Bedaquiline

Indications

Bedaquiline is used for: Multidrug Resistant Pulmonary Tuberculosis Diarylquinoline antimycobacterial indicated as part of combination therapy for pulmonary multidrug resistant tuberculosis (MDR-TB); reserve bedaquiline for when an effective treatment TB regimen cannot otherwise be provided

Adult Dose

Multidrug Resistant Pulmonary Tuberculosis Weeks 1-2: 400 mg PO once daily for 2 weeks, THEN Weeks 3-24: 200 mg 3 times/week with at least 48 hr between doses Use in combination with at least 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible; reserve bedaquiline for when an effective treatment TB regimen cannot otherwise be provided

Child Dose

Multidrug Resistant Pulmonary Tuberculosis Diarylquinoline antimycobacterial indicated as part of combination therapy for pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid Only use in combination with at least 3 other drugs to which the patient’s TB isolate has been shown to be susceptible in vitro; if in vitro testing results are unavailable, may be initiated in combination with at least 4 other drugs to which the patient’s TB isolate is likely to be susceptible <5 years: Safety and efficacy not established >5 years Weight >30 kg Weeks 1-2: 400 mg PO once daily for 2 weeks, THEN Weeks 3-24: 200 mg 3 times/week with at least 48 hr between doses >16 years and weight >30 kg: If treatment is considered necessary beyond 24 weeks, may continue at 200 mg PO 3 times/week Weight 15 to <30 kg Weeks 1-2: 200 mg PO once daily for 2 weeks, THEN Weeks 3-24: 100 mg 3 times/week with at least 48 hr between doses

Renal Dose

Renal impairment Mild-to-moderate: No dosage adjustment required Severe or end-stage renal disease requiring hemodialysis or peritoneal dialysis: Use with caution; if used, monitor for adverse reactions of bedaquiline

Administration

Must take with food

Contra Indications

Precautions

Increased Mortality An increased risk of death was seen in the bedaquiline treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial in adults. Only use bedaquiline in patients 5 years of age and older when an effective treatment regimen cannot otherwise be provided. QT prolongation QT prolongation can occur Coadministration with drugs that prolong the QT interval may cause additive QT prolongation Discontinue if significant ventricular arrhythmia or QTc interval >500 ms develops Hepatotoxicity Hepatic-related adverse effects increased when bedaquiline added to multidrug regimen; avoid alcohol and other hepatotoxic drugs, especially in patients with hepatic impairment Discontinue if Aminotransferase increases are accompanied by total bilirubin elevation >2x ULN Aminotransferase elevations >8x ULN Aminotransferase elevations persist beyond 2 weeks Monitoring Parameters Monitor symptoms (eg, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed; test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs Determine serum potassium, calcium, and magnesium before starting treatment (correct if abnormal)—remeasure if QT prolongation occurs during treatment. Monitor ECGs. Obtain ECG before starting treatment, and then at least monthly during treatment or more frequently if concomitant use with other drugs known to prolong the QT interval. Monitor liver function before starting treatment and then at least monthly during treatment—discontinue treatment if severe abnormalities in liver function tests.

Pregnancy-Lactation

Pregnancy Available data from published literature of use in pregnant women are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Clinical considerations 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 Animal studies Reproduction studies in rats and rabbits revealed no evidence of harm to fetuses of pregnant rats and rabbits during organogenesis at exposures up to 6x the clinical dose based on AUC comparisons Lactation No data are available regarding the presence in human milk Monitor infants exposed for signs of bedaquiline-related adverse reactions (eg, hepatotoxicity) Animal studies Bedaquiline concentrations in rat milk were 6-fold to 12-fold higher than the maximum concentration observed in maternal plasma at exposures 1-2x the clinical exposure (based on AUC comparisons)

Interactions

May prolong QT interval; assess thoroughly and if possible, avoid coadministration with other drugs that prolong QT interval Metabolized by CYP3A4; avoid strong CYP3A4 inducers (eg, rifampin, rifapentine, rifabutin) and antiretroviral drugs that are moderate inducers (eg, efavirenz) that may reduce bedaquiline’s effect Coadministration with CYP3A4 inhibitors may increase systemic exposure and result in adverse effects; avoid coadministration with strong CYP3A4 inhibitors >14 consecutive days, unless the benefit of treatment outweighs the risk Use bedaquiline with caution when coadministered with lopinavir/ritonavir and only if the benefit outweighs the risk There are no clinical data on the combined use of antiretroviral agents and bedaquiline in HIV/MDR-TB coinfected patients and only limited clinical data on use in HIV/MDR-TB coinfected patients not receiving antiretroviral therapy Contraindicated (1) lefamulin

Adverse Effects

Side effects of Bedaquiline : >10% Adults Nausea (38%) Arthralgia (33%) Headache (28%) Chest pain (11%) Pediatrics Arthralgia (40%) Nausea (13%) Abdominal pain (13%) 1-10% Adults Anorexia (9%) Rash (8%) Adults or children Transaminases increased (9%) Blood amylase increased (3%) Frequency Not Defined QT prolongation

Mechanism of Action

Diarylquinoline; inhibits mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme essential for the generation of energy in Mycobacterium tuberculosis