Drug-Drug Interactions

CYP3A4 Inducers/Inhibitors

SIRTURO^® exposure may be reduced during co-administration with inducers of CYP3A4 and increased during co-administration with inhibitors of CYP3A4.

CYP3A4 Inducers

Due to the possibility of a reduction of the therapeutic effect of SIRTURO^® because of the decrease in systemic exposure, co-administration of strong CYP3A4 inducers, such as rifamycins (i.e., rifampin, rifapentine and rifabutin), or moderate CYP3A4 inducers should be avoided during treatment with SIRTURO^®.

CYP3A4 inhibitors

Due to the potential risk of adverse reactions to SIRTURO^® because of the increase in systemic exposure, prolonged co-administration of SIRTURO^® and strong CYP3A4 inhibitors, such as ketoconazole or itraconazole, for more than 14 consecutive days should be avoided unless the benefit outweighs the risk. Appropriate clinical monitoring for SIRTURO^®-related adverse reactions is recommended.

Other Antimicrobial Medications

No dose-adjustment of isoniazid or pyrazinamide is required during co-administration with SIRTURO^®.

In a placebo-controlled clinical trial in adult patients with MDR-TB, no major impact of co-administration of SIRTURO^® on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.

Antiretroviral Medications

Lopinavir/ritonavir

Although clinical data in HIV/MDR-TB co-infected patients on the combined use of lopinavir (400 mg)/ritonavir (100 mg) with SIRTURO^® are not available, use SIRTURO^® with caution when co-administered with lopinavir/ritonavir and only if the benefit outweighs the risk.

Nevirapine

No dosage adjustment of SIRTURO^® is required when co-administered with nevirapine.

Efavirenz

Concomitant administration of SIRTURO^® and efavirenz, or other moderate CYP3A inducers, should be avoided.

QT Interval Prolonging Drugs

In a drug interaction study of SIRTURO^® and ketoconazole in adults, a greater effect on QTc was observed after repeated dosing with SIRTURO^® and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when SIRTURO^® was co-administered with other drugs that prolong the QT interval.

In Study 3, mean increases in QTc were larger in the 17 adult patients who were taking clofazimine with SIRTURO ^® at Week 24 (mean change from reference of 31.9 ms) than in patients who were not taking clofazimine with bedaquiline at Week 24 (mean change from baseline of 12.3 ms). Monitor ECGs if SIRTURO^® is co-administered to patients receiving other drugs that prolong the QTc interval, and discontinue SIRTURO^® if evidence of serious ventricular arrhythmia, or QTcF interval greater than 500 ms.