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 qDay 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 Hepatic impairment Mild or moderate (Child-Pugh A or B): No dosage adjustment required Severe (Child-Pugh C): Not studied; use only if benefits outweigh risks

Child Dose

Multidrug Resistant Pulmonary Tuberculosis <12 years: Safety and efficacy not established >12 years with weight >30 kg Weeks 1-2: 400 mg PO qDay 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

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

Contra Indications

Precautions

Increased risk of death in bedaquiline treatment group Administered by directly observed therapy (DOT) Potential for development of resistance to bedaquiline in M tuberculosis exists; must only be used in an appropriate combination regimen fo treatment of pulmonary MDR-TB to reduce risk of developing resistance Hepatotoxicity Hepatic-related adverse effects increased when bedaquiline added to multidrug regimen; avoid alcohol and other hepatotoxic drugs, especially in patients with hepatic impairment 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 Monitor ALT, AST, Alkaline phosphatase, and bilirubin at baseline, and monthly while on treatment

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 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

Side 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

Mode of Action