SIRTURO

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

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 reactions were identified from the uncontrolled Study 3. Transaminase Elevations In both Studies 1 and 2, transaminase 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 (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times the upper limit of normal during the overall treatment period. In Study 4 during the treatment phase, transaminase elevations of at least 3 times the upper limit of normal developed in 45/211 (21%) in the 40-week SIRTURO treatment group, 45/202 (22%) in the 40-week active comparator group, and 23 /143 (16%) in the 28-week SIRTURO-containing group. Table 4 presents select adverse reactions occurring in 5% or greater of patients receiving SIRTURO in combination with other antimycobacterial drugs in the 40-week SIRTURO arm in Study 4. The most common adverse reactions reported in 10% or more patients in the 40-week SIRTURO arm were QTc prolongation, nausea, vomiting, arthralgia, transaminases increased, abdominal pain, pruritus, dizziness, headache, chest pain, rash, insomnia, dry skin, and palpitations. Table 4: Select Adverse Reactions Occurring in 5% or Greater of Patients Receiving the 40-Week SIRTURO Regimen in Study 4 Adverse Reactions SIRTURO 40-week, bedaquiline, levofloxacin, clofazimine, ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase). N=211 n (%) Active Control 40-week control treatment of moxifloxacin or levofloxacin, clofazimine, ethambutol, pyrazinamide, supplemented by injectable kanamycin, high dose isoniazid and prothionamide in the first 16 weeks (intensive phase). , Study 4 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the SIRTURO and the active control treatment groups. N=202 n (%) QTc prolongation 128 (61) 113 (56) Nausea 114 (54) 126 (62) Vomiting 112 (53) 125 (62) Arthralgia 93 (44) 67 (33) Transaminases increased Terms represented by 'transaminases increased' included AST increased, ALT increased, hepatic enzyme increased, hepatic function abnormal, hypertransaminasemia, and transaminases increased. 63 (30) 59 (29) Abdominal pain Terms represented by 'abdominal pain' included abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal tenderness. 60 (28) 48 (24) Pruritus Terms represented by 'pruritus' included pruritus, pruritus generalized, and rash pruritic. 58 (27) 44 (22) Dizziness 37 (18) 42 (21) Headache 36 (17) 36 (18) Chest pain 33 (16) 24 (12) Rash Terms represented by 'rash' included rash, rash papular and rash maculopapular. 30 (14) 17 (8) Insomnia 30 (14) 19 (9) Dry skin 25 (12) 16 (8) Palpitations 21 (10) 13 (6) Myalgia 19 (9) 6 (3) Paresthesia 16 (8) 8 (4) Diarrhea 12 (6) 17 (8) In the 28-week SIRTURO-containing arm (N=143), in which SIRTURO was used in combination with other antimycobacterial drugs, the most common selected adverse reactions (greater than 10%) were QTc prolongation (56%), arthralgia (55%), nausea (43%), vomiting (29%), pruritus (25%), transaminases increased (21%), dizziness (21%), chest pain (17%), abdominal pain (17%), headache (16%), rash (12%), and hemoptysis (11%). Mortality Imbalance in Clinical Studies 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 TB-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 TB, HIV status, and severity of disease was observed. In the open-label Study 3, 16/233 (6.9%) patients died. The most common cause of death as reported by the investigator was TB (nine patients). In Study 4, patients originally assigned to non-SIRTURO containing regimens could receive SIRTURO as salvage when the original therapy was not tolerated or ineffective. At Week 132, deaths were observed in 11/211 (5.2%) patients in the 40-week SIRTURO arm versus 8/202 (4.0%) patients in the 40-week active control arm. For the 40-week SIRTURO arm, the most common cause of death was related to TB (five patients). In the 40-week active control arm, which included four of 29 patients who received SIRTURO as part of a salvage treatment, the most common cause of death was related to respiratory disease (e.g., TB, lobar pneumonia, respiratory distress in an HIV-positive patient). The adjusted difference in proportion of fatal adverse reactions between the 40-week SIRTURO arm and the 40-week active control arm was 1.2% [95% CI (-2.8%; 5.2%)]. In the 28-week SIRTURO arm at Week 132, 2/143 (1.4%) patients died; one of the two deaths was also related to TB. The overall mortality for patients treated with SIRTURO was 17/383 (4.4%). Clinical Studies Experience in Pediatric Patients The safety assessment of SIRTURO in pediatric patients is based on data from 45 pediatric patients in an ongoing, single-arm, open-label, multi-cohort trial. Pediatric Patients (12 years to less than 18 years of age) The first cohort was designed to enroll patients 12 years to less than 18 years of age (fifteen patients 14 years to less than 18 years of age were enrolled) with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampin who received SIRTURO (400 mg once daily for the first 2 weeks and 200 mg 3 times per week for the following 22 weeks) in combination with a background regimen [see Clinical Studies (14.2) ] . The most common adverse 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 were reported during the study (Week 120 analysis). Observed laboratory abnormalities were comparable to those in adults. Pediatric Patients (5 years to less than 12 years of age) The second cohort was designed to enroll patients 5 years to less than 12 years of age (fifteen patients aged 5 years to less than 11 years of age were enrolled) with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampin who received SIRTURO (200 mg once daily for the first 2 weeks and 100 mg 3 times per week for the following 22 weeks) in combination with a background regimen [see Clinical Studies (14.2) ] . The most common adverse reactions were related to elevations in liver enzymes (5/15, 33%), and led to discontinuation of SIRTURO in three patients. Elevations in liver enzymes were reversible upon discontinuation of SIRTURO and some of the background regimen drugs. Among these 15 pediatric patients, no deaths were reported during the study (Week 120 analysis). Pediatric Patients (2 years to less than 5 years of age) The third cohort enrolled 15 patients aged 2 years to less than 5 years of age with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampin who received SIRTURO (80 to 120 mg once daily for the first 2 weeks and 40 to 60 mg 3 times per week for the following 22 weeks based on weight), in combination with a background regimen [see Clinical Studies (14.2) ] . The most common adverse reaction was vomiting in 3/15 (20%) patients. Among these 15 pediatric patients, no deaths were reported during treatment with SIRTURO (Week 24 analysis).