Bedaquiline (Monograph)

Brand name: Sirturo
Drug class: Antituberculosis Agents
Chemical name: (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol (2E)-but-2-enedioate salt (1:1)
Molecular formula: C₃₂H₃₁BrN₂O₂•C₄H₄O₄
CAS number: 845533-86-0

Medically reviewed by Drugs.com on Nov 15, 2021. Written by ASHP.

Introduction

Antituberculosis agent; diarylquinoline antimycobacterial.

Uses for Bedaquiline

Tuberculosis

Treatment of multidrug-resistant (MDR) pulmonary tuberculosis (i.e., caused by Mycobacterium tuberculosis resistant to isoniazid and rifampin) in conjunction with other antituberculosis agents. Designated an orphan drug by FDA for use in treatment of active tuberculosis.

Safety and efficacy for treatment of drug-susceptible tuberculosis, extrapulmonary tuberculosis, or latent tuberculosis infection not established. Although safety and efficacy for treatment of infections caused by nontuberculous mycobacteria (NTM) not established, designated an orphan drug by FDA for treatment of NTM infections.

ATS, CDC, IDSA, and WHO recommend that bedaquiline be included in multiple-drug regimens used for treatment of MDR tuberculosis. Considered a first-line antituberculosis agent for inclusion in such regimens. There is some evidence that bedaquiline-containing regimens are more likely to achieve treatment success in patients with MDR tuberculosis than those that do not include bedaquiline.

Used in a 3-drug combination regimen that includes pretomanid and linezolid for treatment of extensively drug resistant (XDR) pulmonary tuberculosis (i.e., caused by M. tuberculosis resistant to isoniazid, rifampin, any fluoroquinolone, and at least one injectable antituberculosis agent) or treatment-intolerant or non-responsive MDR pulmonary tuberculosis. WHO states that the 3-drug regimen of pretomanid, bedaquiline, and linezolid (also known as BPaL) may be used for treatment of MDR tuberculosis in patients who have not previously received either bedaquiline or linezolid (or received the drugs for ≤2 weeks) and have documented evidence that the MDR strain also is resistant to a fluoroquinolone.

Patients with MDR and XDR tuberculosis are at high risk for treatment failure and acquisition of further drug resistance. ATS, CDC, IDSA, and others recommend that such patients be referred to or that consultation be obtained from a specialized treatment center as identified by local or state health departments or the CDC.

For additional information on treatment of MDR and XDR tuberculosis, consult current guidelines from ATS/CDC/IDSA and WHO.

Bedaquiline Dosage and Administration

General

• Prior to and during bedaquiline therapy, perform laboratory tests to evaluate liver function and assess for signs and symptoms of liver disease. (See Hepatic Effects under Cautions.)

• Assess serum electrolyte concentrations prior to initiation of bedaquiline therapy and perform ECGs prior to and during bedaquiline therapy. (See Prolongation of QT Interval under Cautions.)

• Administer using directly observed (supervised) therapy (DOT).

Administration

Oral Administration

Administer orally with food.

Swallow 100-mg tablets whole with water. Swallow 20-mg tablets whole or divide into 2 equal halves and take with water.

For patients unable to swallow tablets, may disperse 20-mg tablets in water and administer with a beverage or soft food. Place no more than five 20-mg tablets in a clean cup, add 5 mL (e.g., a teaspoonful) of water, and mix well to disperse the tablets. Swallow resulting mixture immediately with food or further mix with a small amount (e.g., a teaspoonful) of a beverage (e.g., milk product, apple juice, orange juice, cranberry juice, carbonated beverage) or soft food (e.g., yogurt, applesauce, mashed banana, oatmeal). If more than five 20-mg tablets are required for the dose, repeat this procedure until desired total dose is reached. To ensure administration of entire dose, add an additional small amount of beverage or soft food to the cup to disperse any remaining residue and immediately swallow.

Alternatively, crush appropriate number of 20-mg tablets, mix with soft food (e.g., yogurt, applesauce, mashed banana, oatmeal), and immediately swallow. To ensure administration of entire dose, add an additional small amount of beverage or soft food to the container to disperse any residue and immediately swallow.

Feeding tube: Place no more than five 20-mg tablets in a container with 50 mL of noncarbonated water and mix well to disperse tablets; mixture should be white to almost white, with visible particles. Administer immediately through a feeding tube. If more than five 20-mg tablets are required for the dose, repeat procedure until desired total dose is reached. To ensure administration of the entire dose, use an additional 25 mL of water to rinse the container and flush the feeding tube.

Dosage

Available as bedaquiline fumarate; dosage expressed in terms of bedaquiline.

Must be used in conjunction with other antituberculosis agents.

Manufacturer states use in conjunction with ≥3 other drugs selected based on results of in vitro susceptibility testing. If results of in vitro testing not available, manufacturer states may use in conjunction with ≥4 other drugs to which the patient's isolate is likely to be susceptible. A 3-drug regimen that includes bedaquiline is used for treatment of XDR or treatment-intolerant or non-responsive MDR pulmonary tuberculosis.

Pediatric Patients

Active Tuberculosis

MDR Tuberculosis

Oral

Pediatric patients ≥5 years of age weighing 15–29 kg: Manufacturer recommends 200 mg once daily for 2 weeks, followed by 100 mg 3 times weekly (with ≥48 hours between doses) for 22 weeks (total of 24 weeks).

Pediatric patients ≥5 years of age weighing ≥30 kg: Manufacturer recommends 400 mg once daily for 2 weeks, followed by 200 mg 3 times weekly (with ≥48 hours between doses) for 22 weeks (total of 24 weeks).

Adults

Active Tuberculosis

MDR Tuberculosis

Oral

Manufacturer recommends 400 mg once daily for 2 weeks, followed by 200 mg 3 times weekly (with ≥48 hours between doses) for 22 weeks (total of 24 weeks).

XDR Tuberculosis or Treatment-intolerant or Non-responsive MDR Tuberculosis

Oral

400 mg once daily for 2 weeks, followed by 200 mg 3 times weekly (with ≥48 hours between doses) for 24 weeks (total of 26 weeks).

Must administer in conjunction with oral pretomanid (200 mg once daily for 26 weeks) and oral linezolid (1.2 g once daily for 26 weeks). Adjustment of linezolid dosage to 600 mg daily with further reductions to 300 mg daily or interruption of linezolid therapy may be required if myelosuppression, peripheral neuropathy, or optic neuropathy occurs.

The 3-drug combination regimen should be continued for 26 weeks, but may be extended beyond 26 weeks if necessary.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustment not needed.

Severe hepatic impairment: Use with caution and only when benefits outweigh risks.

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not needed.

Severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis: Use with caution and monitor for adverse effects.

Geriatric Patients

Dosage adjustments not needed.

Cautions for Bedaquiline

Contraindications

• Manufacturer states none.

Warnings/Precautions

Increased Mortality

Increased risk of death reported in adults receiving bedaquiline in a placebo-controlled clinical trial (11.4 versus 2.5%, based on data through week 120). Cause of increased risk of death unknown. No correlation demonstrated between death and sputum culture conversion, relapse, susceptibility to other antituberculosis drugs, HIV status, or disease severity.

Use bedaquiline only when an effective treatment regimen for MDR tuberculosis cannot otherwise be provided.

Prolongation of QT Interval

Prolongation of QT interval reported. Concomitant use of bedaquiline with other drugs associated with QT interval prolongation may result in additive or synergistic effects on QT interval.

Perform ECG prior to initiation of bedaquiline and at least at 2, 12, and 24 weeks after starting the drug. Measure serum potassium, calcium, and magnesium concentrations at baseline and correct if necessary. If QT prolongation detected, monitor electrolyte concentrations.

Risk of QT interval prolongation may be increased in patients receiving other drugs that prolong QT interval (e.g., clofazimine, fluoroquinolones, macrolides); patients with hypocalcemia, hypokalemia, or hypomagnesemia; patients with a history of or ongoing hypothyroidism or bradyarrhythmias; or patients with a history of torsades de pointes, congenital long QT syndrome, or uncompensated heart failure. Consider risks and benefits of initiating therapy and closely monitor ECG in such patients.

Discontinue bedaquiline and all other drugs that may prolong QT interval if patient develops clinically important ventricular arrhythmia or QT_cF >500 msec (confirmed by repeat ECG). If syncope occurs, perform ECG to detect prolongation of QT interval.

Not evaluated to date in patients with ventricular arrhythmias or recent MI.

Concentrations of the major metabolite of bedaquiline (an N-monodesmethyl metabolite [M2]) appear to correlate with QT interval prolongation.

Hepatic Effects

Higher incidence of adverse hepatic effects reported in adult and pediatric patients receiving antituberculosis regimens containing bedaquiline compared with patients receiving regimens not containing the drug.

Monitor liver function tests (AST, ALT, alkaline phosphatase, bilirubin) at baseline, monthly during treatment, and as needed. Also monitor for symptoms of hepatic dysfunction (e.g., fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) at baseline, monthly during treatment, and as needed.

If signs or symptoms of new or worsening liver dysfunction (e.g., clinically important elevation in serum aminotransferases and/or bilirubin, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) develop, test for viral hepatitis and discontinue other hepatotoxic drugs.

Discontinue bedaquiline if elevated aminotransferase concentrations are accompanied by total bilirubin concentrations >2 times ULN, aminotransferase concentrations are >8 times ULN, or aminotransferase concentrations >5 times ULN persist >2 weeks.

Avoid other hepatotoxic drugs or herbal products, especially in patients with hepatic impairment.

HIV-infected Individuals

Safety and efficacy for treatment of MDR tuberculosis in patients with human immunodeficiency virus (HIV) infection not established; data are limited on use of the drug in HIV-infected patients.

Specific Populations

Pregnancy

Data regarding use of bedaquiline in pregnant women insufficient to determine whether there is a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies (rats and rabbits) receiving the drug at doses resulting in exposures approximately 6 times the human exposure at the recommended dosage, no adverse embryofetal toxicities were observed.

Pregnant women are at increased risk for complications from active tuberculosis, which may lead to adverse maternal and neonatal outcomes (e.g., maternal anemia, cesarean delivery, preterm delivery, low birthweight, birth asphyxia, perinatal infant death).

Lactation

Not known whether distributed into human milk, affects milk production, or has effects on the breast-fed infant. Distributed into milk in rats.

Consider benefits of breast-feeding and the importance of bedaquiline to the woman along with potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

If used in a nursing woman, manufacturer recommends monitoring breast-fed infant for bedaquiline-associated adverse effects (e.g., hepatotoxicity).

Pediatric Use

Safety and efficacy not established in patients <5 years of age or weighing <15 kg.

Safety and efficacy for use in pediatric patients ≥5 years of age weighing ≥15 kg is established based on supportive evidence from a study in adults and additional pharmacokinetic and safety data from an open-label study that included pediatric patients 5 through 17 years of age weighing ≥15 kg with MDR tuberculosis.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Not studied in patients with severe hepatic impairment; use with caution in such patients and only when benefits outweigh risks; monitor for adverse reactions.

Renal Impairment

Population pharmacokinetic analysis indicates plasma concentrations of bedaquiline may be increased in individuals with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis; if used in such patients, use caution and monitor for adverse effects.

Common Adverse Effects

Adults: Nausea, arthralgia, headache, hemoptysis, chest pain.

Pediatric patients ≥5 years of age: Arthralgia, nausea, abdominal pain, elevated liver enzymes.

Interactions for Bedaquiline

Metabolized primarily by CYP3A4.

Does not inhibit CYP1A2, 2A6, 2C8/9/10, 2C19, 2D6, 2E1, 3A4, 3A4/5, or 4A to any clinically important extent. Does not induce CYP1A2, 2C9, 2C19, or 3A4.

Drugs Affecting Hepatic Microsomal Enzymes

Moderate and potent CYP3A4 inducers: Pharmacokinetic interaction (decreased bedaquiline AUC with possible decreased therapeutic effects). Avoid concomitant use.

Potent CYP3A4 inhibitors: Pharmacokinetic interaction (increased bedaquiline AUC with possible increased risk of adverse effects). Avoid concomitant use for durations >14 consecutive days, unless benefits of concomitant use outweigh risks; monitor for adverse effects.

Drugs that Prolong QT Interval

Pharmacologic interaction (increased risk of QT interval prolongation); closely monitor ECG.

Hepatotoxic Drugs

Pharmacologic interaction (increased risk of hepatotoxicity); avoid concomitant use, especially in patients with hepatic impairment.

Specific Drugs

Bedaquiline Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentration attained at approximately 5 hours.

Proportional increases in peak plasma concentration and AUC with single doses up to 700 mg and multiple doses up to 400 mg daily.

Food

Administration with standard meal (22 g fat, 558 calories) results in twofold increase in relative bioavailability compared with fasting conditions.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

>99.9%.

Elimination

Metabolism

Metabolized primarily by CYP3A4.

Major metabolite of bedaquiline, an N-monodesmethyl metabolite (M2), has 4–6 times less antimycobacterial activity compared with parent drug.

Elimination Route

Primarily eliminated in feces; negligible renal clearance of unchanged drug.

Unlikely to be substantially removed from plasma by hemodialysis or peritoneal dialysis.

Half-life

Mean terminal elimination half-lives of bedaquiline and M2 metabolite are similar and are approximately 5.5 months; long half-life probably related to slow release of drug and metabolite from peripheral tissues.

Special Populations

Patients with moderate hepatic impairment (Child-Pugh class B): Mean AUC of bedaquiline and M2 metabolite following single 400-mg dose are approximately 20% lower compared with healthy individuals.

Pharmacokinetics do not appear to correlate with Cl_cr.

No clinically important differences in pharmacokinetics related to age, gender, or race.

Pharmacokinetics in children not studied to date.

Stability

Storage

Oral

Tablets

25°C in tight container; may be exposed to 15–30°C.

20-mg tablets: Store in original container; protect from light and moisture.

100-mg tablets: Dispense in original container; if dispensed outside original container, store in tight, light-resistant container with expiration date ≤3 months.

Actions and Spectrum

• Diarylquinoline antimycobacterial; antituberculosis agent.

• Inhibits mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme essential for generation of energy in M. tuberculosis.

• Active in vitro against M. tuberculosis, including drug-susceptible M. tuberculosis and multidrug-resistant strains resistant to isoniazid, rifampin, ethambutol, ethionamide, pyrazinamide, streptomycin, and/or ofloxacin. MIC of bedaquiline reported for clinical isolates of multidrug-resistant M. tuberculosis generally has ranged from 0.003–0.25 mcg/mL.

• Also active in vitro against some other mycobacteria (e.g., M. avium, M. intracellulare, M. abscessus, M. ulcerans).

• M. tuberculosis with reduced susceptibility or resistance to bedaquiline (4- to 133-fold increase in MIC) have been produced in vitro, and strains with reduced susceptibility have emerged during treatment with the drug. Mutations in the atpE target gene have been identified as a mechanism of mycobacterial resistance to bedaquiline; other mechanisms of resistance also exist.

• M. tuberculosis with an efflux-based mutation (Rv0678) that results in reduced susceptibility to bedaquiline may also have reduced susceptibility to clofazimine.

Advice to Patients

• Importance of providing patient a copy of the manufacturer's patient information (medication guide). Importance of patient reading the medication guide prior to initiation of therapy and each time the prescription is refilled.

• Importance of taking bedaquiline exactly as prescribed and completing the full course of therapy with bedaquiline and other antituberculosis drugs.

• Advise patients that missed doses may decrease treatment effectiveness and increase the risk of developing resistance to bedaquiline and other antituberculosis drugs. If a dose of bedaquiline is missed during the first 2 weeks of therapy, the missed dose should be skipped and the usual dosing schedule continued. If a dose of bedaquiline is missed after the first 2 weeks, the missed dose should be taken as soon as possible and the usual 3-times-weekly regimen resumed at least 24 hours after taking the missed dose; no more than 3 doses should be taken during a 7-day period.

• Importance of taking bedaquiline with food.

• Importance of storing bedaquiline tablets in original container and protecting from light.

• Possibility of serious adverse effects, including increased risk of death, heart rhythm abnormalities, and/or hepatitis.

• Importance of informing clinicians of personal or family history of congenital QT interval prolongation or heart failure.

• Importance of informing clinicians if symptoms suggestive of hepatotoxicity (e.g., nausea, vomiting, abdominal pain, fever, weakness, pruritus, fatigue, anorexia, jaundice, dark urine, light-colored stools) occur.

• Potential for bedaquiline to cause nausea, arthralgia, headache, increased amylase concentrations, hemoptysis, chest pain, anorexia, or rash.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses. Advise patients to abstain from alcohol and other hepatotoxic drugs or herbal products.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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