Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 22 November 2019

Indication(s)

1 INDICATIONS AND USAGE SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (12 to less than 18 years of age and weighing at least 30 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. This indication is approved under accelerated approval based on time to sputum culture conversion [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adult and pediatric patients (12 to less than 18 years of age and weighing at least 30 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. (1) 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. (1, 14) Limitations of Use: Do not use SIRTURO for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria (1). Safety and efficacy of SIRTURO in HIV-infected patients with MDR-TB have not been established, as clinical data are limited. (14) Limitations of Use: Do not use SIRTURO for the treatment of: Latent infection due to Mycobacterium tuberculosis Drug-sensitive tuberculosis Extra-pulmonary 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 [see Clinical Studies (14)].

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Increased mortality [see Warnings and Precautions (5.1)] QT Prolongation [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)] Hepatotoxicity [see Warnings and Precautions (5.3)] Drug Interactions [see Warnings and Precautions (5.4)] The most common adverse reactions reported in 10% or more of adult patients treated with SIRTURO were nausea, arthralgia, headache, hemoptysis and chest pain. (6.1) The most common adverse reactions reported in 10% or more of pediatric patients (12 to less than 18 years of age) treated with SIRTURO were arthralgia, nausea and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Therapeutics, Division of Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Use SIRTURO only in combination with other anti-mycobacterial drugs [see Dosage and Administration (2.3)]. Refer to the prescribing information of the drugs used in combination with SIRTURO for their respective adverse reactions. Clinical Studies Experience in Adults Adverse drug reactions for SIRTURO were identified from the pooled safety data from 335 SIRTURO-exposed patients who received 8 weeks (Study 2) and 24 weeks (Studies 1 and 3) at the proposed dose. Studies 1 and 2 were randomized, double-blind, placebo-controlled trials 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 was an open-label, noncomparative study with SIRTURO administered as part of an individualized pulmonary MDR-TB treatment regimen in previously treated patients. In Study 1, 35% 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 reaction. Table 2: Select Adverse Reactions from Study 1 That Occurred More Frequently Than Placebo During Treatment with SIRTURO Adverse Reactions SIRTURO Treatment Group N=79 n (%) Placebo Treatment Group N=81 n (%) Nausea 30 (38) 26 (32) Arthralgia 26 (33) 18 (22) Headache 22 (28) 10 (12) Hemoptysis 14 (18) 9 (11) Chest Pain 9 (11) 6 (7) Anorexia 7 (9) 3 (4) Transaminases IncreasedTerms represented by 'transaminases increased' included transaminases increased, AST increased, ALT increased, hepatic enzyme increased, and hepatic function abnormal. 7 (9) 1 (1) Rash 6 (8) 3 (4) Blood Amylase Increased 2 (3) 1 (1) No additional unique adverse reactions were identified from the uncontrolled Study 3. In both Studies 1 and 2, aminotransferase elevations of at least 3 times the upper limit of normal developed more frequently in the SIRTURO treatment group (11/102 [10.8%] vs 6/105 [5.7%]) than in the placebo treatment group. In Study 3, 22/230 (9.6%) patients had alanine aminotransferase or aspartate aminotransferase greater than or equal to 3 times the upper limit of normal during the overall treatment period. Increased Mortality In Study 1, there was a statistically significant increased mortality risk by Week 120 in the SIRTURO treatment group compared to the placebo treatment group (9/79 (11.4%) versus 2/81 (2.5%), p-value=0.03, an exact 95% confidence interval of the difference [1.1%, 18.2%]). Five of the 9 SIRTURO deaths and the 2 placebo deaths were tuberculosis-related. One death occurred during the 24-week SIRTURO treatment period. The median time to death for the remaining eight patients in the SIRTURO treatment group was 329 days after last intake of SIRTURO. The imbalance in deaths is unexplained; no discernible pattern between death and sputum conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, and severity of disease was observed. In the open-label Study 3, 6.9% (16/233) of patients died. The most common cause of death as reported by the investigator was TB (9 patients). All but one patient who died of TB had not converted or had relapsed. The causes of death in the remaining patients varied. Clinical Studies Experience in Pediatric Patients The safety assessment of bedaquiline is based on the Week 24 analysis of the single-arm, open-label trial, TMC207-C211, in 15 pediatric patients. The trial was designed to enroll patients 12 to less than 18 years of age (only patients 14 to less than 18 years of age were enrolled) with confirmed or probable pulmonary MDR-TB infection who received SIRTURO at the recommended dosage regimen in combination with a background regimen [see Clinical Studies (14.2)]. The most common adverse drug reactions were arthralgia in 6/15 (40%) patients, nausea in 2/15 (13%) patients, and abdominal pain in 2/15 (13%) patients. Among the 15 patients, no deaths occurred during treatment with SIRTURO. Observed laboratory abnormalities were comparable to those in adults.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Administer SIRTURO by directly observed therapy (DOT). (2.1) Emphasize need for compliance with full course of therapy. (2.1) Prior to administration, obtain ECG, liver enzymes and electrolytes. Obtain susceptibility information for the background regimen against Mycobacterium tuberculosis isolate if possible. (2.2) Only use SIRTURO 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, may initiate SIRTURO in combination with at least 4 other drugs to which patient's MDR-TB isolate is likely to be susceptible. (2.3) Recommended dosage in adult and pediatric patients (12 to less than 18 years of age and weighing at least 30 kg): 400 mg once daily for 2 weeks followed by 200 mg 3 times per week (with at least 48 hours between doses) for 22 weeks. (2.3) Swallow SIRTURO tablets whole with water and take with food. (2.3) 2.1 Important Administration Instructions Administer SIRTURO by directly observed therapy (DOT). Use SIRTURO only in combination with other anti-mycobacterial drugs [see Dosage and Administration (2.3)]. Emphasize the need for compliance with full course of therapy. 2.2 Required Testing Prior to Administration Prior to treatment with SIRTURO, obtain the following: Susceptibility information for the background regimen against M. tuberculosis isolate if possible [see Dosage and Administration (2.3)] ECG [see Warnings and Precautions (5.2)] Serum potassium, calcium, and magnesium concentrations [see Warnings and Precautions (5.2)] Liver enzymes [see Warnings and Precautions (5.3)] 2.3 Recommended Dosage in Combination Therapy Only use SIRTURO 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, SIRTURO treatment may be initiated in combination with at least 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible. Refer to the prescribing information of the drugs used in combination with SIRTURO. See Table 1 for the recommended dosage of SIRTURO in adult and pediatric patients (12 to less than 18 years of age). Table 1: Recommended Dosage of SIRTURO Population Dosage Adult patients (18 years of age and older) 400 mg orally once daily for the first two weeks, followed by 200 mg orally three times per week (with at least 48 hours between doses) for 22 weeks (total duration of 24 weeks) Pediatric patients (12 to less than 18 years of age) and weighing at least 30 kg The SIRTURO tablet should be swallowed whole with water and taken with food. If a dose is missed during the first 2 weeks of treatment, do not administer the missed dose (skip the dose and then continue the daily dosing regimen). From Week 3 onwards, if a 200 mg dose is missed, administer the missed dose as soon as possible, and then resume the 3 times a week dosing regimen.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Monitor infants exposed to bedaquiline through breast milk for signs of bedaquiline-related adverse reactions, such as hepatotoxicity. (6, 8.2) Pediatrics: The safety and effectiveness of SIRTURO in pediatric patients less than 12 years of age and/or weighing less than 30 kg have not been established. (8.4) Use with caution in patients with severe hepatic impairment and only when the benefits outweigh the risks. Monitor for SIRTURO-related adverse reactions. (8.6) Use with caution in patients with severe renal impairment. (8.7) 8.1 Pregnancy Risk Summary Available data from published literature of SIRTURO use in pregnant women are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with active tuberculosis during pregnancy (see Clinical Considerations). Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oral administration of bedaquiline to pregnant rats and rabbits during organogenesis at exposures up to 6 times the clinical dose based on AUC comparisons (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death. Data Animal Data Pregnant rats were treated with bedaquiline at 5, 15 and 45 mg/kg (approximately 0.7, 2 and 6 times the clinical dose based on AUC comparisons) during the period of organogenesis (gestational Days 6–17, inclusive). Pregnant rabbits were treated with bedaquiline at 10, 30 and 100 mg/kg (approximately 0.05, 0.2 and 1.5 times the clinical dose based on AUC comparisons) during the period of organogenesis (gestational Days 6–19, inclusive). No embryotoxic effects were found in rats or rabbits at dose exposures up to 6 times the clinical dose exposures based on AUC comparisons. 8.2 Lactation Risk Summary There is no information regarding the presence of bedaquiline in human milk. Minimal data are available on the effects of the drug on breastfed infants. No data are available on the effects of the drug on milk production. Bedaquiline is concentrated in the milk of rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SIRTURO and any potential adverse effects on the breastfed infant from SIRTURO or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to bedaquiline through breast milk for signs of bedaquiline-related adverse reactions, such as hepatotoxicity [see Adverse Reactions (6)]. Data Bedaquiline concentrations in rat milk were 6-fold to 12-fold higher than the maximum concentration observed in maternal plasma at exposures 1 time to 2 times the clinical exposure (based on AUC comparisons). Pups from these dams were exposed to bedaquiline via milk during the lactation period and showed reduced body weights compared to control animals. 8.4 Pediatric Use The safety and effectiveness of SIRTURO have been established in pediatric patients 12 to less than 18 years of age and weighing at least 30 kg. The use of SIRTURO in this pediatric population is supported by evidence from the study of SIRTURO in adults together with additional pharmacokinetic and safety data from the single-arm, open-label, trial that enrolled 15 pediatric patients 14 to less than 18 years of age with confirmed or probable MDR-TB infection who were treated with SIRTURO for 24 weeks in combination with a background regimen [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The use of SIRTURO in pediatric patients 12 to less than 14 years of age is based on information obtained from the studies conducted in adults and pediatric patients 14 to less than 18 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. The safety and effectiveness of SIRTURO in pediatric patients less than 12 years of age and/or weighing less than 30 kg have not been established. 8.5 Geriatric Use Because of limited data, differences in outcomes or specific risks with SIRTURO cannot be ruled out for patients 65 years of age and older. 8.6 Hepatic Impairment The pharmacokinetics of bedaquiline were assessed after single-dose administration to adult patients with moderate hepatic impairment (Child-Pugh B) [see Clinical Pharmacology (12.3)]. 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 (5.3)]. 8.7 Renal Impairment SIRTURO has mainly been studied in adult patients with normal renal function. Renal excretion of unchanged bedaquiline is not substantial (less than or equal to 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 Clinical Pharmacology (12.3)]. Monitor adult and pediatric patients for adverse reactions of SIRTURO when administered to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis.

Interactions

7 DRUG INTERACTIONS Avoid use of strong and moderate CYP3A4 inducers with SIRTURO. (7.1, 7.3) Avoid use for more than 14 consecutive days of systemic strong CYP3A4 inhibitors with SIRTURO unless the benefit outweighs the risk. Monitor for SIRTURO-related adverse reactions. (7.1) 7.1 CYP3A4 Inducers/Inhibitors Bedaquiline exposure may be reduced during co-administration with inducers of CYP3A4 and increased during co-administration with inhibitors of CYP3A4. CYP3A4 Inducers Due to the possibility of a reduction of the therapeutic effect of bedaquiline because of the decrease in systemic exposure, co-administration of strong CYP3A4 inducers, such as rifamycins (i.e., rifampin, rifapentine and rifabutin), or moderate CYP3A4 inducers should be avoided during treatment with SIRTURO [see Clinical Pharmacology (12.3)]. CYP3A4 inhibitors Due to the potential risk of adverse reactions to bedaquiline because of the increase in systemic exposure, prolonged co-administration of bedaquiline and strong CYP3A4 inhibitors, such as ketoconazole or itraconazole, for more than 14 consecutive days should be avoided unless the benefit outweighs the risk [see Clinical Pharmacology (12.3)]. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended. 7.2 Other Antimicrobial Medications No dose-adjustment of isoniazid or pyrazinamide is required during co-administration with SIRTURO. In a placebo-controlled clinical trial in adult patients with MDR-TB, no major impact of co-administration of SIRTURO on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed. 7.3 Antiretroviral Medications Lopinavir/ritonavir Although clinical data in HIV/MDR-TB co-infected patients on the combined use of lopinavir (400 mg)/ritonavir (100 mg) with SIRTURO are not available, use SIRTURO with caution when co-administered with lopinavir/ritonavir and only if the benefit outweighs the risk [see Clinical Pharmacology (12.3)]. Nevirapine No dosage adjustment of bedaquiline is required when co-administered with nevirapine [see Clinical Pharmacology (12.3)]. Efavirenz Concomitant administration of bedaquiline and efavirenz, or other moderate CYP3A inducers, should be avoided [see Warnings and Precautions (5.4)]. 7.4 QT Interval Prolonging Drugs In a drug interaction study of bedaquiline and ketoconazole in adults, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval. In Study 3, mean increases in QTc were larger in the 17 adult patients who were taking clofazimine with bedaquiline at Week 24 (mean change from reference of 31.9 ms) than in patients who were not taking clofazimine with bedaquiline at Week 24 (mean change from baseline of 12.3 ms). Monitor ECGs if SIRTURO is co-administered to patients receiving other drugs that prolong the QTc interval, and discontinue SIRTURO if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

More information

Category Value
Authorisation number NDA204384
Agency product number P04QX2C1A5
Orphan designation No
Product NDC 59676-701
Date Last Revised 01-10-2019
Type HUMAN PRESCRIPTION DRUG
RXCUI 1364509
Storage and handling 16.2 Storage and Handling Dispense in original container. Store tablets dispensed outside the original container in a tight light-resistant container with an expiration date not to exceed 3 months. Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). [See USP Controlled Room Temperature] Keep out of reach of children.
Marketing authorisation holder Janssen Products, LP
Warnings WARNING: INCREASED MORTALITY and QT PROLONGATION WARNING: INCREASED MORTALITY and QT PROLONGATION See full prescribing information for complete boxed warning. 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 in adults. Only use SIRTURO in patients 12 years of age and older when an effective treatment regimen cannot otherwise be provided. (5.1) 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 QTcF interval >500 ms develops. (5.2) 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 in adults. Only use SIRTURO in patients 12 years of age and older when an effective treatment regimen cannot otherwise be provided [see Indications and Usage (1), Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. 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 [see Warnings and Precautions (5.2)].