Bedaquiline - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS A mortality imbalance was seen in clinical trials in SIRTURO-treated patients with pulmonary TB due to Mycobacterium tuberculosis resistant to at least rifampin.

Hepatotoxicity may occur with use of SIRTURO.

Monitor liver-related laboratory tests.

Discontinue SIRTURO if evidence of liver injury occurs.

5.1 QTc Prolongation SIRTURO prolongs the QTc interval [see Clinical Pharmacology ] .

Use with drugs that prolong the QTc interval may cause additive QTc prolongation [see Adverse Reactions ] .

In Study 4, where SIRTURO was administered with the QTc prolonging drugs clofazimine and levofloxacin, 5% of patients in the 40-week SIRTURO treatment group experienced a QTc ≥500 ms and 43% of patients experienced an increase in QTc ≥60 ms over baseline.

Of the clofazimine- and levofloxacin-treated patients in the 40-week control arm, 7% of patients experienced a QTc ≥500 ms and 39% experienced an increase in QTc ≥60 ms over baseline.

Obtain an ECG before initiation of treatment, 2 weeks after initiation, during treatment, as clinically indicated and at the expected time of maximum increase in the QTc interval of the concomitantly administered QTc prolonging drugs (as applicable).

Obtain electrolytes at baseline and during treatment and correct electrolytes as clinically indicated.

The following may increase the risk for QTc prolongation when patients are taking SIRTURO: use with other QTc prolonging drugs a history of Torsade de Pointes a history of congenital long QTc syndrome a history of or ongoing hypothyroidism a history of or ongoing bradyarrhythmias a history of uncompensated heart failure serum calcium, magnesium, or potassium levels below the lower limits of normal Discontinue SIRTURO if the patient develops: Clinically significant ventricular arrhythmia A QTc interval of greater than 500 ms (confirmed by repeat ECG) If syncope occurs, obtain an ECG to detect QTc prolongation.

5.2 Mortality Imbalance in Clinical Trials 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 in adults (Study 1; 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 tuberculosis, HIV status, or severity of disease could be observed.

In a subsequent active-controlled trial in adults (Study 4), deaths by Week 132 occurred in 11/211 (5.2%) patients in the 40-week SIRTURO treatment group, 8/202 (4%) patients in the active-control treatment group including four of 29 patients who received SIRTURO as part of a salvage treatment, and 2/143 (1.4%) patients in the 28-week SIRTURO treatment group [see Adverse Reactions ] .

5.3 Risk of Development of Resistance to Bedaquiline A potential for development of resistance to bedaquiline in M. tuberculosis exists [see Microbiology ].

Bedaquiline must only be used in an appropriate combination regimen for the treatment of pulmonary TB due to M. tuberculosis resistant to at least rifampin and isoniazid, to reduce the risk of development of resistance to bedaquiline [see Indications and Usage ] .

5.4 Hepatotoxicity In clinical trials, more hepatic-related adverse reactions were reported in adults 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 impaired hepatic function.

Hepatic-related adverse reactions have also been reported in pediatric patients 5 years of age and older [see Adverse Reactions ] .

Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and 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.

Discontinue SIRTURO if: transaminase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal transaminase elevations are greater than eight times the upper limit of normal transaminase elevations are greater than five times the upper limit of normal and persist beyond two weeks 5.5 Drug Interactions CYP3A4 Inducers Coadministration of SIRTURO with a moderate or strong CYP3A4 inducer decreases the systemic exposure of bedaquiline and may reduce the therapeutic effect of SIRTURO.

Avoid coadministration of SIRTURO with moderate or strong CYP3A4 inducers, such as efavirenz and rifamycins (i.e., rifampin, rifapentine and rifabutin) [see Drug Interactions ] .