SIRTURO- bedaquiline fumarate_tablet

Bedaquiline is a diarylquinoline antimycobacterial drug [see Microbiology (12. 4) Bedaquiline has activity against M. tuberculosis Cardiac Electrophysiology In Study 1, the largest mean increase in QTc during the 24 weeks of SIRTURO treatment was 16 ms compared to 6 ms with placebo treatment (at Week 18). After SIRTURO treatment ended, the QTc gradually decreased, and the mean value was similar to that in the placebo group by study Week 60. In Study 4, the mean change from baseline in QTc for the SIRTURO-containing arm was 22 ms (95% CI: 19; 24) at Week 2 (i. , the end of the 2-week SIRTURO loading period), and 8 ms (95% CI: 2; 13) in the levofloxacin-containing control arm subgroup. In Study 4, the mean QTc increased from baseline over the first 12 weeks for both SIRTURO and the non-SIRTURO containing control arm, when a plateau was reached. The largest mean QTc increase from baseline was 35 ms (95% CI: 32 to 38 ms) for the SIRTURO-containing arm and 28 ms (95% CI: 21 to 34 ms) for the levofloxacin-containing control arm subgroup [see Warnings and Precautions (5. 1) Drug Interactions (7. 3) Pharmacokinetics (PK) parameters The pharmacokinetic properties of bedaquiline are summarized in Table 5 as mean (SD) in adult patients. Table 5: Model-Derived Pharmacokinetic Parameters of Bedaquiline and M2 (mean [SD]) after Multiple Doses of SIRTURO at the Recommended Dosing Regimen Pharmacokinetic Parameters Bedaquiline SD=Standard Deviation Absorption Food effect High fat meal (22 grams of fat, 558 total Kcal) increased C max T max Around 5 hours after single oral dose administration of SIRTURO C max Week 2: 3060 (1124) ng/mL C max Week 2: 326 (135) ng/mL Exposure AUC 168h 24h Week 2: 41510 (15064) ng. h/mL AUC 168h 24h Week 2: 7267 (3029) ng. h/mL Distribution Percent bound to human plasma protein greater than 99. apparent central volume of distribution approximately 117 Liters. Proportionality C max Elimination After reaching C max Apparent clearance of bedaquiline 2. 62 L/h Apparent clearance of M2 4. 95 L/h Terminal half-life ~ 5. 5 months for both bedaquiline and N Metabolism Metabolized to the M2 by CYP3A4; Relative exposure M2 versus bedaquiline: 23%~31% Excretion Major route of excretion Fecal excretion is the major route of elimination %Excreted unchanged in urine less than or equal to 0. 001% of the dose in clinical studies Specific Populations Patients with Hepatic Impairment: 672h [see Warnings and Precautions (5. 4) Use in Specific Populations (8. 6) Patients with Renal Impairment: In a population pharmacokinetic analysis of adult TB patients treated with SIRTURO 200 mg three times per week, creatinine clearance was not found to influence the pharmacokinetic parameters of bedaquiline. It is therefore not expected that mild or moderate renal impairment will have a clinically relevant effect on the exposure to bedaquiline. However, in patients with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis bedaquiline concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. As bedaquiline is highly bound to plasma proteins, it is unlikely that it will be significantly removed from plasma by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8. 7) Male and Female Patients: Race or Ethnicity: HIV Coinfection: Geriatric Patients: In a population pharmacokinetic analysis of adult TB patients treated with SIRTURO, age was not found to influence the pharmacokinetics of bedaquiline. In five patients 65 to 69 years of age, the systemic bedaquiline exposure was similar to that in other adults. Pediatric Patients: Pediatric patients 12 years to less than 18 years of age with TB due to M. tuberculosis resistant to at least rifampin The pharmacokinetic parameters of bedaquiline in 15 pediatric patients (body weight at baseline: 38 to 75 kg) who received the same adult dosage regimen of SIRTURO (400 mg once daily for the first two weeks and 200 mg three times per week for the following 22 weeks) in combination with a background regimen were comparable to those in adults. There was no impact of body weight on bedaquiline pharmacokinetics in this cohort. Pediatric patients 5 years to less than 12 years of age with TB due to M. tuberculosis resistant to at least rifampin Fifteen pediatric patients (body weight at baseline: 14 to 36 kg) received SIRTURO (200 mg once daily for the first two weeks and 100 mg three times per week for the following 22 weeks) in combination with a background regimen. Of these 15 pediatric patients, complete pharmacokinetic data were obtained for 10 patients at the aforementioned dosage regimen of SIRTURO. In nine of these 10 pediatric patients who weighed at least 15 kg at baseline, the mean bedaquiline C max 24h max 24h max 24h Pediatric patients 2 years to less than 5 years of age with TB due to M. tuberculosis resistant to at least rifampin Fifteen pediatric patients (body weight at baseline: 10 to 16 kg) received SIRTURO at a dose of 8 mg/kg once daily for 2 weeks (dose range: 80 to 120 mg; not an approved dosing regimen) followed by 4 mg/kg three times per week (dose range: 40 to 60 mg; not an approved dosing regimen) in combination with a background regimen. The results showed that the pediatric patients receiving the dosing regimens used in this pediatric study had mean bedaquiline C max 24h [see Use in Specific Populations (8. 4) The recommended dosing regimens for pediatric patients weighing 8 kg to less than 15 kg differ from those used in the pediatric clinical study. For pediatric patients weighing 8 kg to less than 15 kg, the recommended dosing regimens [see Dosage and Administration (2. 4) [see Use in Specific Populations (8. 4) See Table 6 Table 6: Pharmacokinetic Parameters of Bedaquiline Following Repeat Dose Administration of SIRTURO to Pediatric Patients 2 to Less than 18 Years of Age at Week 12 Administered with Food Pharmacokinetic Parameter Bedaquiline 14 years to less than 18 years 5 years to less than 12 years 2 years to less than 5 years SD=Standard Deviation AUC 24h 26,300 (10,300) 32,200 (16,300) 26,700 (7,270) N=10 C max 1,800 (736) 2,430 (1,670) 1,810 (872) T max Median (range) 4 (2 to 8) 4 (2 to 8) 6 (2 to 24) C min 544 (263) 461 (173) 486 (161) Drug Interactions Studies In vitro, bedaquiline did not significantly inhibit the activity of the following CYP450 enzymes that were tested: CYP1A2, CYP2A6, CYP2C8/9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A4/5 and CYP4A, and it does not induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4 activities. Bedaquiline is an in vitro substrate of CYP3A4, and because of this, the following clinical drug interaction studies were performed. Clinical Studies Ketoconazole: 24h max min [see Drug Interactions (7. 3) Clarithromycin: 240h Clofazimine: Rifampin: [see Drug Interactions (7. 1) Antimicrobial agents: [see Drug Interactions (7. 2) In a placebo-controlled study in adult patients with, no major impact of coadministration of bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed. Lopinavir/ritonavir: max 168h [see Drug Interactions (7. 1) Nevirapine: 168h Efavirenz: inf max max [see Drug Interactions (7. 3) Mechanism of Action SIRTURO is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'- triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of energy in M. tuberculosis Resistance A potential for development of resistance to bedaquiline in M. tuberculosis atpE Rv0678 M. tuberculosis. tuberculosis Rv0678 Rv0678 Antimicrobial Activity SIRTURO has been shown to be active in vitro and in clinical infections against most isolates of M. tuberculosis [see Indications and Usage (1) Clinical Studies (14) Susceptibility Testing MICs for baseline M. tuberculosis Table 7: Culture Conversion Rates in SIRTURO Treatment Groups at Week 24 (Study 1 and 3) and at Week 76 (Study 4), by Baseline Bedaquiline MIC (mITT population) 7H11 agar. Patients who prematurely discontinued were categorized as culture converted (or not) based on the available data. All available data were utilized regardless of changes in treatment. Baseline Bedaquiline MIC SIRTURO Treatment Group 24-Week Culture Conversion Rate SIRTURO Treatment Group 76-Week Culture Conversion Rate In addition, at Week 76 in the 40-week SIRTURO arm, there were 6 patients for whom no baseline MIC data were available. All 6 patients culture converted. N=number of patients with data per baseline BDQ MIC category; n=number of patients with culture conversion; MIC=minimum inhibitory concentration <= 0. 008 2/2 (100) 5/5 (100) 0. 015 13/15 (86. 7) 26/26 (100) 0. 03 36/46 (78. 3) 67/69 (97. 06 82/107 (76. 6) 51/51 (100) 0. 12 36/42 (85. 7) 20/20 (100) 0. 0) 2/2 (100) 0. 3) 0 >= 1 0/1 (0) 0 Nineteen patients in the efficacy population of Study 3 had bedaquiline susceptibility testing results of paired (baseline and post-baseline, all of which were at Week 24 or later) genotypically identical M. tuberculosis Rv0678 Based on available data, response rate (culture conversion at Week 120 endpoint) was similar in patients with >=4-fold increases in bedaquiline MIC (5/12) and patients with <4-fold increases (3/7). In the 40-week SIRTURO arm of Study 4, paired isolates (baseline and postbaseline, genotypically identical) susceptibility testing (MIC) results were available for 30 of 196 patients in the mITT population. At Week 132, three of five patients with a >=4-fold increase in bedaquiline MIC and 25 of 25 patients with <4-fold increases had culture converted. Similarly, in the 28-week arm of Study 4, for 25 of 134 patients in the mITT population with paired isolates, two of four patients, with a >=4-fold increase in bedaquiline MIC and 20 of 21 patients with <4-fold increases had culture converted. Based on the limited data, there was no clear relationship between bedaquiline MIC and microbiological outcomes. For specific information regarding susceptibility test criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: www.

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 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 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.

Administer SIRTURO by directly observed therapy (DOT). 1 Emphasize need for compliance with full course of therapy. 1 Prior to administration, obtain ECG, liver enzymes and electrolytes. Obtain susceptibility information for the background regimen against Mycobacterium tuberculos isisolate if possible. 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. 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. 3 Recommended dosage in pediatric patients (2 years and older and weighing at least 8 kg) is based on body weight. 4 Take SIRTURO tablets with food. 6 See full prescribing information for the different methods of administration of SIRTURO 20 mg tablet and administration of the 100 mg tablet. 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. Prior to treatment with SIRTURO, obtain the following: Susceptibility information for the background regimen against M. tuberculos isisolate 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) 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) 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 Studies (14. 1) 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 dose is missed, administer the missed dose as soon as possible, and then resume the 3 times a week dosing regimen. The total dose of SIRTURO during a 7-day period should not exceed the recommended weekly dose (with at least 24 hours between each intake). There is one method of administration of SIRTURO 100 mg tablet and four different methods of administration of SIRTURO 20 mg tablet as follows, each of which must be taken with food: For SIRTURO 100 mg tablet, administer the tablet whole with water. Take with food. For SIRTURO 20 mg tablet, the four different methods of administration are outlined below. Each administration method requires SIRTURO to be taken with food in addition to any soft food or beverage used to administer SIRTURO by the different methods for patients who cannot swallow intact SIRTURO 20 mg tablets. Methods of Administration of SIRTURO 20 mg Tablet Administration of 20 mg Tablets to Patients Who Can Administer SIRTURO 20 mg tablet whole or split in half along the functional score line into two equal halves of 10 mg each. Administer SIRTURO 20 mg tablet with water. Administration of 20 mg Tablets to Patients Who Cannot Dispersed in Water and Mixed with Beverage or Soft Food For patients who have difficulty swallowing intact tablets, SIRTURO 20 mg tablet can be dispersed in water prior to administration with food. If needed to aid with administration, the dispersed mixture in water can be further mixed with a beverage (e. , water, milk products, apple juice, orange juice, cranberry juice or carbonated beverage) or soft food (e. , yogurt, apple sauce, mashed banana or porridge) as follows: Disperse tablets in water (maximum of 5 tablets in 5 mL of water) in a drinking cup. Mix the contents of the cup well until the tablets are completely dispersed and then orally administer the contents of the cup immediately with food. If needed to aid with oral administration, the dispersed mixture in water can be further mixed with at least 5 mL of beverage or 1 teaspoonful of soft food and then orally administer the contents of the cup immediately. If the total dose requires more than 5 tablets, repeat the above preparation steps with the appropriate number of additional tablets until the desired dose is reached. Ensure no tablet residue is left in the cup, rinse with beverage or add more soft food and orally administer the contents of the cup immediately. Take with food in addition to any beverage or soft food used to aid in administration. Crushed and Mixed with Soft Food SIRTURO 20 mg tablet can be crushed and mixed with soft food Administration Through a Feeding Tube SIRTURO 20 mg tablet can be administered through a feeding tube Disperse 5 tablets or less in 50 mL of non-carbonated water and mix well. Mixture should be white to almost white with visible particles expected. Administer through the feeding tube immediately. Repeat with additional tablets until desired dose is reached. Rinse and flush with 25 mL of additional water to ensure no tablet residue is left in materials used for preparation or the feeding tube. Administer with food.

The following serious adverse reactions are discussed elsewhere in the labeling: QTc Prolongation [see Warnings and Precautions (5. 1) 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. 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. 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. 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. 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. 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. gov/medwatch 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 M. tuberculosis 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. 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 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 Placebo Treatment Group 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). 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. 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. 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. , 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. 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. 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 [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. 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. 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).

Lactation: Breastfeeding is not recommended unless infant formula is not available. If an infant is exposed to bedaquiline through breast milk, monitor for signs of bedaquiline-related adverse reactions, such as hepatotoxicity. 2 Pediatrics: The safety and effectiveness of SIRTURO in pediatric patients less than 2 years of age and/or weighing less than 8 kg have not been established. 4 Use with caution in patients with severe hepatic impairment and only when the benefits outweigh the risks. Monitor for SIRTURO-related adverse reactions. 6 Use with caution in patients with severe renal impairment. 7 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 TB 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. 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 TB 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 to 17, inclusive). Pregnant rabbits were treated with bedaquiline at 10, 30 and 100 mg/kg (approximately 0. 5 times the clinical dose based on AUC comparisons) during the period of organogenesis (gestational Days 6 to 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. Risk Summary Data from a published clinical lactation study demonstrate higher bedaquiline concentrations in breast milk compared to maternal plasma, suggesting that bedaquiline accumulates in breast milk (see Data Clinical Considerations If an infant is exposed to bedaquiline through breast milk, monitor for signs of bedaquiline-related adverse reactions, such as hepatotoxicity [see Adverse Reactions (6) Data A clinical lactation study was conducted in two lactating women who were approximately 7 weeks' postpartum. Bedaquiline and M2, its active metabolite, levels were measured between approximately 27 and 48 hours after the last bedaquiline dose, and concentrations of bedaquiline and M2 ranged from 2. 11 mg/L and 0. 81 mg/L, respectively. The milk:plasma ratios for bedaquiline and M2 at 27 to 48 hours after the last dose of bedaquiline ranged from approximately 19 to 29 and 4 to 6, respectively. The safety and effectiveness of SIRTURO have been established in pediatric patients 2 years and older weighing at least 8 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, multi-cohort trial that enrolled 45 pediatric patients 2 years to less than 18 years of age with confirmed or probable pulmonary TB caused by M. tuberculosis [see Dosage and Administration (2. 4) Adverse Reactions (6. 1) Clinical Pharmacology (12. 3) Clinical Studies (14. 2) The safety, effectiveness and dosage of SIRTURO in pediatric patients less than 2 years of age and/or weighing less than 8 kg have not been established. Clinical studies of SIRTURO did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients [see Clinical Pharmacology (12. 3) 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) [see Warnings and Precautions (5. 4) 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. 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.

Avoid use of strong and moderate CYP3A4 inducers with SIRTURO. 1 Closely monitor patient safety (e. , liver function) when SIRTURO is coadministered with CYP3A4 inhibitors. 1 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. No dose adjustment of SIRTURO is needed when coadministered with CYP3A4 inhibitors [see Clinical Pharmacology (12. 3) 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. 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) Clinical Pharmacology (12.

OVERDOSAGE
There is no experience with the treatment of acute overdose with SIRTURO. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QTc interval) in case of deliberate or accidental overdose. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma.
NONCLINICAL TOXICOLOGY
Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. Exposures at this dose in rats (AUCs) were within 1-fold to 2-fold of those observed in adult patients in the clinical trials. 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 did not affect fertility when evaluated in male and female rats at approximately twice the clinical exposure based on AUC comparisons. There was no effect of maternal treatment on sexual maturation, mating performance or fertility in F1 generation exposed to bedaquiline in utero at approximately twice the human exposure. Bedaquiline is a cationic, amphiphilic drug that induced phospholipidosis (at almost all doses, even after very short exposures) in drug-treated animals, mainly in cells of the monocytic phagocytic system (MPS). All species tested showed drug-related increases in pigment-laden and/or foamy macrophages, mostly in the lymph nodes, spleen, lungs, liver, stomach, skeletal muscle, pancreas and/or uterus. After treatment ended, these findings were slowly reversible. Muscle degeneration was observed in several species at the highest doses tested. For example, the diaphragm, esophagus, quadriceps and tongue of rats were affected after 26 weeks of treatment at doses similar to clinical exposures based on AUC comparisons. These findings were not seen after a 12-week, treatment-free, recovery period and were not present in rats given the same dose biweekly. Degeneration of the fundic mucosa of the stomach, hepatocellular hypertrophy and pancreatitis were also seen.
CLINICAL STUDIES
Study 1 (NCT00449644, Stage 2) was a placebo-controlled, double-blind, randomized trial conducted in patients with newly diagnosed sputum smear-positive pulmonary TB due to M. tuberculosis Sixty-seven patients randomized to SIRTURO and 66 patients randomized to placebo had confirmed pulmonary TB due to M. tuberculosis Time to sputum culture conversion was defined as the interval in days between the first dose of study drug and the date of the first of two consecutive negative sputum cultures collected at least 25 days apart during treatment. In this trial, the SIRTURO treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at Week 24. Median time to culture conversion was 83 days for the SIRTURO treatment group compared to 125 days for the placebo treatment group. Table 8 shows the proportion of patients with sputum culture conversion at Week 24 and Week 120. Table 8: Culture Conversion Status and Clinical Outcome at Week 24 and Week 120 in Study 1 Microbiologic Status SIRTURO (24 weeks) + combination of other antimycobacterial drugs Placebo (24 weeks) + combination of other antimycobacterial drugs Difference [95% CI] Week 24 Sputum Culture Conversion 78% 58% 20. 6%] Treatment failure A patient''s reason for treatment failure was counted only in the first row for which a patient qualifies. 22% 42% Died 1% 0% Lack of conversion 21% 35% Discontinuation 0% 8% Week 120 Patients received 24 weeks of SIRTURO or placebo for the first 24 weeks and received a combination of other antimycobacterial drugs for up to 96 weeks. Sputum Culture Conversion 61% 44% 17. 0%] Treatment failure 39% 56% Died 12% 3% Lack of conversion/relapse 16% 35% Discontinuation 10% 18% Study 2 (NCT00449644, Stage 1) was a smaller placebo-controlled study designed similarly to Study 1 except that SIRTURO or placebo was given for only eight weeks instead of 24 weeks. Patients were randomized to either SIRTURO and other drugs used to treat pulmonary TB due to M. tuberculosis M. tuberculosis Study 3 (NCT00910871) was a Phase 2b, uncontrolled study to evaluate the safety, tolerability, and efficacy of SIRTURO as part of an individualized treatment regimen in 233 patients with sputum smear positive (within 6 months prior to screening) pulmonary TB due to M. tuberculosis Study 4 (NCT02409290) was a Phase 3, open-label, multicenter, active-controlled, randomized trial to evaluate the efficacy and safety of SIRTURO, coadministered with other oral anti-TB drugs for 40 weeks in patients with sputum smear-positive pulmonary TB caused by M. tuberculosis Patients were randomized to one of four treatment arms: Arm A (N=32), the locally used treatment in accordance with 2011 WHO treatment guidelines with a recommended 20-month duration Arm B (N=202), a 40-week treatment of moxifloxacin (N=140) or levofloxacin (N=62), clofazimine, ethambutol, pyrazinamide, supplemented by injectable kanamycin, high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase) Arm C (N=211), a 40-week, all-oral treatment of SIRTURO, levofloxacin, clofazimine, ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase) Arm D (N=143), a 28-week treatment consisting of SIRTURO, levofloxacin, clofazimine, and pyrazinamide, supplemented by kanamycin injectable and a higher isoniazid dose for the first eight weeks (intensive phase) SIRTURO was administered 400 mg once daily for the first two weeks and 200 mg three times a week for the following 38 weeks (in Arm C) or 26 weeks (in Arm D). All patients were to be followed up until study completion at Week 132. During study conduct, enrollment in Arms A and D was stopped due to changes in the standard of care for TB treatment. Patients already randomized to these study arms were to complete their assigned treatment and follow-up. The primary objective was to assess whether the proportion of patients with a favorable efficacy outcome in Arm C was noninferior to that in Arm B at Week 76. The primary efficacy outcome measure was the proportion of patients with a favorable outcome at Week 76. A favorable outcome at Week 76 was defined as the last two consecutive cultures being negative, and with no unfavorable outcome. An unfavorable outcome at Week 76 was assessed as a composite endpoint, covering both clinical and microbiological aspects such as changes in TB treatment, all-cause mortality, at least one of the last two culture results positive, or no culture results within the Week 76 window. In case of treatment failure, recurrence or serious toxicity on the allocated treatment, salvage treatment that could include SIRTURO was provided, based on investigator judgment. The modified intent-to-treat population (mITT) was the primary efficacy population and included all randomized patients with a positive sputum culture for M. tuberculosis For efficacy analyses beyond Week 76, data collection was stopped at the point when the last recruited patient was projected to reach Week 96. The long-term efficacy data therefore include data up to at least Week 96 for all patients, and up to Week 132 for 146/196 (74. 5%) patients in Arm C and 145/187 (77. 5%) patients in Arm B. Table 9 shows results for favorable and unfavorable outcomes at Week 76 and Week 132 in Study 4. Table 9: Clinical Outcome at Week 76 and Week 132 in the mITT Population in Study 4 SIRTURO Arm C 40-week, all-oral regimen of SIRTURO, levofloxacin, clofazimine, ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase). Active Control Arm B 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). mITT = modified intent-to-treat Favorable outcome at Week 76 162 (82. 1) Difference The adjusted difference in proportions was estimated using a stratified analysis of the risk difference from each stratum using Cochran Mantel-Haenszel weights. The analysis was stratified by randomization protocol and HIV and CD4 cell count status. 0% Unfavorable outcome at Week 76 34 (17. 9) Reasons for unfavorable outcome through Week 76 Patients were classified by the first event that made the patient unfavorable. Of the patients with an unfavorable outcome at Week 76 in the control arm, 29 patients had a treatment modification from their allocated treatment that included SIRTURO as part of a salvage regimen. Treatment modified or extended 16 (8. 0) No culture results within Week 76 window 12 (6. 7) Death through Week 76 5 (2. 1) At least one of last 2 cultures positive at Week 76 1 (0. 1) Favorable outcome at Week 132 n (%) Week 132 outcome reflects efficacy follow up until the last patient reached Week 96. 0) Difference 9. 0% The pediatric trial, (NCT02354014), was designed as a single-arm, open-label, multi-cohort trial to evaluate the pharmacokinetics, safety and tolerability of SIRTURO in combination with a background regimenin patients 2 to less than 18 years of age with confirmed or probable pulmonary TB due to M. tuberculosis Pediatric Patients (12 years to less than 18 years of age) Fifteen patients 14 years to less than 18 years of age were enrolled in the first cohort. The median age was 16 years, 80% were female, 53% were Black, 33% were White and 13% were Asian. No patient 12 years to less than 14 years of age was enrolled in this cohort. SIRTURO was administered as 400 mg once daily for the first two weeks and 200 mg three times per week for the following 22 weeks using the 100 mg tablet. In the subset of patients with mycobacteria growth indicator tube (MGIT) culture positive pulmonary TB resistant to at least rifampin at baseline, treatment with SIRTURO resulted in conversion to a negative culture in 75% (6/8 patients) at Week 24, which was sustained at Week 120. Pediatric Patients (5 years to less than 12 years of age) Fifteen patients 5 years to 10 years of age were enrolled in the second cohort. The median age was seven years, 60% were female, 60% were Black, 33% were White and 7% were Asian. No patient older than 10 years to less than 12 years of age was enrolled in this cohort. The body weight range was 14 kg to 36 kg; only one patient weighing 14 kg was enrolled. SIRTURO was administered as 200 mg once daily for the first two weeks and 100 mg three times per week for the following 22 weeks using the 20 mg tablet. In the subset of patients with MGIT culture positive pulmonary TB resistant to at least rifampin at baseline, treatment with SIRTURO resulted in conversion to a negative culture in 100% (3/3 patients) at Week 24, which was sustained at Week 120. Pediatric Patients (2 years to less than 5 years of age) Fifteen patients 2 years to less than 5 years of age were enrolled in the third cohort. The median age was 4 years, 47% were female, 27% were Black and 73% were Asian. At baseline, the body weight ranged from 10 kg to 16 kg. SIRTURO was administered as 8 mg/kg once daily for the first two weeks (dose range: 80 to 120 mg; not an approved dosing regimen) followed by 4 mg/kg three times per week (dose range: 40 to 60 mg; not an approved dosing regimen) for the following 22 weeks using the 20 mg tablet. In the one patient with MGIT culture positive pulmonary TB resistant to at least rifampin at baseline, treatment with SIRTURO resulted in conversion to a negative culture (1/1 MGIT culture evaluable patient) at Week 24, which was sustained at Week 120.

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