susceptible at 2 mcg/mL or less. Susceptibility breakpoints are based on a dosage regimen of 150 mg IV every 12 hours or 600 mg PO every 12 hours and are not routinely reported on urinary isolates.
Resistance mechanisms that affect lefamulin include specific protection or modification of the ribosomal target by ABC-F proteins such as vga (A, B, E), lsa(E), sal(A), Cfr methyl transferase, or by mutations of ribosomal proteins L3 and L4. Cfr methyl transferase has the potential to mediate cross-resistance between lefamulin and phenicols, lincosamides, oxazolidinones, and streptogramin A antibacterials. Some isolates resistant to beta-lactams, glycopeptides, macrolides, mupirocin, quinolones, tetracyclines, and sulfamethoxazole; trimethoprim may be susceptible to lefamulin. Synergy has been demonstrated in vitro with doxycycline against S. aureus.
Lefamulin is administered orally and intravenously. The mean plasma protein binding ranges from 94.8% to 97.1% in healthy adults. The mean steady-state volume of distribution is 86.1 L (34.2 to 153 L) in patients with pneumonia after IV administration. After a single lefamulin 150 mg IV dose to healthy adults, the mean lefamulin epithelial lining fluid (ELF) concentration and plasma AUC0-8 were 3.87 mcg x hour/mL and 5.27 mcg x hour/mL, respectively, with the estimated ratio of ELF AUC to unbound plasma approximating 15.
The mean total body clearance of lefamulin is 11.9 L/hour (2.94 to 30 L/hour) in patients with pneumonia after IV administration. Lefamulin is primarily metabolized by CYP3A4. In healthy adults, the mean percent of total radioactivity excreted in the urine was 15.5% (9.6% to 14.1% unchanged) after intravenous dosing and 5.3% (unchanged not determined) after oral dosing. The mean percent of total radioactivity excreted in the feces was 77.3% (4.2% to 9.1% unchanged) after intravenous dosing and 88.5% (7.8% to 24.8% unchanged) after oral dosing. The mean elimination half-life is approximately 8 hours (3 to 20 hours) in patients with pneumonia.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C8, CYP3A4, BCRP, MATE1, P-gp
Lefamulin is a CYP3A4 and P-glycoprotein (P-gp) substrate. Lefamulin inhibits CYP2C8, Breast Cancer Resistance Protein (BCRP), and MATE1 in vitro.
-Route-Specific Pharmacokinetics
Oral Route
The mean oral bioavailability of lefamulin is approximately 25%, and peak plasma concentrations occur 0.88 to 2 hours after administration to healthy adults. After single-dose oral administration, the AUC of lefamulin increased more than dose proportionally over a dose range of 500 to 750 mg. The mean AUC and Cmax in patients with pneumonia were 73% and 30% higher, respectively, compared to healthy adults. In patients with pneumonia receiving lefamulin 600 mg PO every 12 hours under fasting conditions, the steady-state Cmax was 2.24 mcg/mL and the steady-state AUC was 32.7 mcg x hour/mL. Concomitant administration of a single oral lefamulin dose with a high fat, high-calorie breakfast slightly reduced bioavailability. The mean relative reduction was on average 22.9% for the Cmax and 18.43% for the AUC.
Intravenous Route
After single-dose IV administration, the AUC of lefamulin increased approximately dose-proportionally while the Cmax increased less than dose-proportionally over a dose range of 25 to 400 mg. The mean AUC and Cmax in patients with pneumonia were 73% and 30% higher, respectively, compared to healthy adults. In patients with pneumonia receiving lefamulin 150 mg IV every 12 hours, the steady-state Cmax was 3.6 mcg/mL and the steady-state AUC was 28.6 mcg x hour/mL.
-Special Populations
Hepatic Impairment
After intravenous administration, the half-life of lefamulin is prolonged (17.5 hours vs. 11.5 hours) in patients with severe hepatic impairment compared to subjects with normal hepatic function. Protein binding is also reduced in patients with hepatic impairment; therefore, unbound (biologically active) lefamulin concentrations increase with the degree of hepatic impairment. On average, unbound lefamulin plasma AUC was increased 3-fold in patients with severe hepatic impairment compared to subjects with normal hepatic function. There is no information to evaluate the effect of hepatic impairment on the disposition of lefamulin after oral administration.
Renal Impairment
No clinically significant differences in the pharmacokinetics of lefamulin were observed based on renal impairment, including patients receiving hemodialysis.
Geriatric
No clinically significant differences in the pharmacokinetics of lefamulin were observed based on age.
Gender Differences
No clinically significant differences in the pharmacokinetics of lefamulin were observed based on gender.
Ethnic Differences
No clinically significant differences in the pharmacokinetics of lefamulin were observed based on race.
Obesity
No clinically significant differences in the pharmacokinetics of lefamulin were observed based on weight.