Bedaquiline

5 WARNINGS AND PRECAUTIONS A mortality imbalance was seen in clinical trials in SIRTURO-treated patients with pulmonary TB due to Mycobacterium tuberculosis resistant to at least rifampin. ( 5.2 ) Hepatotoxicity may occur with use of SIRTURO. Monitor liver-related laboratory tests. Discontinue SIRTURO if evidence of liver injury occurs. ( 5.4 ) 5.1 QTc Prolongation SIRTURO prolongs the QTc interval [see Clinical Pharmacology (12.2) ] . Use with drugs that prolong the QTc interval may cause additive QTc prolongation [see Adverse Reactions (6) ] . In Study 4, where SIRTURO was administered with the QTc prolonging drugs clofazimine and levofloxacin, 5% of patients in the 40-week SIRTURO treatment group experienced a QTc ≥500 ms and 43% of patients experienced an increase in QTc ≥60 ms over baseline. Of the clofazimine- and levofloxacin-treated patients in the 40-week control arm, 7% of patients experienced a QTc ≥500 ms and 39% experienced an increase in QTc ≥60 ms over baseline. Obtain an ECG before initiation of treatment, 2 weeks after initiation, during treatment, as clinically indicated and at the expected time of maximum increase in the QTc interval of the concomitantly administered QTc prolonging drugs (as applicable). Obtain electrolytes at baseline and during treatment and correct electrolytes as clinically indicated. The following may increase the risk for QTc prolongation when patients are taking SIRTURO: use with other QTc prolonging drugs a history of Torsade de Pointes a history of congenital long QTc syndrome a history of or ongoing hypothyroidism a history of or ongoing bradyarrhythmias a history of uncompensated heart failure serum calcium, magnesium, or potassium levels below the lower limits of normal Discontinue SIRTURO if the patient develops: Clinically significant ventricular arrhythmia A QTc interval of greater than 500 ms (confirmed by repeat ECG) If syncope occurs, obtain an ECG to detect QTc prolongation. 5.2 Mortality Imbalance in Clinical Trials 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 (Study 1; based on the 120 week visit window). One death occurred during the 24 weeks of administration of SIRTURO. The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, or severity of disease could be observed. In a subsequent active-controlled trial in adults (Study 4), deaths by Week 132 occurred in 11/211 (5.2%) patients in the 40-week SIRTURO treatment group, 8/202 (4%) patients in the active-control treatment group including four of 29 patients who received SIRTURO as part of a salvage treatment, and 2/143 (1.4%) patients in the 28-week SIRTURO treatment group [see Adverse Reactions (6.1) ] . 5.3 Risk of Development of Resistance to Bedaquiline A potential for development of resistance to bedaquiline in M. tuberculosis exists [see Microbiology (12.4) ]. Bedaquiline must only be used in an appropriate combination regimen for the treatment of pulmonary TB due to M. tuberculosis resistant to at least rifampin and isoniazid, to reduce the risk of development of resistance to bedaquiline [see Indications and Usage (1) ] . 5.4 Hepatotoxicity In clinical trials, more hepatic-related adverse reactions were reported in adults with the use of SIRTURO plus other drugs used to treat TB compared to other drugs used to treat TB without the addition of SIRTURO. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO, especially in patients with impaired hepatic function. Hepatic-related adverse reactions have also been reported in pediatric patients 5 years of age and older [see Adverse Reactions (6.1) ] . Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed. Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs. Discontinue SIRTURO if: transaminase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal transaminase elevations are greater than eight times the upper limit of normal transaminase elevations are greater than five times the upper limit of normal and persist beyond two weeks 5.5 Drug Interactions CYP3A4 Inducers Coadministration of SIRTURO with a moderate or strong CYP3A4 inducer decreases the systemic exposure of bedaquiline and may reduce the therapeutic effect of SIRTURO. Avoid coadministration of SIRTURO with moderate or strong CYP3A4 inducers, such as efavirenz and rifamycins (i.e., rifampin, rifapentine and rifabutin) [see Drug Interactions (7.1) ] . 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 [see Drug Interactions (7.1) ] .

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).

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.

8 USE IN SPECIFIC POPULATIONS 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. ( 6 , 8.2 ) 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. ( 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 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. 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 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 0.05, 0.2 and 1.5 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. 8.2 Lactation 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 ) . Data are insufficient to determine effects of the drug on the breastfed infants. No data are available on the effects of the drug on milk production. Because of the potential for serious adverse reactions in a breastfed infant, including hepatotoxicity, advise patients that breastfeeding is not recommended during treatment with SIRTURO and for 27.5 months (5 times the half-life) after the last dose unless infant formula is not available. 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 2.61 to 8.11 mg/L and 0.27 to 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. 8.4 Pediatric Use 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 resistant to at least rifampin who were treated with SIRTURO for 24 weeks in combination with a background regimen [see Dosage and Administration (2.4) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and 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. 8.5 Geriatric Use 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) ] . 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 (5.4) ] . 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.

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 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. 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 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 0.05, 0.2 and 1.5 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.