Bedaquiline Fumarate

Tuberculosis

Treatment of pulmonary multidrug-resistant tuberculosis (i.e., caused by Mycobacterium tuberculosis resistant to isoniazid and rifampin) in conjunction with other antituberculosis agents.1 5 6 10

Designated an orphan drug by FDA for use in treatment of active tuberculosis.3

Use only when an effective treatment regimen for multidrug-resistant tuberculosis cannot otherwise be provided.1 10

Safety and efficacy for treatment of drug-susceptible tuberculosis, extrapulmonary (e.g., CNS) tuberculosis, or latent tuberculosis infection not established; use not recommended.1

Safety and efficacy for treatment of infections caused by nontuberculous mycobacteria (NTM) not established; use not recommended.1

Patients with multidrug-resistant tuberculosis are at high risk for treatment failure and acquisition of further drug resistance.4 ATS, CDC, and IDSA 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.4

Absorption

Bioavailability

Following oral administration, peak plasma concentration attained at approximately 5 hours.1 8

Proportional increases in peak plasma concentration and AUC with single doses up to 700 mg and multiple doses up to 400 mg daily.1 8

Food

Administration with standard meal (22 g fat, 558 calories) results in twofold increase in relative bioavailability compared with fasting conditions.1 8

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

>99.9%.1

Elimination

Metabolism

Metabolized primarily by CYP3A4.1

Major metabolite of bedaquiline, an N-monodesmethyl metabolite (M2), has 4–6 times less antimycobacterial activity compared with parent drug.1

Elimination Route

Primarily eliminated in feces; negligible renal clearance of unchanged drug.1

Unlikely to be substantially removed from plasma by hemodialysis or peritoneal dialysis.1

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.1 6

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.1

Pharmacokinetics do not appear to correlate with Clcr.1

No clinically important differences in pharmacokinetics related to age, gender, or race.1

Pharmacokinetics in children not studied to date.1

• Diarylquinoline antimycobacterial; antituberculosis agent.1 5 6 7 8

• Inhibits mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme essential for generation of energy in M. tuberculosis.1 5 6 7 8 13 15

• Active in vitro against M. tuberculosis,1 6 8 12 including drug-susceptible M. tuberculosis and multidrug-resistant strains resistant to isoniazid, rifampin, ethambutol, ethionamide, pyrazinamide, streptomycin, and/or ofloxacin.6 7 8 12 MIC of bedaquiline reported for clinical isolates of multidrug-resistant M. tuberculosis generally has ranged from 0.003–0.25 mcg/mL.1 6

• Also active in vitro against some other mycobacteria (e.g., M. avium,8 12 M. intracellulare,8 12 M. abscessus,8 M. ulcerans).8

• M. tuberculosis with reduced susceptibility or resistance to bedaquiline (4- to 133-fold increase in MIC) have been produced in vitro,7 14 and strains with reduced susceptibility have emerged during treatment with the drug.1 Mutations in the atpE target gene have been identified as a mechanism of mycobacterial resistance to bedaquiline;1 7 8 14 other mechanisms of resistance also exist.1 14

• Importance of providing patient a copy of the manufacturer's patient information (medication guide).2 Importance of patient reading the medication guide prior to initiation of therapy and each time the prescription is refilled.2

• Importance of taking bedaquiline exactly as prescribed and completing the full course of therapy with bedaquiline and other antituberculosis drugs.1

• Advise patients that missed doses may decrease treatment effectiveness and increase the risk of developing resistance to bedaquiline and other antituberculosis drugs.1 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.1 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.1

• Importance of taking bedaquiline with food.1

• Importance of storing bedaquiline tablets in original container and protecting from light.2

• Possibility of serious adverse effects, including increased risk of death, heart rhythm abnormalities, and/or hepatitis.1

• Importance of informing clinicians of personal or family history of congenital QT interval prolongation or heart failure.1

• 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.2

• Potential for bedaquiline to cause nausea, arthralgia, headache, increased amylase concentrations, hemoptysis, chest pain, anorexia, or rash.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.1 Advise patients to abstain from alcohol and other hepatotoxic drugs or herbal products.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.