Bedaquiline

12.1 Mechanism of Action Bedaquiline is a diarylquinoline antimycobacterial drug [see Microbiology (12.4) ] .

1 INDICATIONS AND USAGE SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (2 years and older and weighing at least 8 kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid. SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adult and pediatric patients (2 years and older and weighing at least 8 kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid. ( 1 ) Limitations of Use : Do not use SIRTURO for the treatment of latent, extra-pulmonary or drug-sensitive TB or for the treatment of infections caused by non-tuberculous mycobacteria. ( 1 ) Limitations of Use Do not use SIRTURO for the treatment of: Latent infection due to Mycobacterium tuberculosis ( M. tuberculosis ) Drug-sensitive pulmonary TB Extra-pulmonary TB Infections caused by non-tuberculous mycobacteria

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 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 TB isolate is likely to be susceptible. ( 2.1 ) Recommended dosage in adult patients: 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) once daily for 2 weeks followed by 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) 3 times per week (with at least 48 hours between doses) for 22 weeks. ( 2.3 ) Recommended dosage in pediatric patients (2 years and older and weighing at least 8 kg) is based on body weight. ( 2.4 ) Take SIRTURO tablets with food. ( 2.6 ) See full prescribing information for the different methods of administration of SIRTURO 20 mg tablet and administration of the 100 mg tablet. 2.1 Important Administration Instructions Administer SIRTURO by directly observed therapy (DOT). Only use SIRTURO in combination with at least three other drugs to which the patient's 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 four other drugs to which the patient's TB isolate is likely to be susceptible. Refer to the prescribing information of the drugs used in combination with SIRTURO for further information. SIRTURO (20 mg and 100 mg) must be taken with food. SIRTURO 20 mg are functionally scored tablets which can be split at the scored lines into two equal halves of 10 mg each to provide doses less than 20 mg [see Dosage and Administration (2.6) ]. As an alternative method of administration, SIRTURO 20 mg tablets can be dispersed in water and administered or dispersed in water and further mixed with a beverage or soft food, or crushed and mixed with soft food, or administered through a feeding tube [see Dosage and Administration (2.6) ]. Emphasize the need for compliance with the 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 (2.1) ] ECG [see Warnings and Precautions (5.1) ] Serum potassium, calcium, and magnesium concentrations [see Warnings and Precautions (5.1) ] Liver enzymes [see Warnings and Precautions (5.4) ] 2.3 Recommended Dosage in Adult Patients The recommended dosage of SIRTURO in adult patients is: Table 1: Recommended Dosage of SIRTURO in Adult Patients Dosage Recommendation Weeks 1 and 2 Weeks 3 to 24 At least 48 hours between doses 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) orally once daily 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally three times per week Recommended dosage in pediatric patients is described in Table 2 below [see Dosage and Administration (2.4) ]. Administer SIRTURO tablets with food. The total duration of treatment with SIRTURO in adults is 24 weeks. When treatment with SIRTURO is considered necessary beyond 24 weeks, treatment may be continued at a dose of 200 mg three times per week [see Clinical Studies (14.1) ] . 2.4 Recommended Dosage in Pediatric Patients (2 years and older and weighing at least 8 kg) The recommended dosage of SIRTURO in pediatric patients (2 years and older and weighing at least 8 kg) is based on body weight and shown in Table 2: Table 2: Recommended Dosage of SIRTURO in Pediatric Patients (2 years and older and weighing at least 8 kg) Body Weight Dosage Recommendation Weeks 1 and 2 Weeks 3 to 24 At least 48 hours between doses 8 kg to less than 10 kg 80 mg (4 of the 20 mg tablets) orally once daily 40 mg (2 of the 20 mg tablets) orally three times per week 10 kg to less than 15 kg 120 mg (6 of the 20 mg tablets) orally once daily 60 mg (3 of the 20 mg tablets) orally three times per week 15 kg to less than 30 kg 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally once daily 100 mg (1 of the 100 mg tablets OR 5 of the 20 mg tablets) orally three times per week Greater than or equal to 30 kg 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) orally once daily 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally three times per week Administer SIRTURO tablets with food. The total duration of treatment with SIRTURO is 24 weeks. When treatment with SIRTURO is considered necessary beyond 24 weeks in patients 16 years and older, and weighing at least 30 kg, treatment may be continued at a dose of 200 mg three times per week [see Clinical St

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: QTc Prolongation [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] Mortality Imbalance in Clinical Trials [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Drug Interactions [see Warnings and Precautions (5.5) ] The most common adverse reactions reported in 10% or more adult patients treated with SIRTURO in Study 1 were nausea, arthralgia, headache, hemoptysis and chest pain. ( 6.1 ) The most common adverse reactions reported in 10% or more adult patients treated with SIRTURO (40-week arm) in Study 4 were QTc prolongation, nausea, vomiting, arthralgia, transaminases increased, abdominal pain, pruritus, dizziness, headache, chest pain, rash, insomnia, dry skin, and palpitations. ( 6.1 ) The most common adverse reactions reported in 10% or more of pediatric patients (12 years to less than 18 years of age) treated with SIRTURO were arthralgia, nausea and abdominal pain. ( 6.1 ) The most common adverse reaction reported in 10% or more of pediatric patients (5 years to less than 12 years of age) treated with SIRTURO was elevation in liver enzymes. ( 6.1 ) The most common adverse reaction reported in 10% or more of pediatric patients (2 years to less than 5 years of age) treated with SIRTURO was vomiting. ( 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. Refer to the prescribing information of the drugs used in combination with SIRTURO for their respective adverse reactions. Clinical Studies Experience in Adults Adverse reactions for SIRTURO were identified from safety data from 335 patients who received SIRTURO for eight weeks (Study 2) and 24 weeks (Studies 1 and 3), and 354 patients who received SIRTURO for 40 weeks or 28 weeks (Study 4). In these studies, patients received SIRTURO in combination with other antimycobacterial drugs. Studies 1 and 2 were randomized, double-blind, placebo-controlled trials in newly diagnosed patients with pulmonary TB due to M. tuberculosis resistant to at least rifampin and isoniazid. Study 3 was an open-label, noncomparative study with SIRTURO administered as part of an individualized treatment regimen in previously treated patients with pulmonary TB due to M. tuberculosis resistant to at least rifampin and isoniazid, including patients resistant to second-line injectables and/or fluroquinolones. In Study 1, 35% were Black, 17% were Hispanic, 13% were White, 9% were Asian, and 26% were of another race. Eight of 79 (10%) patients in the SIRTURO group and 16 of 81 (20%) 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. Study 4 was an open-label, randomized, active-controlled trial in patients with pulmonary TB due to M. tuberculosis resistant to at least rifampin that evaluated a 40-week arm of SIRTURO in combination with other oral antimycobacterial drugs compared with a 40-week active control arm that included an injectable antimycobacterial drug in combination with other oral antimycobacterial drugs. A 28-week arm including SIRTURO, an injectable and other antimycobacterial drugs, was also evaluated in the trial, but recruitment was stopped early due to changes in the standard of care. In the population treated in the two 40-week arms (N=413), the median age was 32.8 years, 61% were male, 46% were Asian, 36% were Black, 18% were White and 16% were HIV infected. Common Adverse Reactions Table 3 presents select adverse reactions that occurred more frequently in the SIRTURO arm than the placebo arm in Study 1. The most common adverse reactions reported in 10% or more patients treated with SIRTURO and occurred more frequently than the placebo arm were nausea, arthralgia, headache, hemoptysis and chest pain. Table 3: 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 Increased Terms 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

7 DRUG INTERACTIONS Avoid use of strong and moderate CYP3A4 inducers with SIRTURO. ( 7.1 ) Closely monitor patient safety (e.g., liver function) when SIRTURO is coadministered with CYP3A4 inhibitors. ( 5.4 , 7.1 ) 7.1 Effect of Other Drugs on SIRTURO Strong and Moderate CYP3A4 Inducers Coadministration of SIRTURO with moderate or strong CYP3A4 inducers may decrease systemic exposure of bedaquiline. Avoid coadministration of SIRTURO with strong or moderate CYP3A4 inducers [see Clinical Pharmacology (12.3) ] . CYP3A4 Inhibitors Coadministration of SIRTURO with CYP3A4 inhibitors increases the systemic exposure of bedaquiline which may increase the risk of adverse reactions. Closely monitor patient safety (e.g., liver function) when SIRTURO is coadministered with CYP3A4 inhibitors. No dose adjustment of SIRTURO is needed when coadministered with CYP3A4 inhibitors [see Clinical Pharmacology (12.3) ] . 7.2 Other Antimicrobial Medications No dose adjustment of isoniazid or pyrazinamide is required during coadministration with SIRTURO. In a placebo-controlled clinical trial in adult patients, no major impact of coadministration of SIRTURO on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed. 7.3 QTc Interval Prolonging Drugs In clinical trials of adult patients, additional QTc interval prolongation was observed during combination treatment with SIRTURO and other QTc prolonging drugs. In Study 3, concurrent use of clofazimine with SIRTURO resulted in QTc prolongation: mean increases in QTc were larger in the 17 adult patients who were taking clofazimine with bedaquiline at Week 24 (mean change from Day-1 of 32 ms) than in patients who were not taking clofazimine with bedaquiline at Week 24 (mean change from Day-1 of 12 ms). Monitor ECGs if SIRTURO is coadministered to patients receiving other drugs that prolong the QTc interval, and discontinue SIRTURO if there is evidence of serious ventricular arrhythmia or QTc interval greater than 500 ms [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] . ECG monitoring should be performed prior to initiation and at the expected time of maximum increase in the QTc interval of the concomitantly administered QTc prolonging drugs.