HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use SIRTURO ® safely and effectively. See full prescribing information for SIRTURO.
SIRTURO ® (bedaquiline) tablets, for oral use
Initial U.S. Approval 2012
WARNINGS: INCREASED MORTALITY; QT PROLONGATION
See full prescribing information for complete boxed warning.
Increased Mortality
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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. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided. (5.1)
QT Prolongation
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QT prolongation can occur with SIRTURO. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO if significant ventricular arrhythmia or QTcF interval >500 ms develops. (5.2)
INDICATIONS AND USAGE
SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (18 years and older) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. Administer SIRTURO by directly observed therapy (DOT). (1, 2.1)
This indication is approved under accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1, 14)
Limitations of Use: Do not use SIRTURO for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria (1). Safety and efficacy of SIRTURO in HIV-infected patients with MDR-TB have not been established, as clinical data are limited (14).
DOSAGE AND ADMINISTRATION
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Emphasize need for compliance with full course of therapy (2.1)
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Prior to administration, obtain ECG, liver enzymes and electrolytes. Obtain susceptibility information for the background regimen against Mycobacterium tuberculosis isolate if possible. (2.2)
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Only use SIRTURO in combination with at least 3 other drugs to which the patient's MDR-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 MDR-TB isolate is likely to be susceptible (2.3)
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Recommended dosage: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week (with at least 48 hours between doses) for 22 weeks (2.3)
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Swallow SIRTURO tablets whole with water and take with food. (2.3)
DOSAGE FORMS AND STRENGTHS
Tablets: 100 mg (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
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QT prolongation can occur with SIRTURO. Monitor ECGs and discontinue SIRTURO if significant ventricular arrhythmia or QTcF interval > 500 ms develops. (5.2)
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Hepatotoxicity may occur with use of SIRTURO. Monitor liver-related laboratory tests. Discontinue if evidence of liver injury. (5.3)
ADVERSE REACTIONS
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The most common adverse reactions reported in 10% or more of patients treated with SIRTURO were nausea, arthralgia, headache, hemoptysis and chest pain. (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.
DRUG INTERACTIONS
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Avoid use of strong and moderate CYP3A4 inducers with SIRTURO. (7.1, 7.3)
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Avoid use for more than 14 consecutive days of systemic strong CYP3A4 inhibitors with SIRTURO unless the benefit outweighs the risk. Monitor for SIRTURO-related adverse reactions. (7.1)
USE IN SPECIFIC POPULATIONS
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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)
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Use with caution in patients with severe renal impairment. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 1/2017
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adults (18 years and older) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. Administer SIRTURO by directly observed therapy (DOT).
This indication is approved under accelerated approval based on time to sputum culture conversion [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Limitations of Use:
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Do not use SIRTURO for the treatment of:
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Latent infection due to Mycobacterium tuberculosis
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Drug-sensitive tuberculosis
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Extra-pulmonary tuberculosis
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Infections caused by non-tuberculous mycobacteria
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The safety and efficacy of SIRTURO in the treatment of HIV infected patients with MDR-TB have not been established as clinical data are limited [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
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Administer SIRTURO by directly observed therapy (DOT).
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Use SIRTURO only in combination with other anti-mycobacterial drugs [see Dosage and Administration (2.3)].
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Emphasize the need for compliance with full course of therapy.
2.2 Required Testing Prior to Administration
Prior to treatment with SIRTURO, obtain the following:
2.3 Recommended Dosage in Combination Therapy
Only use SIRTURO in combination with at least 3 other drugs to which the patient's MDR-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 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible. Refer to the prescribing information of the drugs used in combination with SIRTURO.
The recommended dosage of SIRTURO is 400 mg orally once daily for the first two weeks, followed by 200 mg orally three times per week (with at least 48 hours between doses) for 22 weeks (total duration of 24 weeks).
The SIRTURO tablet should be swallowed whole with water and taken with food.
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 200 mg dose is missed, administer the missed dose as soon as possible, and then resume the 3 times a week dosing regimen.
3 DOSAGE FORMS AND STRENGTHS
SIRTURO tablets, 100 mg are uncoated white to almost white round biconvex with debossing of "T" over "207" on one side and "100" on the other side.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality
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 (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. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided [see Adverse Reactions (6)].
5.2 QT Prolongation
SIRTURO prolongs the QT interval. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected [see Adverse Reactions (6.1) and Drug Interactions (7.4)]. SIRTURO has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
The following may increase the risk for QT prolongation when patients are receiving SIRTURO:
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use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine
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a history of Torsade de Pointes
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a history of congenital long QT syndrome
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a history of or ongoing hypothyroidism
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a history of or ongoing bradyarrhythmias
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a history of uncompensated heart failure
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serum calcium, magnesium, or potassium levels below the lower limits of normal
If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.
Discontinue SIRTURO and all other QT prolonging drugs if the patient develops:
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Clinically significant ventricular arrhythmia
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A QTcF interval of greater than 500 ms (confirmed by repeat ECG)
If syncope occurs, obtain an ECG to detect QT prolongation.
5.3 Hepatotoxicity
More hepatic-related adverse reactions were reported with the use of SIRTURO plus other drugs used to treat tuberculosis compared to other drugs used to treat tuberculosis without the addition of SIRTURO. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO, especially in patients with impaired hepatic function.
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:
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aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
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aminotransferase elevations are greater than eight times the upper limit of normal
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aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two weeks
5.4 Drug Interactions
CYP3A4 inducers/inhibitors
Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Avoid co-administration of strong CYP3A4 inducers, such as rifamycins (i.e., rifampin, rifapentine and rifabutin), or moderate CYP3A4 inducers, such as efavirenz, during treatment with SIRTURO [see Drug Interactions (7.1)].
Co-administration of SIRTURO with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, avoid the use of strong CYP3A4 inhibitors for more than 14 consecutive days while on SIRTURO, unless the benefit of treatment with the drug combination outweighs the risk [see Drug Interactions (7.1)]. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
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.
Use SIRTURO only in combination with other anti-mycobacterial drugs [see Dosage and Administration (2.3)]. Refer to the prescribing information of the drugs used in combination with SIRTURO for their respective adverse reactions.
Adverse drug reactions for SIRTURO were identified from the pooled safety data from 335 SIRTURO-exposed patients who received 8 weeks (Study 2) and 24 weeks (Studies 1 and 3) at the proposed dose. Studies 1 and 2 were randomized, double-blind, placebo-controlled trial in newly diagnosed patients with pulmonary MDR-TB. In both treatment arms, patients received SIRTURO or placebo in combination with other drugs used to treat MDR-TB. Study 3 was an open-label, noncomparative study with SIRTURO administered as part of an individualized pulmonary MDR-TB treatment regimen in previously treated patients.
In Study 1, 35% were Black, 17.5% were Hispanic, 12.5% were White, 9.4% were Asian, and 25.6% were of another race. Eight of 79 (10.1%) patients in the SIRTURO group and 16 of 81 (19.8%) 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.
No additional unique Adverse Reactions were identified from the uncontrolled Study 3.
In both Studies 1 and 2, aminotransferase 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 or aspartate aminotransferase greater than or equal to 3 times the upper limit of normal during the overall treatment period.
Increased Mortality
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 tuberculosis-related. One death occurred during the 24-week SIRTURO treatment period. The median time to death for the remaining eight subjects 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 tuberculosis, HIV status, and severity of disease was observed.
In the open-label Study 3, 6.9% (16/233) subjects died. The most common cause of death as reported by the investigator was TB (9 subjects). All but one subject who died of TB had not converted or had relapsed. The causes of death in the remaining subjects varied.
7 DRUG INTERACTIONS
7.1 CYP3A4 Inducers/Inhibitors
Bedaquiline exposure may be reduced during co-administration with inducers of CYP3A4 and increased during co-administration with inhibitors of CYP3A4.
CYP3A4 Inducers
Due to the possibility of a reduction of the therapeutic effect of bedaquiline because of the decrease in systemic exposure, co-administration of strong CYP3A4 inducers, such as rifamycins (i.e., rifampin, rifapentine and rifabutin), or moderate CYP3A4 inducers should be avoided during treatment with SIRTURO [see Clinical Pharmacology (12.3)].
CYP3A4 inhibitors
Due to the potential risk of adverse reactions to bedaquiline because of the increase in systemic exposure, prolonged co-administration of bedaquiline and strong CYP3A4 inhibitors, such as ketoconazole or itraconazole, for more than 14 consecutive days should be avoided unless the benefit outweighs the risk [see Clinical Pharmacology (12.3)]. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended.
7.2 Other Antimicrobial Medications
No dose-adjustment of isoniazid or pyrazinamide is required during co-administration with SIRTURO.
In a placebo-controlled clinical trial in patients with MDR-TB, no major impact of co-administration of SIRTURO on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed.
7.3 Antiretroviral Medications
Lopinavir/ritonavir
Although clinical data in HIV/MDR-TB co-infected patients on the combined use of lopinavir (400 mg)/ritonavir (100 mg) with SIRTURO are not available, use SIRTURO with caution when co-administered with lopinavir/ritonavir and only if the benefit outweighs the risk [see Clinical Pharmacology (12.3)].
Efavirenz
Concomitant administration of bedaquiline and efavirenz, or other moderate CYP3A inducers, should be avoided [see Warnings and Precautions (5.4)].
7.4 QT Interval Prolonging Drugs
In a drug interaction study of bedaquiline and ketoconazole, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval.
In Study 3, mean increases in QTc were larger in the 17 subjects who were taking clofazimine with bedaquiline at Week 24 (mean change from reference of 31.9 ms) than in subjects who were not taking clofazimine with bedaquiline at Week 24 (mean change from baseline of 12.3 ms). Monitor ECGs if SIRTURO is co-administered to patients receiving other drugs that prolong the QTc interval, and discontinue SIRTURO if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 ms. [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to bedaquiline. In these studies, the corresponding plasma exposure (AUC) was 2-fold higher in rats compared to humans. There are, however, no adequate and well-controlled studies of SIRTURO in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether bedaquiline or its metabolites are excreted in human milk, but rat studies have shown that drug is concentrated in breast milk.
In rats, treated with bedaquiline at doses 1 time to 2 times the clinical dose (based on AUC comparisons), concentrations in milk were 6-fold to 12-fold higher than the maximum concentration observed in maternal plasma. Pups from these dams showed reduced body weights compared to control animals throughout the lactation period.
Because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of SIRTURO in pediatric patients have not been established.
8.5 Geriatric Use
Because of limited data, differences in outcomes or specific risks with SIRTURO cannot be ruled out for patients 65 years of age and older.
8.6 Hepatic Impairment
The pharmacokinetics of bedaquiline were assessed after single-dose administration to subjects 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 (5.3)].
8.7 Renal Impairment
SIRTURO has mainly been studied in 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 for adverse reactions of SIRTURO when administered to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis.
10 OVERDOSAGE
There is no experience with the treatment of acute overdose with SIRTURO. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose. Removal of unabsorbed bedaquiline may be achieved by the administration of activated charcoal. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma.
11 DESCRIPTION
SIRTURO (bedaquiline) for oral administration is available as 100 mg strength tablets. Each tablet contains 120.89 mg of bedaquiline fumarate drug substance, which is equivalent to 100 mg of bedaquiline. Bedaquiline is a diarylquinoline antimycobacterial drug.
Bedaquiline fumarate is a white to almost white powder and is practically insoluble in aqueous media. The chemical name of bedaquiline fumarate is (1R, 2S)-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 C32H31BrN2O2∙C4H4O4 and a molecular weight of 671.58 (555.50 + 116.07). The molecular structure of bedaquiline fumarate is the following:
SIRTURO (bedaquiline) 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).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Bedaquiline is a diarylquinoline antimycobacterial drug [see Microbiology (12.4)].
12.2 Pharmacodynamics
Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4-fold to 6-fold lower) compared to the parent compound. However, M2 plasma concentrations appeared to correlate with QT prolongation.
Cardiac Electrophysiology
In Study 1, the mean increases in QTcF, corrected using the Fridericia method, were greater in the SIRTURO treatment group compared to the placebo treatment group from the first week of treatment (9.9 ms at Week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase in QTcF during the 24 weeks of SIRTURO treatment was 15.7 ms compared to 6.2 ms with placebo treatment (at Week 18). After bedaquiline treatment ended, the QTcF gradually decreased, and the mean value was similar to that in the placebo group by study week 60.
In Study 3, where patients with no treatment options received other QT-prolonging drugs used to treat tuberculosis, including clofazimine, concurrent use with SIRTURO resulted in additive QTcF prolongation, proportional to the number of QT prolonging drugs in the treatment regimen. Patients taking SIRTURO alone with no other QT prolonging drug developed a mean QTcF increase over baseline of 23.7 ms with no QTcF segment duration in excess of 480 ms, whereas patients taking at least 2 other QT prolonging drugs developed a mean QTcF prolongation of 30.7 ms over baseline, and resulted in QTcF segment duration in excess of 500 ms in one patient. [See Warnings and Precautions (5.3)]
12.3 Pharmacokinetics
Absorption
After oral administration of SIRTURO maximum plasma concentrations (Cmax) are typically achieved at approximately 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied [700 mg single-dose (1.75 times the 400 mg loading dose)] [see Dosage and Administration (2.3)]. Administration of SIRTURO with a standard meal containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by about 2-fold compared to administration under fasted conditions. Therefore, SIRTURO should be taken with food to enhance its oral bioavailability.
Distribution
The plasma protein binding of bedaquiline is greater than 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 Liters.
Metabolism
CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of antimycobacterial potency.
Elimination
After reaching Cmax, bedaquiline concen
