Use in Specific Populations

Pregnancy

Pregnancy Category B, however, there are no adequate and well-controlled studies of SIRTURO® (bedaquiline) in pregnant women. This drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether SIRTURO® or its metabolites are excreted in human milk, but rat studies have shown the drug is concentrated in breast milk.

Because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of SIRTURO® in pediatric patients has not been established.

Geriatric Use

There are limited data on the use of SIRTURO® in tuberculosis patients 65 years and older. Because of limited data, differences in outcomes or specific risks with SIRTURO® cannot be ruled out for patients 65 years of age and older

Race/Ethnicity

In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO®, systemic exposure (AUC) to SIRTURO® was found to be 34% lower in Black patients than in patients from other race categories. This lower exposure was not considered to be clinically relevant as no clear relationship between exposure to SIRTURO® and response has been observed in clinical trials. Furthermore, response rates were comparable in patients of different race categories that completed 24 weeks of SIRTURO® treatment.

Hepatic Impairment

No dose adjustment is deemed necessary in patients with mild or moderate hepatic impairment. After single dose administration of 400 mg SIRTURO® to 8 patients with moderate hepatic impairment (Child Pugh B), mean exposure to SIRTURO® and and its active metabolite M2 (AUC672h) was approximately 20% lower compared to healthy subjects.

SIRTURO® has not been studied in patients with severe hepatic impairment and should be used with caution in these patients only when the benefits outweigh the risks. Clinical monitoring for SIRTURO®-related adverse reactions is recommended.

Renal Impairment

Renal excretion of unchanged SIRTURO® is not substantial (<0.001%). No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis, SIRTURO® should be used with caution. Monitor for adverse reactions of SIRTURO® when administered to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis.

HIV Co-infection

There are limited data on the use of SIRTURO® in HIV co-infected patients.

INDICATIONS AND USAGE

SIRTURO® (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adults (≥18 years) with pulmonary multi drug resistant tuberculosis (MDR TB). Reserve SIRTURO® for use when an effective treatment regimen cannot otherwise be provided. Administer SIRTURO® by directly observed therapy (DOT).

This indication is approved under accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use

Do not use SIRTURO® for the treatment of:

  • Latent infection due to Mycobacterium tuberculosis
  • Drug-sensitive tuberculosis
  • Extrapulmonary tuberculosis
  • Infections caused by non-tuberculous mycobacteria

The safety and efficacy of SIRTURO® in the treatment of HIV-infected patients with MDR-TB have not been established as clinical data are limited.

IMPORTANT SAFETY INFORMATION

WARNINGS: INCREASED MORTALITY; QT PROLONGATION

    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. Only use SIRTURO® when an effective treatment regimen cannot otherwise be provided.
    QT Prolongation
  • QT prolongation can occur with SIRTURO®. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO® if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops.

Warnings and Precautions

Increased Mortality

An increased risk of death was seen in the SIRTURO® treatment group. 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. Only use SIRTURO® when an effective treatment regimen cannot otherwise be provided.

QT Prolongation

SIRTURO® prolongs the QT interval. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO®. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected.

SIRTURO® has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

The following may increase the risk for QT prolongation when patients are receiving SIRTURO®: 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 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

If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.

Discontinue SIRTURO® and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG).

If syncope occurs, obtain an ECG to detect QT prolongation.

Hepatotoxicity

More hepatic-related adverse drug reactions were reported with the use of SIRTURO® plus other drugs to treat tuberculosis compared to other drugs used to treat tuberculosis without the addition of SIRTURO®. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO®, especially in patients with impaired hepatic function.

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:

  • aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
  • aminotransferase elevations are greater than eight times the upper limit of normal
  • aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two 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. Avoid coadministration of strong CYP3A4 inducers such as rifamycins (i.e., rifampin, rifapentine, and rifabutin) or moderate CYP3A4 inducers such as efavirenz. 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, avoid the use of strong CYP3A4 inhibitors used for more than 14 consecutive days 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.

Adverse Reactions

Adverse reactions that occurred more frequently than placebo during treatment with SIRTURO® included: nausea (38% vs. 32%), arthralgia (33% vs. 22%), headache (28% vs. 12%), hemoptysis (18% vs. 11%), chest pain (11% vs. 7%), anorexia (9% vs. 4%), transaminases increased (9% vs. 1%), rash (8% vs. 4%), and blood amylase increased (3% vs. 1%).

Please see full Prescribing Information, including Boxed Warnings and Medication Guide, for more details.