Bedaquiline warnings and precautions

# Warnings and Precautions

## Increased Mortality
An increased risk of death was seen in the SIRTURO treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial (based on the 120-week visit window). One death occurred during the 24 weeks of administration of SIRTURO. The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat TB, HIV status, or severity of disease could be observed. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided .

## QT Prolongation
SIRTURO prolongs the QT interval. An 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. Follow-up monitoring of electrolytes should be performed if QT prolongation is detected .
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
Discontinue SIRTURO and all other QT prolonging drugs if the patient develops:
Clinically significant ventricular arrhythmia
A QTcF interval of > 500 ms (confirmed by repeat ECG)
Monitor ECGs frequently to confirm that the QTc interval has returned to baseline.
If syncope occurs, obtain an ECG to detect QT prolongation.
SIRTURO has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

## Hepatic-Related Adverse Drug Reactions (ADRs)=
More hepatic-related adverse drug reactions were reported with the use of SIRTURO plus other drugs used 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 laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed.
An increase of serum aminotransferases to > 3ULN should be followed by repeat testing within 48 hours. Testing for viral hepatitis should be performed and other hepatotoxic medications discontinued.
Evidence of new or worsening liver dysfunction (including clinically significant elevation of aminotransferases and/or bilirubin and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on SIRTURO should prompt additional evaluation by the prescriber.
Discontinue SIRTURO if:
aminotransferase elevations are accompanied by total bilirubin elevation > 2ULN
aminotransferase elevations are > 8ULN
aminotransferase elevations persist beyond 2 weeks

## Drug Interactions

### CYP3A4 inducers/inhibitors
Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Co-administration of rifamycins (e.g., rifampin, rifapentine and rifabutin) or other strong CYP3A4 inducers used systemically should therefore be avoided while on treatment with SIRTURO .
Co-administration of SIRTURO with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, the use of strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided while on SIRTURO, unless the benefit of treatment with the drug combination outweighs the risk . 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 of SIRTURO in HIV/MDR-TB co-infected patients (n = 22) who were not receiving antiretroviral (ARV) therapy .

### Treatment Failure
SIRTURO should be administered by directly observed therapy (DOT). SIRTURO should only be administered in combination with at least 3 drugs active against the patient's TB isolate. Isolates from patients who fail to convert or relapse following treatment should be tested for bedaquiline minimum inhibitory concentrations.