Bedaquiline is a diarylquinoline antimycobacterial that is used in the treatment of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis infection (XDR-TB). It is FDA-approved for adults and pediatric patients as young as 5 years weighing at least 15 kg; however, it is used off-label in pediatric patients as young infants. It is not indicated for monotherapy and should only be used in combination with at least 3 other drugs proven to be or at least 4 other drugs suspected of being active against the patient's Mycobacterium tuberculosis isolate. Approval was based on the results of clinical trials comparing bedaquiline plus other MDR-TB active drugs with placebo plus MDR-TB active drugs. In clinical trials, the bedaquiline treatment groups experienced decreased time to culture conversion and improved culture conversion rates when compared to the placebo treatment groups. However, despite its efficacy, it should only be used when other treatment options are unavailable because, in 1 trial in adult patients, more deaths occurred in the bedaquiline treatment group (9/79, 11.4%) than in the placebo treatment group (2/81, 2.5%). According to the FDA-approved labeling, data could not explain the increased risk of death. A Black Box Warning has been issued to alert health care providers of these data and of the potential for QT prolongation.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Administer by directly observed therapy (DOT).
-Emphasize the need for compliance with the full course of therapy to patients.
When used for pulmonary multidrug-resistant tuberculosis infection (MDR-TB) as part of a combination regimen when other effective treatment regimens are not available:
-Administer in combination with at least 3 other drugs proven to be or 4 other drugs suspected of being active against the patient's Mycobacterium tuberculosis isolate.
-If a dose is missed during the first 2 weeks of treatment, instruct the patient not to make up the missed dose but to continue with the usual dosing schedule. If a dose is missed during treatment weeks 3 through 24, the patient should take the missed dose as soon as possible and then resume the 3 times weekly regimen.
-Make sure there is at least 24 hours between taking the missed dose and the next scheduled dose. Do not take more than the prescribed weekly dose in a 7-day period.
When used for pulmonary extensively drug-resistant tuberculosis infection (XDR-TB) or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis infection (MDR-TB) as part of a combination regimen with linezolid and pretomanid:
-If the combination regimen is interrupted by a healthcare provider for safety reasons, missed doses can be made up at the end of treatment; do not make up doses of linezolid alone missed due to linezolid adverse reactions.
-If pretomanid or bedaquiline is discontinued, discontinue the entire combination regimen. If linezolid is permanently discontinued during the initial 4 consecutive weeks of treatment, discontinue the entire combination regimen. If linezolid is discontinued after the initial 4 weeks of consecutive treatment, continue pretomanid and bedaquiline therapy.
Route-Specific Administration
Oral Administration
-Administer with food.
-When using a 3 times weekly regimen, allow at least 48 hours between doses.
Oral Solid Formulations
100 mg tablet
-Swallow tablet whole with water.
20 mg tablet
Intact tablets
-Administer the tablet(s) whole or divided in half along the functional score line into two equal halves of 10 mg each.
-Administer with water.
Dispersed in water and administered with a beverage or soft food
-Disperse tablets in water (maximum of 5 tablets in 5 mL of water) in a drinking cup.
-Mix the contents of the cup well until the tablets are completely dispersed. Either administer the contents of the cup immediately or further mix the contents of the cup.
-To aid with administration, the dispersed mixture in water can be further mixed with at least 5 mL of a beverage (e.g., water, milk products, apple juice, orange juice, cranberry juice, or carbonated beverage) or soft food (e.g., yogurt, applesauce, mashed banana, or porridge) and then orally administer the contents of the cup immediately.
-If the dose requires more than 5 tablets, repeat the above preparation steps with the appropriate number of additional tablets until the desired dose is reached.
-Ensure no tablet residue is left in the cup.
-Rinse with a beverage or add more soft food and orally administer the contents of the cup immediately.
Crushed and mixed with soft food
-Tablets can be crushed and mixed with soft food (e.g., yogurt, applesauce, mashed banana, or porridge) immediately before use and administered.
-Ensure no tablet residue is left in the cup.
-Add more soft food and orally administer the contents of the cup immediately.
Administration through a feeding tube (8 French or more)
-Disperse 5 tablets or less in 50 mL of non-carbonated water and mix well.
-The mixture should be white to almost white with visible particles expected.
-Administer through the feeding tube immediately.
-Repeat with additional tablets until the desired dose is reached.
-Rinse and flush with 25 mL of additional water to ensure no tablet residue is left in materials used for preparation or the feeding tube.
Data from a clinical trial in adults have associated bedaquiline with an increased risk of death. In this trial, more deaths occurred in the bedaquiline treatment group (9/79, 11.4%) than in the placebo treatment group (2/81, 2.5%; p = 0.03). Of the 9 deaths, 5 were tuberculosis-related. Only 1 death occurred during the 24-week treatment period; median time to death for the other 8 patients was 329 days after the last dose. In an open-label study, 6.9% (16/23) of patients died with the most common cause of death reported as tuberculosis (n = 9). All but 1 patient who died of tuberculosis had not converted or relapsed.
During clinical trials in adults, treatment with bedaquiline resulted in prolongation of the QT interval. QT prolongation was found to develop within the first week of treatment and persist even after drug discontinuation. Data from 1 trial found the largest mean increase in QTc (15.7 milliseconds) occurred during treatment week 18. In another trial, additive QT prolongation occurred when bedaquiline was used concurrently with other QT-prolonging drugs; the increase was proportional to the number of QT-prolonging drugs in the treatment regimen. Chest pain (unspecified) was reported in 11% of treated patients. Monitor electrocardiogram (ECG) and serum electrolyte concentrations before and during treatment.
More cases of elevated hepatic enzymes (at least 3 times upper limit of normal) were reported in adult patients receiving treatment regimens containing bedaquiline than in those without (9% to 10.8%). Hepatic-related adverse reactions were also reported in pediatric patients, and laboratory abnormalities in 15 pediatric patients, 14 to 17 years old, were comparable to those observed in adult patients. The most common adverse reaction in 15 pediatric patients, 5 to 11 years old, was elevated hepatic enzymes (5/15, 33%), which led to discontinuation of therapy in 3 patients. Elevations in hepatic enzymes were reversible upon treatment discontinuation. Obtain liver function tests and monitor for symptoms of hepatotoxicity prior to initiating treatment, monthly while on treatment, and as needed. Counsel patients to promptly report any evidence of new or worsening hepatic dysfunction as these patients may require additional evaluation.
Adverse reactions occurring more frequently in adult patients receiving treatment regimens containing bedaquiline than in those without included nausea (38%), anorexia (9%), and elevated blood amylase (3%). In a small pediatric clinical trial (n = 15, ages 14 to 17 years), the most common adverse reactions observed with bedaquiline treatment included nausea (13%) and abdominal pain (13%).
Adverse reactions occurring more frequently in adult patients receiving treatment regimens containing bedaquiline than in those without included rash (8%).
Adverse reactions occurring more frequently in adult patients receiving treatment regimens containing bedaquiline than in those without included hemoptysis (18%).
Adverse reactions occurring more frequently in adult patients receiving treatment regimens containing bedaquiline than in those without included headache (28%).
Adverse reactions occurring more frequently in adult patients receiving treatment regimens containing bedaquiline than in those without included arthralgia (33%). In a small pediatric clinical trial (n = 15; ages 14 to 17 years), one of the most common adverse reactions observed with bedaquiline treatment was arthralgia (40%).
Bedaquiline may cause QT prolongation. Obtain an electrocardiogram (ECG) before and at least 2, 12, and 24 weeks after starting therapy. Obtain serum potassium, calcium, and magnesium concentrations at baseline, correct if abnormal, and further monitor if QT prolongation is detected. Discontinue bedaquiline if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of more than 500 msec (confirmed by repeat ECG). If syncope occurs, obtain ECG to detect possible QT prolongation. Use bedaquiline 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 patients, 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. Use has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
Bedaquiline has been associated with an increased risk for hepatotoxicity in adult and pediatric patients. Patients with severe hepatic disease (Child-Pugh C) should receive the drug only if the benefits justify the potential risks. Caution is also recommended for patients with alcoholism as concurrent use with alcohol or other hepatotoxic drugs should be avoided. Prior to treatment initiation and monthly while on treatment, obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) and monitor for symptoms of hepatotoxicity (e.g., fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, or hepatomegaly); additional monitoring may be needed. If the patient has evidence of new or worsening hepatic dysfunction, test for viral hepatitis and discontinue other hepatotoxic drugs. Discontinue bedaquiline if aminotransferase elevations are more than 5 times the upper limit of normal (ULN) and persist beyond 2 weeks; aminotransferase elevations are accompanied by total bilirubin elevations more than 2 times ULN; or aminotransferase elevations are more than 8 times ULN. Instruct patients to promptly report any evidence of new or worsening hepatic dysfunction as these patients may require additional evaluation.
Available data from bedaquiline use during human pregnancy are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, no evidence of fetal harm was found during animal reproductive studies. Active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death.
Advise patients that breast-feeding is not recommended during treatment with bedaquiline and for 27.5 months (5 times the half-life) after the last dose unless infant formula is not available because of the potential for serious adverse reactions in a breastfed infant, including hepatotoxicity. Data from a published clinical lactation study in 2 women demonstrate higher bedaquiline concentrations in breast milk compared to maternal plasma, suggesting that bedaquiline accumulates in breast milk. Bedaquiline and M2, its active metabolite, concentrations were measured between approximately 27 and 48 hours after the last bedaquiline dose, and concentrations of bedaquiline and M2 ranged from 2.61 to 8.11 mg/L and 0.27 to 0.81 mg/L, respectively. The milk to plasma ratios for bedaquiline and M2 at 27 to 48 hours after the last dose of bedaquiline ranged from approximately 19 to 29 and 4 to 6, respectively. Data are insufficient to determine effects of the drug on the breastfed infants or the effects of the drug on milk production. Monitor infants exposed to bedaquiline through breast-feeding for signs of bedaquiline-related adverse reactions, such as hepatotoxicity (i.e., yellowing of the eyes, lighter than usual stool color or stool that is pale or light brown, darker than usual urine color).
An increased risk of mortality was noted in a clinical trial in adult patients treated with bedaquiline. In this trial, more deaths occurred in the bedaquiline treatment group (9/79, 11.4%) than in the placebo treatment group (2/81, 2.5%). Data could not explain the imbalance in deaths, and no identifiable pattern between the deaths and sputum culture conversion, relapse, susceptibility to other drugs, HIV status, or disease severity could be determined. Use of this drug is recommended only when no other effective treatment option is available.
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: Mycobacterium sp., Mycobacterium tuberculosis
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.
This drug may also have activity against the following microorganisms: Mycobacterium abscessus, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium kansasii
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.
For the treatment of drug-resistant tuberculosis infection, including multidrug-resistant tuberculosis infection (MDR-TB) and extensively drug-resistant tuberculosis infection (XDR-TB), as part of combination therapy:
NOTE: Bedaquiline is not FDA-approved for the treatment of drug-sensitive tuberculosis, latent M. tuberculosis infection, extra-pulmonary M. tuberculosis infection, or infections caused by non-tuberculosis mycobacteria.
Oral dosage:
Adults: 400 mg PO once daily for 2 weeks, then 200 mg PO 3 days/week. Alternatively, 200 mg PO once daily for 8 weeks, then 100 mg PO daily may be considered with a combination of pretomanid, linezolid, and moxifloxacin. The FDA-approved duration for pulmonary MDR-TB as part of standard combination therapy is 24 weeks and with linezolid and pretomanid is 26 weeks, which may be extended beyond 26 weeks if needed. Guidelines suggest bedaquiline may be considered for use in extrapulmonary disease.
Children and Adolescents 5 to 17 years weighing 30 kg or more: 400 mg PO once daily for 2 weeks, then 200 mg PO 3 days/week. The FDA-approved duration for pulmonary MDR-TB as part of combination therapy is 24 weeks. Guidelines suggest use may be considered for use in patients with extrapulmonary disease.
Children and Adolescents 5 to 17 years weighing 15 to 29 kg: 200 mg PO once daily for 2 weeks, then 100 mg PO 3 days/week. The FDA-approved duration for pulmonary MDR-TB as part of combination therapy is 24 weeks.
Children* 1 to 4 years weighing 16 to 29 kg: 200 mg PO once daily for 2 weeks, then 100 mg PO 3 days/week.
Infants* and Children* 7 months to 4 years weighing 10 to 15 kg: 120 mg PO once daily for 2 weeks, then 60 mg PO 3 days/week.
Infants* and Children* 7 months to 4 years weighing 7 to 9 kg: 80 mg PO once daily for 2 weeks, then 40 mg PO 3 days/week.
Infants* 3 to 6 months: 60 mg PO once daily for 2 weeks, then 20 mg PO 3 days/week.
Infants* 1 to 2 months: 30 mg PO once daily for 2 weeks, then 10 mg PO 3 days/week.
Maximum Dosage Limits:
-Adults
400 mg/day PO.
-Geriatric
400 mg/day PO.
-Adolescents
weighing 30 kg or more: 400 mg/day PO.
weighing 15 to 29 kg: 200 mg/day PO.
-Children
5 to 12 years weighing 30 kg or more: 400 mg/day PO.
5 to 12 years weighing 15 to 29 kg: 200 mg/day PO.
1 to 4 years weighing 16 to 29 kg: Safety and efficacy have not been established; however 200 mg/day PO has been used off-label.
1 to 4 years weighing 10 to 15 kg: Safety and efficacy have not been established; however 120 mg/day PO has been used off-label.
1 to 4 years weighing 7 to 9 kg: Safety and efficacy have not been established; however 80 mg/day PO has been used off-label.
-Infants
7 months and older weighing 10 to 15 kg: Safety and efficacy have not been established; however 120 mg/day PO has been used off-label.
7 months and older weighing 7 to 9 kg: Safety and efficacy have not been established; however 80 mg/day PO has been used off-label.
3 to 6 months: Safety and efficacy have not been established; however 60 mg/day PO has been used off-label.
1 to 2 months: Safety and efficacy have not been established; however 30 mg/day PO has been used off-label.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed for mild to moderate hepatic impairment (Child-Pugh A and B). Bedaquiline has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed for mild to moderate renal impairment. Caution and patient monitoring are advised when administering to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis.
*non-FDA-approved indication
Adagrasib: (Major) Avoid using bedaquiline and adagrasib together for more than 14 days as prolonged coadministration may increase the risk for bedaquiline toxicity and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is required, monitor patients for bedaquiline-related adverse effects. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Bedaquiline is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concurrent use of another strong CYP3A inhibitor increased bedaquiline exposure by 22%.
Alfuzosin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with alfuzosin. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Alfuzosin also has a slight QT prolonging effect, based on electrophysiology studies performed by the manufacturer. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg.
Amiodarone: (Major) Concomitant use of amiodarone and bedaquiline 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. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with bedaquiline. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. Bedaquiline prolongs the QT interval. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amobarbital: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as clarithromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, clarithromycin may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Anagrelide: (Major) Torsade de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an electrocardiogram (ECG), should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include bedaquiline.
Apalutamide: (Major) Avoid coadministration of apalutamide with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased bedaquiline exposure by 52%.
Apomorphine: (Major) Use apomorphine and bedaquiline together with caution due to the risk of additive QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Aprepitant, Fosaprepitant: (Moderate) Use caution if bedaquiline and a multi-day regimen of oral aprepitant are used concurrently and monitor for an increase in bedaquiline-related adverse effects for several days after administration. Bedaquiline is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of bedaquiline. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Armodafinil: (Major) Avoid concurrent use of armodafinil with bedaquiline. Armodafinil is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If possible, bedaquiline should be discontinued prior to initiating arsenic trioxide therapy. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. QT prolongation should also be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported.
Artemether; Lumefantrine: (Major) Concurrent use of artemether; lumefantrine and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Asenapine: (Major) Concurrent use of asenapine and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Atazanavir: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as atazanavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, atazanavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Atazanavir; Cobicistat: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as atazanavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, atazanavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity. (Major) Concurrent use of bedaquiline and cobicistat should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include bedaquiline.
Azithromycin: (Major) Avoid coadministration of azithromycin with bedaquiline 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. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Bedaquiline prolongs the QT interval.
Barbiturates: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Bexarotene: (Major) Avoid concurrent use of bexarotene with bedaquiline. Bexarotene is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and bedaquiline 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 bedaquiline 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 concurrent use of bosentan with bedaquiline. Bosentan is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with bedaquiline. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Bedaquiline has also been reported to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval. Monitor the ECG.
Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with bedaquiline. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Bedaquiline has also been reported to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval. Monitor the ECG.
Butalbital; Acetaminophen: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Cabotegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with rilpivirine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Carbamazepine: (Major) Avoid concurrent use of carbamazepine with bedaquiline. Carbamazepine may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Cenobamate: (Major) Avoid coadministration of cenobamate with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Ceritinib: (Major) Concurrent use of bedaquiline and ceritinib should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure; there is also an increased risk of QT prolongation. Bedaquiline is a CYP3A4 substrate that has been reported to prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor associated with concentration-dependent QT prolongation. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Chloramphenicol: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as chloramphenicol, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, chloramphenicol may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Chloroquine: (Major) Avoid coadministration of chloroquine with bedaquiline 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. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 msec. Bedaquiline prolongs the QT interval. 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.
Chlorpromazine: (Major) Concurrent use of bedaquiline and chlorpromazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Chlorpromazine, a phenothiazine, is also associated with an established risk of QT prolongation and TdP.
Ciprofloxacin: (Major) Concomitant use of ciprofloxacin and bedaquiline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Due to the potential for torsade de pointes (TdP), concurrent use of cisapride with bedaquiline is contraindicated. Both drugs are associated with QT prolongation, and ventricular arrhythmias, including TdP and death, have been reported with cisapride.
Citalopram: (Major) Concurrent use of citalopram and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Citalopram also causes dose-dependent QT interval prolongation.
Clarithromycin: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as clarithromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, clarithromycin may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Clofazimine: (Major) Concomitant use of clofazimine and bedaquiline 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.
Clozapine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with clozapine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Cobicistat: (Major) Concurrent use of bedaquiline and cobicistat should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and bedaquiline 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.
Codeine; Promethazine: (Major) Concomitant use of promethazine and bedaquiline 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.
Crizotinib: (Major) Avoid coadministration of crizotinib with bedaquiline due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Bedaquiline has also been reported to prolong the QT interval.
Dabrafenib: (Major) Avoid concurrent use of dabrafenib with bedaquiline. Dabrafenib is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Darunavir: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as darunavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, darunavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Darunavir; Cobicistat: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as darunavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, darunavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity. (Major) Concurrent use of bedaquiline and cobicistat should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as darunavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, darunavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity. (Major) Concurrent use of bedaquiline and cobicistat should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Dasatinib: (Major) Monitor ECGs if bedaquiline is coadministered with dasatinib. Bedaquiline has been reported to prolong the QT interval. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval.
Deferasirox: (Major) Avoid concurrent use of deferasirox with bedaquiline. Deferasirox is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Degarelix: (Major) Monitor ECGs if bedaquiline is coadministered with degarelix. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. Bedaquiline prolongs the QT interval and androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as delavirdine, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, delavirdine may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Desflurane: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with halogenated anesthetics. Both bedaquiline and halogenated anesthetics have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Deutetrabenazine: (Major) Monitor ECGs if bedaquiline is coadministered with deutetrabenazine. Discontinue bedaquiline if evidence of significant ventricular arrhythmia or QTcF interval greater than 500 msec. Bedaquiline prolongs the QT interval. 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 bedaquiline 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) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with quinidine or quinidine-containing products, such as dextromethorphan; quinidine. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Disopyramide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with disopyramide. Both drugs have been reported to prolong the QT interval, and disopyramide is also associated with TdP. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Dofetilide: (Major) Coadministration of dofetilide and bedaquiline is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs during treatment. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 milliseconds. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Bedaquiline also prolongs the QT interval.
Dolasetron: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with dolasetron. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline electrocardiogram (ECG). An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an ECG. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower and caution is advised.
Dolutegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with rilpivirine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include bedaquiline.
Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include bedaquiline.
Dronedarone: (Contraindicated) Due to the potential for torsade de pointes (TdP), concurrent use of dofetilide with bedaquiline is contraindicated. Prolongation of the QT interval is known to occur with both drugs, and concurrent use may result in additive QT prolongation.
Droperidol: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with droperidol. Both drugs have been reported to prolong the QT interval, and droperidol is associated with an established risk for TdP. In addition, both drugs have black box warnings regarding their association with QT prolongation. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Droperidol administration
Efavirenz: (Major) Avoid concurrent use of efavirenz with bedaquiline. Efavirenz is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. In addition, both drugs have been reported to prolong the QT interval. If coadministration is necessary, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of efavirenz with bedaquiline. Efavirenz is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. In addition, both drugs have been reported to prolong the QT interval. If coadministration is necessary, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of efavirenz with bedaquiline. Efavirenz is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. In addition, both drugs have been reported to prolong the QT interval. If coadministration is necessary, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Elagolix: (Major) Avoid coadministration of elagolix with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of elagolix with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Elbasvir; Grazoprevir: (Moderate) Administering bedaquiline with elbasvir; grazoprevir may result in elevated bedaquiline plasma concentrations. Bedaquiline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include bedaquiline.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Concurrent use of bedaquiline and cobicistat should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Concurrent use of bedaquiline and cobicistat should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with rilpivirine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with rilpivirine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Encorafenib: (Major) Avoid concurrent use of encorafenib with bedaquiline due to the risk for decreased bedaquiline exposure and additive risk for QT/QTc prolongation and torsade de pointes (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. Bedaquiline is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased bedaquiline exposure by 52%.
Entrectinib: (Major) Avoid coadministration of entrectinib with bedaquiline due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 milliseconds. Bedaquiline prolongs the QT interval. Entrectinib has been associated with QT prolongation.
Enzalutamide: (Major) Avoid coadministration of enzalutamide with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased bedaquiline exposure by 52%.
Eribulin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with eribulin. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline electrocardiogram (ECG). An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Erythromycin: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as erythromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, erythromycin may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. An interaction with topically applied erythromycin is not expected.
Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as bedaquiline, should be done with caution and close monitoring.
Eslicarbazepine: (Major) Avoid concurrent use of eslicarbazepine with bedaquiline. Eslicarbazepine is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Ethanol: (Major) Alcohol and other hepatotoxic drugs should be avoided while on bedaquiline, especially in patients with impaired hepatic function, due to a risk for hepatotoxicity.
Etrasimod: (Major) Concomitant use of etrasimod and bedaquiline 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. 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 concurrent use of etravirine with bedaquiline. Etravirine is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Fexinidazole: (Major) Concomitant use of fexinidazole and bedaquiline 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.
Fingolimod: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with fingolimod. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with flecainide. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Major) Caution is advised when administering bedaquiline concurrently with fluconazole due to the risk for increased bedaquiline concentrations and a potential for QT prolongation. Fluconazole may inhibit the CYP3A4 metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval and torsade de pointes (TdP). Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Fluoxetine: (Major) Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with bedaquiline include fluoxetine.
Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with fluphenazine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Fluphenazine, a phenothiazine, is also associated with a theoretical risk for QT prolongation.
Fluvoxamine: (Major) Coadministration of fluvoxamine and bedaquiline may result in additive or synergistic prolongation of the QT interval. Coadminister with caution. Bedaquiline has been reported to prolong the QT interval. QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of fluvoxamine. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Fosamprenavir: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as fosamprenavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, fosamprenavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as bedaquiline. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Bedaquiline has also been reported to prolong the QT interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Major) Avoid concurrent use of fosphenytoin with bedaquiline. Fosphenytoin is a strong CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Fostemsavir: (Major) Monitor ECGs if bedaquiline is coadministered with fostemsavir. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. Bedaquiline prolongs the QT interval. 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.
Gemifloxacin: (Major) Coadministration of bedaquiline with other QT prolonging drugs, such as gemifloxacin, may result in additive or synergistic prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Following oral administration of gemifloxacin, the maximal change in the QTc interval occurs in approximately 5 to 10 hours. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and bedaquiline together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during therapy (at least 2, 12, and 24 weeks after starting bedaquiline therapy). Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Bedaquiline has been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Gilteritinib: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and bedaquiline is necessary. Both drugs have been associated with QT prolongation. Coadministration may result in additive or synergistic prolongation of the QT interval.
Glasdegib: (Major) Avoid coadministration of glasdegib with bedaquiline due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Bedaquiline has been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Goserelin: (Major) Frequently monitor ECGs for QT prolongation if coadministration of bedaquiline with goserelin is necessary. Bedaquiline has been reported to prolong the QT interval; coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Granisetron: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with granisetron. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Grapefruit juice: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as grapefruit juice, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, grapefruit may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation.
Halogenated Anesthetics: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with halogenated anesthetics. Both bedaquiline and halogenated anesthetics have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Haloperidol: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with haloperidol. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. QT prolongation and TdP have also 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) Frequently monitor ECGs for QT prolongation if coadministration of bedaquiline with histrelin is necessary. Bedaquiline has been reported to prolong the QT interval; coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Avoid coadministration of bedaquline and hydroxychloroquine due to the risk of increased 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 and bedaquiline prolong the QT interval. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 msec.
Hydroxyzine: (Major) Monitor ECGs if bedaquiline is coadministered with hydroxyzine. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. Bedaquiline prolongs the QT interval. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes.
Ibutilide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with ibutilide. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Ibutilide administration can also cause QT prolongation and TdP; proarrhythmic events should be anticipated.
Idelalisib: (Major) Avoid prolonged (greater than 14 days) concomitant use of idelalisib and bedaquiline unless the benefit outweighs the risk; increased bedaquiline exposure may occur resulting in bedaquiline-related adverse events. If concomitant use of these drugs is required, monitor patients for signs and symptoms of bedaquiline-related adverse reactions (e.g., QT prolongation and hepatotoxicity). Idelalisib is a strong CYP3A4 inhibitor and bedaquiline is a CYP3A substrate.
Iloperidone: (Major) Concurrent use of iloperidone and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation; however, TdP has not been reported. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Imatinib: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as imatinib, STI-571, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, imatinib may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Indinavir: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as indinavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, indinavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with bedaquiline due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during therapy (at least 2, 12, and 24 weeks after starting bedaquiline therapy). Inotuzumab has been associated with QT interval prolongation. Bedaquiline has also been reported to prolong the QT interval.
Isavuconazonium: (Major) Concurrent use of bedaquiline and isavuconazonium should be avoided due to the potential risk of adverse reactions. Isavuconazole, the active moiety of isavuconazonium may inhibit the CYP3A4 metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions.
Isoflurane: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with halogenated anesthetics. Both bedaquiline and halogenated anesthetics have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
Itraconazole: (Major) Concurrent use of itraconazole is not recommended for more than 2 weeks at any time during bedaquiline treatment. Both bedaquiline and itraconazole are associated with QT prolongation; coadministration increases this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with bedaquiline (a CYP3A4 substrate) may result in elevated bedaquiline plasma concentrations and could increase the risk for adverse events, including QT prolongation. Monitor ECGs if bedaquiline is coadministered to patients receiving itraconazole; discontinue bedaquiline if evidence of serious ventricular arrhythmia or QT interval greater than 500 msec.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with bedaquiline due to an increased risk of QT prolongation. If concomitant use is unavoidable, obtain serum electrolyte concentrations and a baseline ECG; correct any electrolyte abnormalities as clinically appropriate. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Bedaquiline has been reported to prolong the QT interval.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and bedaquiline due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of bedaquiline, thereby further increasing the risk for adverse effects. If concomitant use of these drugs is required, monitor patients for signs and symptoms of bedaquiline-related adverse reactions (e.g., QT prolongation and hepatotoxicity). Bedaquiline is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concurrent use of ketoconazole increased bedaquiline exposure by 22%. In addition, repeated dosing of this drug combination resulted in additive QT prolongation when compared with repeated dosing of the individual drugs.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as clarithromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, clarithromycin may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Lapatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with bedaquiline is necessary; correct electrolyte abnormalities prior to treatment. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Bedaquiline has also been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Lefamulin: (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.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with bedaquiline due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Bedaquiline has also been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Letermovir: (Moderate) Administering letermovir with bedaquiline may increase bedaquiline concentration and risk for adverse events. Avoid coadministration if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Bedaquiline is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration of strong CYP3A4 inhibitors increased bedaquiline exposure by 22%.
Leuprolide: (Major) Frequently monitor ECGs for QT prolongation if coadministration of bedaquiline with leuprolide is necessary. Bedaquiline has been reported to prolong the QT interval; coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Frequently monitor ECGs for QT prolongation if coadministration of bedaquiline with leuprolide is necessary. Bedaquiline has been reported to prolong the QT interval; coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Levofloxacin: (Major) Concomitant use of levofloxacin and bedaquiline 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 bedaquiline due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of bedaquiline, thereby further increasing the risk for adverse effects. If concomitant use of these drugs is required, monitor patients for signs and symptoms of bedaquiline-related adverse reactions (e.g., QT prolongation and hepatotoxicity). Bedaquiline is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concurrent use of ketoconazole increased bedaquiline exposure by 22%. In addition, repeated dosing of this drug combination resulted in additive QT prolongation when compared with repeated dosing of the individual drugs.
Lithium: (Major) Lithium should be used cautiously and with close monitoring with bedaquiline. Lithium has been associated with QT prolongation. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with bedaquiline due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes (TdP). Bedaquiline has been reported to prolong the QT interval.
Lonafarnib: (Major) Concurrent use of bedaquiline and lonafarnib should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Loperamide: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Bedaquiline has also been reported to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval. Monitor the ECG.
Loperamide; Simethicone: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Bedaquiline has also been reported to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval. Monitor the ECG.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with bedaquiline 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. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval more than 500 msec. Both drugs are associated with QT prolongation. (Major) Concurrent use of bedaquiline and ritonavir should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of bedaquiline by decreasing its systemic exposure; avoid concomitant use. Bedaquiline is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of bedaquiline by decreasing its systemic exposure; avoid concomitant use. Bedaquiline is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as bedaquiline. 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. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Maprotiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with maprotiline. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
Mavacamten: (Major) Avoid coadministration of mavacamten with bedaquiline due to decreased plasma concentrations of bedaquiline which may reduce its efficacy. Bedaquiline is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased bedaquiline exposure by approximately 20%. The overall exposure and peak of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with mefloquine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. There is evidence that the use of halofantrine after mefloquine also causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Methadone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with methadone. The need to coadminister these drugs should be done with extreme caution and a careful assessment of treatment risks versus benefits. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Methadone is also considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. 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 concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Metronidazole: (Major) Concomitant use of metronidazole and bedaquiline 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.
Midostaurin: (Major) The concomitant use of midostaurin and bedaquiline may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms (ECG) to monitor the QT interval during therapy. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
Mifepristone: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as mifepristone, for more than 14 days should be avoided unless the benefits justify the risks. Mifepristone may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and increased risk for adverse reactions. The activity of mifepristone on CYP3A4 inhibition may be prolonged due to its long half-life, particularly with chronic therapy. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive effects on the QT interval. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Mirtazapine: (Major) Concomitant use of mirtazapine and bedaquiline 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.
Mitotane: (Major) Avoid concurrent use of bedaquiline with mitotane due to the potential for decreased efficacy of bedaquiline. Mitotane is a strong CYP3A4 inducer and bedaquiline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of bedaquiline. When administered concurrently with another strong CYP3A4 inducer (rifampin 600 mg PO daily for 21 days, the bedaquiline AUC decreased by 52% in one study.
Mobocertinib: (Major) Concomitant use of mobocertinib and bedaquiline 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.
Modafinil: (Major) Avoid concurrent use of modafinil with bedaquiline. Modafinil is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Moxifloxacin: (Major) Coadministration of bedaquiline with other QT prolonging drugs, such as moxifloxacin, may result in additive or synergistic prolongation of the QT interval and should be avoided. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. The likelihood of QTc prolongation may increase with increasing concentrations of moxifloxacin; therefore, the recommended dose or infusion rate should not be exceeded.
Nafcillin: (Major) Avoid concurrent use of nafcillin with bedaquiline. Nafcillin is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Nefazodone: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as nefazodone, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, nefazodone may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Nelfinavir: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as nelfinavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, nelfinavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Nilotinib: (Major) Avoid the concomitant use of nilotinib with bedaquiline as significant prolongation of the QT interval may occur. Bedaquiline has been reported to prolong the QT interval. Sudden deaths and QT prolongation have also been reported with nilotinib therapy.
Nirmatrelvir; Ritonavir: (Major) Concurrent use of bedaquiline and ritonavir should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Ofloxacin: (Major) Concomitant use of ofloxacin and bedaquiline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with olanzapine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Olanzapine; Fluoxetine: (Major) Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with bedaquiline include fluoxetine. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with olanzapine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Olanzapine; Samidorphan: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with olanzapine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
Ondansetron: (Major) Concomitant use of ondansetron and bedaquiline 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.
Osilodrostat: (Major) Monitor ECGs for QT prolongation when osilodrostat is administered with bedaquiline. Bedaquiline has been reported to prolong the QT interval. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of bedaquiline with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Bedaquiline has been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Oxaliplatin: (Major) Monitor ECGs and electrolytes in patients receiving oxaliplatin and bedaquiline concomitantly; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. Bedaquiline has also been reported to prolong the QT interval; coadministration may result in additive or synergistic prolongation of the QT interval.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking bedaquiline due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs and consult cardiology. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. Bedaquiline prolongs the QT interval. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Pacritinib: (Major) Concomitant use of pacritinib and bedaquiline 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.
Paliperidone: (Major) Concurrent use of paliperidone and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Both drugs have been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of paliperidone overdose. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include bedaquiline.
Pasireotide: (Major) Cautious use of pasireotide and bedaquiline is needed, as coadministration may have additive effects on the prolongation of the QT interval. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Pazopanib: (Major) Caution is advised when administering bedaquiline concurrently with pazopanib. Pazopanib may inhibit the CYP3A4 metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Pentamidine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with pentamidine. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Pentobarbital: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Perphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with perphenazine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with perphenazine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Pexidartinib: (Major) Avoid coadministration of pexidartinib with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Phenobarbital: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Phenytoin: (Major) Avoid concurrent use of phenytoin with bedaquiline. Phenytoin may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as bedaquiline. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. If coadministration cannot be avoided, obtain serum electrolyte concentrations and a baseline ECG prior to initiating bedaquiline. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Pimozide: (Contraindicated) Due to the potential for torsade de pointes (TdP), concurrent use of pimozide with bedaquiline is contraindicated. Prolongation of the QT interval is known to occur with both drugs, and pimozide is also associated with a well-established risk for TdP.
Pitolisant: (Major) Avoid coadministration of pitolisant with bedaquiline as concurrent use may increase the risk of QT prolongation. Monitor ECGs if coadministration is necessary. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. Both bedaquiline and pitolisant prolong the QT interval.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking bedaquiline due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and bedaquiline is considered contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Consider an alternative to posaconazole. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of bedaquiline. These drugs used in combination may result in elevated bedaquiline plasma concentrations, causing an increased risk for adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as bedaquiline.
Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include bedaquiline.
Primidone: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Procainamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with procainamide. Procainamide is associated with a well-established risk of QT prolongation and TdP. Bedaquiline has also been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Prochlorperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with prochlorperazine. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Promethazine: (Major) Concomitant use of promethazine and bedaquiline 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 bedaquiline 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 bedaquiline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and bedaquiline 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.
Quetiapine: (Major) Concomitant use of quetiapine and bedaquiline 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.
Quinidine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with quinidine or quinidine-containing products, such as dextromethorphan; quinidine. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Quinine: (Major) Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with bedaquiline include quinine. Quinine may also inhibit the CYP3A4 metabolism of bedaquiline, resulting in increased bedaquiline systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Quizartinib: (Major) Concomitant use of quizartinib and bedaquiline 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) Caution is advised when administering bedaquiline concurrently with ranolazine. Ranolazine may inhibit the CYP3A4 metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Relugolix: (Major) Monitor ECGs if bedaquiline is coadministered with relugolix. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 msec. Bedaquiline prolongs the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Monitor ECGs if bedaquiline is coadministered with relugolix. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 msec. Bedaquiline prolongs the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with bedaquiline due to decreased plasma concentrations of bedaquiline which may reduce its efficacy. Bedaquiline is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased bedaquiline exposure by approximately 20%. The overall exposure and peak of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Ribociclib: (Major) Avoid coadministration of ribociclib with bedaquiline due to an increased risk for QT prolongation. Systemic exposure of bedaquiline may also be increased resulting in an increase in bedaquiline-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Bedaquiline is a CYP3A4 substrate that has been reported to prolong the QT interval. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with bedaquiline due to an increased risk for QT prolongation. Systemic exposure of bedaquiline may also be increased resulting in an increase in bedaquiline-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Bedaquiline is a CYP3A4 substrate that has been reported to prolong the QT interval. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Rifabutin: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
Rifampin: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
Rifamycins: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
Rifapentine: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with rilpivirine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Risperidone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with risperidone. If coadministration is chosen, and the patient has known risk factors for cardiac disease or arrhythmia, then the patient should be closely monitored clinically. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Risperidone has also been associated with a possible risk for QT prolongation and/or TdP; however, data are currently lacking to establish causality in association with TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
Ritonavir: (Major) Concurrent use of bedaquiline and ritonavir should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Romidepsin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with romidepsin. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline electrocardiogram (ECG). An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Saquinavir: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as saquinavir boosted with ritonavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, saquinavir/ritonavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT and torsade de pointes (TdP). If these drugs must be administered together, obtain serum electrolyte concentrations and a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Secobarbital: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with bedaquiline is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Bedaquiline prolongs the QT interval.
Sertraline: (Major) Concomitant use of sertraline and bedaquiline 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) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with halogenated anesthetics. Both bedaquiline and halogenated anesthetics have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving bedaquiline due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Bedaquiline has been reported to prolong the QT interval.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and bedaquiline 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.
Solifenacin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with solifenacin. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Solifenacin has also been associated with dose-dependent prolongation of the QT interval. TdP has been reported with post-marketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with bedaquiline due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of therapy may be necessary if QT prolongation occurs. Bedaquiline prolongs the QT interval. Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) Concomitant use of sotalol and bedaquiline 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 sotorasib with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of St. John's Wort with bedaquiline. St. John's Wort may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Sunitinib: (Major) Monitor ECGs for QT prolongation if coadministration of bedaquiline with sunitinib is necessary; discontinuation of bedaquiline therapy may be necessary for ventricular arrhythmias or QT prolongation. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Bedaquiline has also been reported to prolong the QT interval.
Tacrolimus: (Major) Bedaquiline and tacrolimus can cause QT prolongation, and both drugs are CYP3A4 substrates. The manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministering with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. The manufacturer of bedaquiline recommends obtaining obtain serum electrolyte concentrations and a baseline ECG prior to initiation of therapy. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Tamoxifen: (Major) Concomitant use of tamoxifen and bedaquiline 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.
Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with telavancin. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Tetrabenazine: (Major) Concurrent use of tetrabenazine and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Thioridazine is considered contraindicated for use along with bedaquiline which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
Tipranavir: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as tipranavir boosted with ritonavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, tipranavir/ritonavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with tolterodine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of bedaquiline with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Bedaquiline has also been reported to prolong the QT interval; coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Trazodone: (Major) Avoid coadministration of bedaquiline and trazodone. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
Triclabendazole: (Major) Concomitant use of triclabendazole and bedaquiline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with trifluoperazine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Trifluoperazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Triptorelin: (Major) Frequently monitor ECGs for QT prolongation if coadministration of bedaquiline with triptorelin is necessary. Bedaquiline has been reported to prolong the QT interval; coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Tucatinib: (Major) Concurrent use of bedaquiline and tucatinib should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Vandetanib: (Major) Avoid coadministration of vandetanib with bedaquiline 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. Bedaquiline has also been reported to prolong the QT interval. Coadministration with other QT-prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Vardenafil: (Major) If possible, avoid the use of vardenafil with bedaquiline due to the risk of QT prolongation. Monitor ECGs if bedaquiline is used in patients receiving other drugs that prolong the QTc interval, such as vardenafil. Also monitor serum electrolytes. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or if a QTcF interval greater than 500 ms occurs. Both therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in the QTc interval.
Vemurafenib: (Major) Avoid concurrent use of bedaquiline with vemurafenib. Vemurafenib may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Venlafaxine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with venlafaxine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use.
Voclosporin: (Major) Monitor ECGs if bedaquiline is coadministered with voclosporin. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 msec. Bedaquiline prolongs the QT interval. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as clarithromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, clarithromycin may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Voriconazole: (Major) Avoid prolonged (more than 14 consecutive days) concurrent administration of bedaquiline and voriconazole unless the benefits outweigh the risks; increased bedaquiline exposure and additive effects on the QT interval may occur. If concomitant use of these drugs is required, monitor patients for signs and symptoms of bedaquiline-related adverse reactions (e.g., hepatotoxicity) and QT prolongation. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Bedaquiline is a CYP3A substrate that has been reported to prolong the QT interval. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Vorinostat: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with vorinostat. Both drugs have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Ziprasidone: (Contraindicated) Due to the potential for torsade de pointes (TdP), concurrent use of bedaquiline with ziprasidone is contraindicated. Prolongation of the QT interval is known to occur with both drugs, and coadministration may result in additive QT prolongation. Ziprasidone is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, such as bedaquiline.
Bedaquiline is a diarylquinoline that binds to the C-ring of adenosine 5'-triphosphate (ATP) synthase. Through this binding, it prevents ATP synthase from using the energy from hydrogen and/or sodium electrochemical gradients to produce ATP. Antimycobacterial activity appears to be time-dependent, as efficacy does not increase with higher drug concentrations.
Since the mechanism of activity is unique, cross-resistance with other antimycobacterial drugs is not expected. However, mutations in the subunit C of ATP synthase (encoded by missense mutations in the atpE gene) have resulted in mycobacterial resistance that affects bedaquiline. This mutation has resulted in 8- to 133-fold increases in the bedaquiline minimum inhibitory concentration (MIC), resulting in MICs ranging from 0.25 to 4 mcg/mL. Additionally, upregulation of the MmpS5-MmpL5 efflux pump has resulted in 2- to 9-fold increases in bedaquiline MICs for M. tuberculosis isolates, leading to MICs ranging from 0.25 to 0.5 mcg/mL. Testing for bedaquiline MICs is recommended for isolates from patients who fail to convert or relapse after therapy. Isolates that have efflux-based mutations have also been found to be cross-resistant to clofazimine. Test isolates that are phenotypically resistant to bedaquiline for cross-resistance to clofazimine, if clofazimine is being considered as part of the treatment regimen.
Bedaquiline is administered orally. After systemic absorption, the estimated volume of distribution is approximately 164 L with more than 99.9% of the drug bound to plasma protein. It undergoes oxidative metabolism, via the hepatic isoenzyme CYP3A4, to form N-monodesmethyl metabolite (M2). Compared with the parent compound, M2 has 4- to 6-times less antimycobacterial activity and does not contribute significantly to clinical efficacy. Drug concentrations decline tri-exponentially after achieving Cmax, with elimination occurring primarily through the feces; 0.001% or less of the dose is excreted unchanged in the urine. The mean terminal elimination half-life of the drug and metabolite is approximately 5.5 months, indicating slow release from peripheral tissues.
Affected cytochrome P450 isoenzymes and transporters: CYP3A4
Bedaquiline is a substrate of CYP3A4, but does not significantly inhibit any CYP isoenzymes.
-Route-Specific Pharmacokinetics
Oral Route
Maximum plasma concentrations (Cmax) occur approximately 5 hours post-dose, with both Cmax and systemic exposure (AUC) increasing proportionally with increasing dose. In a multidose pharmacokinetic study, mean bedaquiline AUC and Cmax at week 8 were 25,863 ng x hour/mL and 1,659 ng/mL, respectively. Additionally, the presence of food increases the relative bioavailability by 2-fold compared to fasting conditions.
-Special Populations
Hepatic Impairment
Administration of a single 400 mg dose to 8 patients with moderate hepatic impairment (Child-Pugh B) resulted in a mean systemic exposure (AUC) to bedaquiline and its metabolite that was 20% lower compared to healthy subjects. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh C).
Renal Impairment
Renal excretion of unchanged bedaquiline is not substantial. Less than or equal to 0.001% of the dose is excreted unchanged in the urine, and changes in creatinine clearance have not been found to influence bedaquiline pharmacokinetic parameters. In addition, since bedaquiline is significantly bound to plasma proteins, it is unlikely to be removed by hemodialysis or peritoneal dialysis.
Pediatrics
The pharmacokinetic parameters of bedaquiline in 15 MDR-TB pediatric patients 14 to 17 years (38 to 75 kg) receiving the adult dosage regimen (400 mg PO once daily for the first 2 weeks, then 200 mg PO 3 times weekly) were comparable to those observed in adults. There was no impact of body weight on bedaquiline pharmacokinetics in these patients. The mean AUC was 26,300 ng x hour/mL and the mean Cmax was 1,800 ng/mL. In 10 pediatric patients 5 to 11 years (14 to 36 kg) receiving 200 mg PO once daily then 100 mg PO 3 times weekly, the mean bedaquiline pharmacokinetic parameters were similar to that of adult patients. The mean AUC was 32,200 ng x hour/mL and the mean Cmax was 2,430 ng/mL. In 1 of these patients (baseline weight 14 kg), the bedaquiline mean Cmax and AUC were 3.8-fold and 2.6-fold higher than those of adult patients, respectively.
Ethnic Differences
Systemic exposure (AUC) to bedaquiline has been found to be 34% lower in black patients than in patients of other races; however, this is not considered to be clinically relevant as no differences in response rates have been observed.