SIRTURO™ adds a novel mechanism of action to the treatment of pulmonary MDR-TB.
SIRTURO™ (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (≥18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO™ for use when an effective treatment regimen cannot otherwise be provided. SIRTURO™ should be administered by directly observed therapy (DOT).
This indication is based on analysis of time to sputum culture conversion from two controlled Phase 2 trials in patients with pulmonary MDR-TB.
Limitations of Use:
The safety and efficacy of SIRTURO™ for the treatment of latent infection due to Mycobacterium tuberculosis have not been established. The safety and efficacy of SIRTURO™ for the treatment of drug-sensitive TB have not been established. In addition, there are no data on the treatment with SIRTURO™ of extrapulmonary TB (e.g., central nervous system). The safety and efficacy of SIRTURO™ for the treatment of infections caused by non-tuberculous mycobacteria (NTM) have not been established. Therefore, use of SIRTURO™ in these settings is not recommended.
Increased Mortality: An increased risk of death was seen in the SIRTURO™ treatment group. The imbalance in deaths is unexplained.
QT Prolongation: SIRTURO™ prolongs the QT interval. An electrocardiogram (ECG) should be obtained before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO™. Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Discontinue SIRTURO™ and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of >500 ms (confirmed by repeat ECG).
The following may increase the risk for QT prolongation when patients are receiving SIRTURO™, and therefore ECGs should be monitored closely: use with other QT-prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine; a history of Torsade de Pointes; a history of congenital long QT syndrome; a history of hypothyroidism and bradyarrhythmias; a history of uncompensated heart failure; serum calcium, magnesium, or potassium levels below the lower limits of normal.
SIRTURO™ has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
Hepatic-related Adverse Drug Reactions: More hepatic-related adverse drug reactions were reported with the use of SIRTURO™ plus other drugs to treat TB compared to other drugs used to treat TB without the addition of SIRTURO™. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO™, especially in patients with diminished hepatic reserve. Monitor symptoms and liver-related laboratory tests. Discontinue SIRTURO™ if aminotransferase elevations are accompanied by total bilirubin elevation >2X ULN; aminotransferase elevations are >8x ULN; or aminotransferase elevations persist beyond 2 weeks.
Drug Interactions: Co-administration of strong systemic CYP3A4 inducers (e.g., rifamycins such as rifampin, rifapentine, and rifabutin) should be avoided. Co-administration with strong systemic CYP3A4 inhibitors for more than 14 consecutive days should be avoided. Appropriate clinical monitoring for SIRTURO™-related adverse reactions is recommended.
HIV-TB Co-infected Patients: There are no clinical data on the combined use of antiretroviral agents and SIRTURO™ in HIV/MDR-TB co-infected patients, and only limited clinical data on the use in HIV/MDR-TB co-infected patients who were not receiving antiretroviral therapy.
Treatment Failure: SIRTURO™ should be administered by directly observed therapy. SIRTURO™ should only be administered in combination with at least 3 drugs active against the patient’s TB isolate. Nonadherence to the treatment regimen could result in failure or resistance.
The most common adverse drug reactions reported in greater than or equal to 10.0% of patients treated with SIRTURO™ compared to the placebo treatment group were nausea (38.0% vs. 32.1%), arthralgia (32.9% vs. 22.2%), headache (27.8% vs. 12.3%), and additional adverse events reported in greater than or equal to 10.0% of patients and with a higher frequency than the placebo treatment group were hemoptysis (17.7% vs. 11.1%) and chest pain (11.4% vs. 7.4%).