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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 [see ADVERSE REACTIONS].
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 [see ADVERSE REACTIONS and DRUG INTERACTIONS].
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 > 3xULN 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 > 2xULN
- aminotransferase elevations are > 8xULN
- aminotransferase elevations persist beyond 2 weeks
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 [see DRUG INTERACTIONS].
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 [see DRUG INTERACTIONS]. 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 [see DRUG INTERACTIONS].
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.
Patient Counseling Information
Tuberculosis is a serious disease that can be fatal; some patients with resistant TB may have limited treatment options. Patients should be advised that the following serious side effects can occur with SIRTURO: death, heart rhythm abnormalities, and/or hepatitis. In addition, patients should also be advised about other potential side effects: nausea, joint pain, headache, increased blood amylase, hemoptysis, chest pain, anorexia, and/or rash. Additional testing may be needed to monitor or reduce the likelihood of adverse effects.
Take SIRTURO in combination with other antimycobacterial drugs as prescribed. Compliance with the full course of therapy must be emphasized. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the treatment and (2) increase the likelihood that their mycobacterium may develop resistance and the disease will not be treatable by SIRTURO or other antibacterial drugs in the future.
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.
Patients should be informed to take SIRTURO with food. Patients should be advised to abstain from alcohol, hepatotoxic medications or herbal products.
Patients should be advised to discuss with their physician the other medications they are taking and other medical conditions before starting treatment with SIRTURO. Patients should be advised to consult with their doctor if they have a personal or family history of congenital QT prolongation or heart failure.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No mutagenic or clastogenic effects were detected in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay and an in vivo mouse bone marrow micronucleus assay.
SIRTURO had no effects on fertility when evaluated in male and female rats. No relevant drug-related effects on developmental toxicity parameters were observed in rats and rabbits. The corresponding plasma exposure (AUC) was 2-fold higher in rats and lower for rabbits compared to humans. There was no effect of maternal treatment with bedaquiline at any dose level on sexual maturation, behavioral development, mating performance, fertility or reproductive capacity of the F1 generation animals. Body weight decreases in pups were noted in high dose groups during the lactation period after exposure to bedaquiline via milk and were not a consequence of in utero exposure. Concentrations of bedaquiline in milk were 6- to 12-fold higher that the maximum concentration observed in maternal plasma.
Use In Specific Populations
Pregnancy Category B. Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to bedaquiline. In these studies, the corresponding plasma exposure (AUC) was 2-fold higher in rats compared to humans. There are, however, no adequate and well-controlled studies of SIRTURO in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether bedaquiline or its metabolites are excreted in human milk, but rat studies have shown that drug is concentrated in breast milk.
In rats, treated with bedaquiline at doses 1 to 2 times the clinical dose (based on AUC comparisons), concentrations in milk were 6- to 12-fold higher than the maximum concentration observed in maternal plasma. Pups from these dams showed reduced body weights compared to control animals throughout the lactation period.
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.
The safety and effectiveness of SIRTURO in children and adolescents less than 18 years of age have not been established.
Clinical studies of SIRTURO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
The pharmacokinetics of bedaquiline were assessed after single-dose administration to subjects with moderate hepatic impairment (Child-Pugh B) [see Pharmacokinetics]. Based on these results, no dose adjustment is necessary for SIRTURO in patients with mild or moderate hepatic impairment. 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 [see WARNINGS AND PRECAUTIONS].
SIRTURO has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline 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 [see Pharmacokinetics].
Last reviewed on RxList: 1/10/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Sirturo Information
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