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

2.1 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. tuberculosisisolate 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:

Recommended dosage in pediatric patients are 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 (5 years and older and weighing at least 15 kg)

The recommended dosage of SIRTURO in pediatric patients (5 years and older and weighing at least 15 kg) is based on body weight and shown in Table 2:

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)] .

2.5 Missed Dose

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).

2.6 Method of Administration

There is one method of administration of SIRTURO 100 mg tablet and four different methods of administration of SIRTURO 20 mg tablet as follows:

• 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.

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. tuberculosisexists [see Microbiology (12.4)]. Bedaquiline must only be used in an appropriate combination regimen for the treatment of pulmonary TB due to M. tuberculosisresistant 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

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.

7.1 Effect of Other Drugs on SIRTURO

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of SIRTURO have been established in pediatric patients 5 years and older weighing at least 15 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 30 pediatric patients 5 years to less than 18 years of age with confirmed or probable pulmonary TB caused by M. tuberculosisresistant to at least rifampin who were treated with SIRTURO for 24 weeks in combination with a background regimen.

The safety, effectiveness and dosage of SIRTURO in pediatric patients less than 5 years of age and/or weighing less than 15 kg have not been established [see Dosage and Administration (2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3)and Clinical Studies (14.2)] .

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.

12.1 Mechanism of Action

Bedaquiline is a diarylquinoline antimycobacterial drug [see Microbiology (12.4)] .

12.2 Pharmacodynamics

Bedaquiline has activity against M. tuberculosis. The major metabolite, M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (3-fold to 6-fold lower) compared to the parent compound. However, M2 plasma concentrations are correlated with QTc prolongation.

12.3 Pharmacokinetics

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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.

13.2 Animal Toxicology and/or Pharmacology

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.

14.1 Adult Patients

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. tuberculosisresistant to at least rifampin and isoniazid. Patients were randomized to receive a combination of SIRTURO or placebo with five other antimycobacterial drugs (i.e., ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative) for a total duration of 18 to 24 months or at least 12 months after the first confirmed negative culture. Treatment was 24 weeks of treatment with SIRTURO 400 mg once daily for the first two weeks followed by 200 mg three times per week for 22 weeks or matching placebo for the same duration. Overall, 79 patients were randomized to the SIRTURO arm and 81 to the placebo arm. A final evaluation was conducted at Week 120.

Sixty-seven patients randomized to SIRTURO and 66 patients randomized to placebo had confirmed pulmonary TB due to M. tuberculosisresistant to at least rifampin and isoniazid, based on susceptibility tests (taken prior to randomization) or medical history if no susceptibility results were available, and were included in the efficacy analyses. Demographics were as follows: 64% of the study population was male, with a median age of 33 years, 38% were Black, 17% were Hispanic, 11% were White, 11% were Asian, and 24% were of another race; and 14% were HIV-positive (median CD4 cell count 446 cells/µL). Most patients had cavitation in one lung (62%); and 20% of patients had cavitation in both lungs.

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.

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. tuberculosisresistant to at least rifampin and isoniazid (SIRTURO treatment group) (n=23) or placebo and other drugs used to treat TB (placebo treatment group) (n=24). Twenty-one patients randomized to the SIRTURO treatment group and 23 patients randomized to the placebo treatment group had confirmed pulmonary TB due to M. tuberculosisresistant to at least rifampin and isoniazid based on patients' baseline M. tuberculosisisolate obtained prior to randomization. The SIRTURO treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at Week 8. At Weeks 8 and 24, the differences in culture conversion proportions were 38.9% [95% CI: (12.3%; 63.1%) and p-value: 0.004], 15.7% [95% CI: (-11.9%; 41.9%) and p-value: 0.32], respectively.

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. tuberculosisresistant to at least rifampin and isoniazid, including patients with isolates resistant to second-line injectables and/or fluoroquinolones. Patients received SIRTURO for 24 weeks in combination with antimycobacterial drugs. Upon completion of the 24-week treatment with SIRTURO, all patients continued to receive their background regimen in accordance with national TB program (NTP) treatment guidelines. A final evaluation was conducted at Week 120. Treatment responses to SIRTURO at Week 120 were generally consistent with those from Study 1.

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. tuberculosisthat was resistant to at least rifampin. Patients in whom the M. tuberculosisstrain was known to be resistant at screening to second-line injectable agents or fluoroquinolones were excluded from enrollment. When phenotypic susceptibility testing of the baseline isolates became available post-randomization, patients infected with M. tuberculosisresistant to either second-line injectable agents or fluoroquinolones were kept in the study, however, those with M. tuberculosisresistant to both second-line injectables and fluoroquinolones were discontinued from the study.

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. tuberculosisthat was resistant to at least rifampin and not resistant to both second-line injectables and fluoroquinolones, based on susceptibility results (taken prior to randomization). A total of 196 and 187 patients were included in the mITT population in Arm C and Arm B, respectively. Overall, in both treatment arms, 62% were male of median age 33 years, 47% were Asian, 34% were Black, 19% were White, and 14% were HIV-coinfected. Most patients had lung cavitation (74%), with multiple cavities in 63% and 47% of patients in Arm C and Arm B, respectively. The baseline drug resistance profile of M. tuberculosisfor Arms C and B were as follows: 14% had resistance to rifampin while susceptible to isoniazid, 75% had resistance to rifampin and isoniazid, and 10% had resistance to rifampin, isoniazid, and either a second-line injectable or a fluoroquinolone.

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.

14.2 Pediatric Patients (5 years to less than 18 years of age)

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 regimen in patients 5 to less than 18 years of age with confirmed or probable pulmonary TB due to M. tuberculosisresistant to at least rifampin.

16.1 How Supplied

SIRTURO ®20 mg tablets are supplied as uncoated white to almost white oblong functionally scored tablets with a score line on both sides, debossed with "2" and "0" on one side and plain on the other side.

SIRTURO ®100 mg tablets are supplied as uncoated white to almost white round biconvex 100 mg tablets with debossing of "T" over "207" on one side and "100" on the other side.

SIRTURO tablets are packaged in white high-density polyethylene (HDPE) bottles with child-resistant polypropylene (PP) closure with induction seal liner in the following configurations:

• 20 mg tablets – bottles of 60 tablets. Each bottle contains silica gel desiccant (NDC 59676-702-60)
• 100 mg tablets – bottles of 188 tablets (NDC 59676-701-01).

16.2 Storage and Handling

Serious Adverse Reactions

Advise patients that the following serious side effects can occur with SIRTURO: heart rhythm abnormalities, death and/or hepatitis. In addition, advise patients about other potential side effects: nausea, vomiting, joint pain, increased transaminases, dizziness, headache, myalgia, diarrhea, increased blood amylase, hemoptysis, chest pain, anorexia, rash, and/or abdominal pain. Additional testing may be needed to monitor or reduce the likelihood of adverse effects.

Compliance with Treatment

Advise patients to take SIRTURO in combination with other antimycobacterial drugs as prescribed. Emphasize compliance with the full course of therapy. Advise patients that skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the treatment and (2) increase the likelihood that their mycobacterium may develop resistance and the disease will not be treatable by SIRTURO or other antimycobacterial drugs in the future.

If a dose is missed during the first 2 weeks of treatment, advise patients not to make up the missed dose but to continue the usual dosing schedule. From Week 3 onwards, if a dose is missed, advise patients to take the missed dose as soon as possible, and then resume the 3 times a week regimen.

Ensure that the total dose of SIRTURO during a 7-day period does not exceed the recommended weekly dose (with at least 24 hours between each intake).

Administration Instructions

Advise patients to take SIRTURO with food.

Advise patients who have difficulty swallowing tablets that SIRTURO 20 mg tablet can be administered by the following methods:

• Dispersed in water and the mixture administered immediately. To aid with administration, the dispersed mixture in water can be further mixed with a beverage (e.g., water, milk products, apple juice, orange juice, cranberry juice or carbonated beverage) or soft food (e.g., yogurt, apple sauce, mashed banana or porridge) and then administered immediately,
• Crushed and mixed with soft food and the mixture administered immediately,
• Administered through a feeding tube [see Dosage and Administration (2.6)] .

Use with Alcohol and other Medications

Instruct patients to abstain from alcohol, hepatotoxic medications or herbal products.

Advise patients to discuss with their physician the other medications they are taking and other medical conditions before starting treatment with SIRTURO.

Lactation

Advise patients not to breastfeed during treatment with SIRTURO and for 27.5 months after the last dose unless infant formula is not available. If an infant is exposed to bedaquiline through breast milk, advise caregivers to monitor the infant for signs of bedaquiline-related adverse reactions, such as hepatotoxicity (yellowing of the eyes and changes in the color of the urine or stool) [see Adverse Reactions (6)and Use in Specific Populations (8.2)] .