bedaquiline 100 MG Oral Tablet
Generic Name: BEDAQUILINE FUMARATE
Brand Name: SIRTURO
- Substance Name(s):
- BEDAQUILINE FUMARATE
DRUG INTERACTIONS
7 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.
OVERDOSAGE
10 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.
DESCRIPTION
11 SIRTURO ® contains bedaquiline fumarate, a diarylquinoline antimycobacterial drug for oral administration.
Each SIRTURO 20 mg tablet contains 20 mg of bedaquiline (equivalent to 24.18 mg of bedaquiline fumarate).
Each SIRTURO 100 mg tablet contains 100 mg of bedaquiline (equivalent to 120.89 mg of bedaquiline fumarate).
Bedaquiline fumarate is a white to almost white powder and is practically insoluble in aqueous media.
The chemical name of bedaquiline fumarate is (1 R , 2 S )-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound with fumaric acid (1:1).
It has a molecular formula of C 32 H 31 BrN 2 O 2 ∙C 4 H 4 O 4 and a molecular weight of 671.58 (555.50 + 116.07).
The molecular structure of bedaquiline fumarate is the following: SIRTURO 20 mg tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose 2910 5 mPa.s, polysorbate 20, purified water (removed during processing), silicified microcrystalline cellulose and sodium stearyl fumarate.
SIRTURO 100 mg tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose 2910 15 mPa.s, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, purified water (removed during processing).
Chemical Structure
CLINICAL STUDIES
14 14.1 SIRTURO Use in Adult Patients With Pulmonary Tuberculosis 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 resistant 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.
tuberculosis resistant 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.
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 N=67 Placebo (24 weeks) + combination of other antimycobacterial drugs N=66 Difference [95% CI] p-value Week 24 Sputum Culture Conversion 78% 58% 20.0% [4.5%, 35.6%] 0.014 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% 17.3% [0.5%, 34.0%] 0.046 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 resistant 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.
tuberculosis resistant to at least rifampin and isoniazid based on patients’ baseline M.
tuberculosis isolate 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.
tuberculosis resistant 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.
tuberculosis that was resistant to at least rifampin.
Patients in whom the M.
tuberculosis strain 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.
tuberculosis resistant to either second-line injectable agents or fluoroquinolones were kept in the study, however, those with M.
tuberculosis resistant 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.
tuberculosis that 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.
tuberculosis for 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.
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).
(N=196) 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).
(N=187) mITT = modified intent-to-treat Favorable outcome at Week 76 n (%) 162 (82.7) 133 (71.1) 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.
SIRTURO vs Active Control (95% CI) 11.0% (2.9%, 19.0%) Unfavorable outcome at Week 76 n (%) 34 (17.3) 54 (28.9) 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 (8.2) 43 (23.0) No culture results within Week 76 window 12 (6.1) 7 (3.7) Death through Week 76 5 (2.6) 2 (1.1) At least one of last 2 cultures positive at Week 76 1 (0.5) 2 (1.1) Favorable outcome at Week 132 n (%) Week 132 outcome reflects efficacy follow up until the last patient reached Week 96.
154 (78.6) 129 (69.0) Difference SIRTURO vs Active Control (95% CI) 9.0% (0.6%,17.5%) 14.2 SIRTURO Use in Pediatric Patients (2 years to less than 18 years of age) With Pulmonary Tuberculosis 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 resistant to at least rifampin.
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.
HOW SUPPLIED
16 /STORAGE AND HANDLING 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 SIRTURO 20 mg Tablet Store in original container.
Bottle contains desiccant.
Do not discard desiccant.
Protect from light and moisture.
Keep the container tightly closed.
Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
SIRTURO 100 mg Tablet Dispense in original container.
Store tablets dispensed outside the original container in a tight light-resistant container with an expiration date not to exceed 3 months.
Protect from light.
Keep the container tightly closed.
Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
RECENT MAJOR CHANGES
Indications and Usage ( 1 ) 7/2025 Dosage and Administration ( 2.4 ) 7/2025
GERIATRIC USE
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) ] .
DOSAGE FORMS AND STRENGTHS
3 SIRTURO 20 mg tablet: uncoated, white to almost white oblong functionally scored tablet, with a score line on both sides, debossed with “2” and “0” on one side and plain on the other side.
SIRTURO 100 mg tablet: uncoated, white to almost white round biconvex tablet with debossing of “T” over “207” on one side and “100” on the other side.
Tablets: 20 mg, functionally scored ( 3 ) Tablets: 100 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Bedaquiline is a diarylquinoline antimycobacterial drug [see Microbiology (12.4) ] .
INDICATIONS AND USAGE
1 SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (2 years and older and weighing at least 8 kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid.
SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adult and pediatric patients (2 years and older and weighing at least 8 kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid.
( 1 ) Limitations of Use : Do not use SIRTURO for the treatment of latent, extra-pulmonary or drug-sensitive TB or for the treatment of infections caused by non-tuberculous mycobacteria.
( 1 ) Limitations of Use Do not use SIRTURO for the treatment of: Latent infection due to Mycobacterium tuberculosis ( M.
tuberculosis ) Drug-sensitive pulmonary TB Extra-pulmonary TB Infections caused by non-tuberculous mycobacteria
PEDIATRIC USE
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.
PREGNANCY
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.
BOXED WARNING
WARNING: QTc PROLONGATION QTc prolongation can occur with SIRTURO.
Use with drugs that prolong the QTc interval may cause additive QTc prolongation.
Monitor ECGs.
Discontinue SIRTURO if significant ventricular arrhythmia or QTc interval greater than 500 ms develops [see Warnings and Precautions (5.1) ] .
WARNING: QTc PROLONGATION See full prescribing information for complete boxed warning.
QTc Prolongation QTc prolongation can occur with SIRTURO.
Use with drugs that prolong the QTc interval may cause additive QTc prolongation.
Monitor ECGs.
Discontinue SIRTURO if significant ventricular arrhythmia or QTc interval greater than 500 ms develops.
( 5.1 )
WARNING AND CAUTIONS
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) ] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide).
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) ] .
DOSAGE AND ADMINISTRATION
2 Administer SIRTURO by directly observed therapy (DOT).
( 2.1 ) Emphasize need for compliance with full course of therapy.
( 2.1 ) Prior to administration, obtain ECG, liver enzymes and electrolytes.
Obtain susceptibility information for the background regimen against Mycobacterium tuberculosis isolate if possible.
( 2.2 ) Only use SIRTURO in combination with at least 3 other drugs to which the patient’s TB isolate has been shown to be susceptible in vitro.
If in vitro testing results are unavailable, may initiate SIRTURO in combination with at least 4 other drugs to which patient’s TB isolate is likely to be susceptible.
( 2.1 ) Recommended dosage in adult patients: 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) once daily for 2 weeks followed by 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) 3 times per week (with at least 48 hours between doses) for 22 weeks.
( 2.3 ) Recommended dosage in pediatric patients (2 years and older and weighing at least 8 kg) is based on body weight.
( 2.4 ) Take SIRTURO tablets with food.
( 2.6 ) See full prescribing information for the different methods of administration of SIRTURO 20 mg tablet and administration of the 100 mg tablet.
2.1 Important Administration Instructions Administer SIRTURO by directly observed therapy (DOT).
Only use SIRTURO in combination with at least three other drugs to which the patient’s TB isolate has been shown to be susceptible in vitro.
If in vitro testing results are unavailable, SIRTURO treatment may be initiated in combination with at least four other drugs to which the patient’s TB isolate is likely to be susceptible.
Refer to the prescribing information of the drugs used in combination with SIRTURO for further information.
SIRTURO (20 mg and 100 mg) must be taken with food.
SIRTURO 20 mg are functionally scored tablets which can be split at the scored lines into two equal halves of 10 mg each to provide doses less than 20 mg [see Dosage and Administration (2.6) ].
As an alternative method of administration, SIRTURO 20 mg tablets can be dispersed in water and administered or dispersed in water and further mixed with a beverage or soft food, or crushed and mixed with soft food, or administered through a feeding tube [see Dosage and Administration (2.6) ].
Emphasize the need for compliance with the full course of therapy.
2.2 Required Testing Prior to Administration Prior to treatment with SIRTURO, obtain the following: Susceptibility information for the background regimen against M.
tuberculosis isolate if possible [see Dosage and Administration (2.1) ] ECG [see Warnings and Precautions (5.1) ] Serum potassium, calcium, and magnesium concentrations [see Warnings and Precautions (5.1) ] Liver enzymes [see Warnings and Precautions (5.4) ] 2.3 Recommended Dosage in Adult Patients The recommended dosage of SIRTURO in adult patients is: Table 1: Recommended Dosage of SIRTURO in Adult Patients Dosage Recommendation Weeks 1 and 2 Weeks 3 to 24 At least 48 hours between doses 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) orally once daily 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally three times per week Recommended dosage in pediatric patients is described in Table 2 below [see Dosage and Administration (2.4) ].
Administer SIRTURO tablets with food.
The total duration of treatment with SIRTURO in adults is 24 weeks.
When treatment with SIRTURO is considered necessary beyond 24 weeks, treatment may be continued at a dose of 200 mg three times per week [see Clinical Studies (14.1) ] .
2.4 Recommended Dosage in Pediatric Patients (2 years and older and weighing at least 8 kg) The recommended dosage of SIRTURO in pediatric patients (2 years and older and weighing at least 8 kg) is based on body weight and shown in Table 2: Table 2: Recommended Dosage of SIRTURO in Pediatric Patients (2 years and older and weighing at least 8 kg) Body Weight Dosage Recommendation Weeks 1 and 2 Weeks 3 to 24 At least 48 hours between doses 8 kg to less than 10 kg 80 mg (4 of the 20 mg tablets) orally once daily 40 mg (2 of the 20 mg tablets) orally three times per week 10 kg to less than 15 kg 120 mg (6 of the 20 mg tablets) orally once daily 60 mg (3 of the 20 mg tablets) orally three times per week 15 kg to less than 30 kg 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally once daily 100 mg (1 of the 100 mg tablets OR 5 of the 20 mg tablets) orally three times per week Greater than or equal to 30 kg 400 mg (4 of the 100 mg tablets OR 20 of the 20 mg tablets) orally once daily 200 mg (2 of the 100 mg tablets OR 10 of the 20 mg tablets) orally three times per week Administer SIRTURO tablets with food.
The total duration of treatment with SIRTURO is 24 weeks.
When treatment with SIRTURO is considered necessary beyond 24 weeks in patients 16 years and older, and weighing at least 30 kg, treatment may be continued at a dose of 200 mg three times per week [see Clinical 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, 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 Swallow Intact Tablets: 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.
Take with food.
Administration of 20 mg Tablets to Patients Who Cannot Swallow Intact Tablets: 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.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) 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 (e.g., yogurt, apple sauce, mashed banana or porridge) immediately prior to use and administered orally.
To ensure no tablet residue is left in the container, add more soft food and administer the contents immediately.
Take with food in addition to any beverage or soft food used to aid in administration.
Administration Through a Feeding Tube SIRTURO 20 mg tablet can be administered through a feeding tube (8 French or greater) as follows: 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.