Bedaquiline fumarate

Bedaquiline fumarate
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Black Box Warning

WARNINGS: See full prescribing information for complete Boxed Warning. * 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 can occur with SIRTURO. Use with drugs that prolong the QT interval may cause additive QT prolongation.

Overview

Bedaquiline fumarate is an antitubercular that is FDA approved for the treatment of multidrug resistant tuberculosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include chest pain, nausea, arthralgia, headache, hemoptysis, increased liver enzymes.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• SIRTURO 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 extra-pulmonary 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.

Dosage

• SIRTURO should only be used in combination with at least 3 other drugs to which the patient's MDR-TB isolate has been shown to be susceptible in vitro. If in vitro testing results are unavailable, treatment may be initiated with SIRTURO in combination with at least 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible.

• Throughout treatment with, and following the last intake of SIRTURO, patients should continue to take their companion drugs as directed.

The recommended dosage of SIRTURO is:

• Weeks 1–2: 400 mg (4 tablets of 100 mg) once daily with food
• Weeks 3–24: 200 mg (2 tablets of 100 mg) 3 times per week with food (with at least 48 hours between doses) for a total dose of 600 mg per week.
• The total duration of treatment with SIRTURO is 24 weeks. The SIRTURO tablet should be swallowed whole with water. Patients should avoid alcohol use while on treatment.

Missed doses

• Patients should be advised of the need to take SIRTURO as prescribed. Compliance with the full course of therapy must be emphasized.

• If a dose is missed during the first 2 weeks of treatment, patients should not make up the missed dose but should continue the usual dosing schedule. From Week 3 onwards, if a 200 mg dose is missed, patients should take the missed dose as soon as possible, and then resume the 3 times a week regimen.

DOSAGE FORMS AND STRENGTHS

• 100 mg Tablet

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

There is limited information regarding Off-Label Guideline-Supported Use of Bedaquiline fumarate in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Bedaquiline fumarate in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Bedaquiline fumarate in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Bedaquiline fumarate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Bedaquiline fumarate in pediatric patients.

Contraindications

• None

Warnings

WARNINGS: See full prescribing information for complete Boxed Warning. * 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 can occur with SIRTURO. Use with drugs that prolong the QT interval may cause additive 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 (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 > 3×ULN 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 > 2×ULN

• Aminotransferase elevations are > 8×ULN

• 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.

Adverse Reactions

Clinical Trials Experience

The most frequent adverse drug reactions (> 10.0% of patients) during treatment with SIRTURO in the controlled trials were nausea, arthralgia, and headache. Additional adverse events reported in ≥10% of patients treated with SIRTURO and with a higher frequency than the placebo treatment group were hemoptysis and chest pain.

Clinical Studies Experience

• Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

• Adverse drug reactions for SIRTURO were identified from the pooled safety data from 335 bedaquiline-exposed patients who received 8 weeks (Study 2) and 24 weeks (Studies 1 and 3) at the proposed dose. Studies 1 and 2 are randomized, double-blind, placebo-controlled trial in newly diagnosed patients with pulmonary MDR-TB. In both treatment arms, patients received SIRTURO or placebo in combination with other drugs used to treat MDR-TB. Study 3 is an ongoing, open-label, noncomparative study with SIRTURO administered as part of an individualized pulmonary MDR-TB treatment regimen in previously treated patients.

• In Study 1 overall, 35.0% were Black, 17.5% were Hispanic, 12.5% were White, 9.4% were Asian, and 25.6% were of another race. Eight of 79 (10.1%) patients in the SIRTURO group and 16 of 81 (19.8%) patients in the placebo treatment group were HIV-infected. Seven (8.9%) SIRTURO-treated patients and six (7.4%) placebo-treated patients discontinued Study 1 because of an adverse event.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Bedaquiline fumarate in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bedaquiline fumarate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Bedaquiline fumarate during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Bedaquiline fumarate with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Bedaquiline fumarate with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Bedaquiline fumarate with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Bedaquiline fumarate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Bedaquiline fumarate with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Bedaquiline fumarate in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Bedaquiline fumarate in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Bedaquiline fumarate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Bedaquiline fumarate in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Bedaquiline fumarate in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Bedaquiline fumarate in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Bedaquiline fumarate in the drug label.

Pharmacology

There is limited information regarding Bedaquiline fumarate Pharmacology in the drug label.

Mechanism of Action

Structure

File:Bedaquiline fumarate01.png

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Bedaquiline fumarate in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Bedaquiline fumarate in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Bedaquiline fumarate in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Bedaquiline fumarate in the drug label.

How Supplied

Storage

There is limited information regarding Bedaquiline fumarate Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Bedaquiline fumarate in the drug label.

Precautions with Alcohol

• Alcohol-Bedaquiline fumarate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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