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Sirturo

Generic Name: Bedaquiline Fumarate
Class: Antituberculosis Agents
Chemical Name: (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol (2E)-but-2-enedioate salt (1:1)
Molecular Formula: C32H31BrN2O2•C4H4O4
CAS Number: 845533-86-0

Warning(s)

  • Increased risk of death reported in patients receiving bedaquiline compared with those receiving placebo (11.4 versus 2.5%, respectively) in one clinical trial.1 Use bedaquiline only when an effective treatment regimen for multidrug-resistant tuberculosis cannot otherwise be provided.1 (See Increased Mortality under Cautions.)

  • QT interval prolongation reported.1 Concomitant use with other drugs associated with QT interval prolongation may result in additive or synergistic effects on QT interval.1 (See Prolongation of QT Interval under Cautions.)

Introduction

Antituberculosis agent; diarylquinoline antimycobacterial.1 5 6 7 8

Uses for Sirturo

Tuberculosis

Treatment of pulmonary multidrug-resistant tuberculosis (i.e., caused by Mycobacterium tuberculosis resistant to isoniazid and rifampin) in conjunction with other antituberculosis agents.1 5 6 10

Designated an orphan drug by FDA for use in treatment of active tuberculosis.3

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Use only when an effective treatment regimen for multidrug-resistant tuberculosis cannot otherwise be provided.1 10

Safety and efficacy for treatment of drug-susceptible tuberculosis, extrapulmonary (e.g., CNS) tuberculosis, or latent tuberculosis infection not established; use not recommended.1

Safety and efficacy for treatment of infections caused by nontuberculous mycobacteria (NTM) not established; use not recommended.1

Patients with multidrug-resistant tuberculosis are at high risk for treatment failure and acquisition of further drug resistance.4 ATS, CDC, and IDSA recommend that such patients be referred to or that consultation be obtained from a specialized treatment center as identified by local or state health departments or the CDC.4

Sirturo Dosage and Administration

General

  • Use in conjunction with ≥3 other drugs to which the patient's multidrug-resistant M. tuberculosis isolate has been shown to be susceptible in vitro.1 If results of in vitro testing not available, use in conjunction with ≥4 other drugs to which the patient's isolate is likely to be susceptible.1

  • Administer using directly observed (supervised) therapy (DOT).1

Administration

Oral Administration

Administer orally with food.1 Swallow tablets whole with water.1

Dosage

Available as bedaquiline fumarate; dosage expressed in terms of bedaquiline.1

Adults

Tuberculosis
Active Tuberculosis
Oral

400 mg once daily for 2 weeks, followed by 200 mg 3 times weekly (with ≥48 hours between doses) for 22 weeks (total of 24 weeks).1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustment not needed.1

Severe hepatic impairment: Use with caution and only when benefits outweigh risks.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not needed.1

Severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis: Use with caution.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments not needed.1

Cautions for Sirturo

Contraindications

  • No known contraindications.1

Warnings/Precautions

Warnings

Increased Mortality

Increased risk of death reported in patients receiving bedaquiline in a placebo-controlled clinical trial (11.4 versus 2.5%, based on data through week 120).1 Cause of increased risk of death unknown.1 No correlation demonstrated between death and sputum culture conversion, relapse, susceptibility to other antituberculosis drugs, HIV status, or disease severity.1

Use bedaquiline only when an effective treatment regimen for multidrug-resistant tuberculosis cannot otherwise be provided.1 10

Prolongation of QT Interval

Prolongation of QT interval reported.1 Concomitant use of bedaquiline with other drugs associated with QT interval prolongation may result in additive or synergistic effects on QT interval.1 (See Interactions.) Documented cases of torsades de pointes not reported to date in patients receiving bedaquiline.1

Perform ECG prior to initiation of bedaquiline and at least at 2, 12, and 24 weeks after starting the drug.1 Measure serum potassium, calcium, and magnesium concentrations at baseline and correct if necessary.1 If QT prolongation detected, monitor electrolyte concentrations.1

Risk of QT interval prolongation may be increased in patients receiving other drugs that prolong QT interval (e.g., clofazimine, fluoroquinolones, macrolides); patients with hypocalcemia, hypokalemia, or hypomagnesemia; or patients with a history of torsades de pointes, congenital long QT syndrome, hypothyroidism and bradyarrhythmias, or uncompensated heart failure.1 Closely monitor ECG in such patients.1

Discontinue bedaquiline and all other drugs that may prolong QT interval if patient develops clinically important ventricular arrhythmia or QTc >500 msec (confirmed by repeat ECG).1 Monitor ECG frequently to confirm that QTc returns to baseline.1 If syncope occurs, perform ECG to detect prolongation of QT interval.1

Has not been evaluated to date in patients with ventricular arrhythmias or recent MI.1

Concentrations of the major metabolite of bedaquiline (an N-monodesmethyl metabolite [M2]) appear to correlate with QT interval prolongation.1

Other Warnings/Precautions

Hepatic Effects

Higher incidence of adverse hepatic effects reported in patients receiving antituberculosis regimens containing bedaquiline compared with patients receiving regimens not containing the drug.1

Monitor liver function tests (AST, ALT, alkaline phosphatase, bilirubin) at baseline, monthly during treatment, and as needed.1 Also monitor for symptoms of hepatic dysfunction.1

If signs or symptoms of new or worsening liver dysfunction (e.g., clinically important elevation in serum aminotransferases and/or bilirubin, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) develop, promptly evaluate patient.1

If AST or ALT increase to >3 times ULN, repeat liver function tests within 48 hours.1 Also test patient for viral hepatitis and discontinue other hepatotoxic drugs.1

Discontinue bedaquiline if elevated aminotransferase concentrations are accompanied by total bilirubin concentrations >2 times ULN, aminotransferase concentrations are >8 times ULN, or aminotransferase elevations persist >2 weeks.1

Avoid other hepatotoxic drugs or herbal products, especially in patients with diminished hepatic reserve.1

HIV-infected Individuals

Data limited to date regarding use in HIV-infected patients, including those receiving antiretroviral therapy.1 (See Specific Drugs under Interactions.)

Use with caution in HIV-infected individuals.10

Selection and Use of Antimycobacterials

Obtain clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response.4 Modify antituberculosis regimen as needed.4

Bedaquiline must be used in conjunction with ≥3 other drugs to which the patient's multidrug-resistant M. tuberculosis isolate has been shown to be susceptible in vitro.1 If results of in vitro testing not available, use in conjunction with ≥4 other drugs to which the patient's multidrug-resistant isolate is likely to be susceptible.1

If patient does not have sputum conversion or if relapse occurs following treatment, perform in vitro susceptibility testing to determine bedaquiline MIC for patient's isolate.1

Compliance with full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical.1 4 Missed doses increase risk of treatment failure and increase likelihood that the patient's M. tuberculosis will develop resistance and will not be treatable.1 4

To ensure compliance, administer treatment regimen using DOT.1 4

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

Not studied in patients with severe hepatic impairment; use with caution in such patients and only when benefits outweigh risks; monitor for adverse reactions.1

Renal Impairment

Use with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis.1

Common Adverse Effects

Nausea,1 5 arthralgia,1 5 headache,1 hemoptysis,1 chest pain.1

Interactions for Sirturo

Metabolized primarily by CYP3A4.1 Does not inhibit CYP1A2, 2A6, 2C8/9/10, 2C19, 2D6, 2E1, 3A4, 3A4/5, or 4A to any clinically important extent.1 Does not induce CYP1A2, 2C9, 2C19, or 3A4.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inducers: Pharmacokinetic interaction (decreased bedaquiline AUC with possible decreased therapeutic effects).1 Avoid concomitant use.1

Potent CYP3A4 inhibitors: Pharmacokinetic interaction (increased bedaquiline AUC with possible increased risk of adverse effects).1 Avoid concomitant use for durations >14 consecutive days, unless benefits of concomitant use outweigh risks;1 monitor for adverse effects.1

Drugs that Prolong QT Interval

Pharmacologic interaction (increased risk of QT interval prolongation); closely monitor ECG.1 (See Prolongation of QT Interval under Cautions.)

Hepatotoxic Drugs

Pharmacologic interaction (increased risk of hepatotoxicity); avoid concomitant use, especially in patients with diminished hepatic reserve.1

Specific Drugs

Drug

Interaction

Comments

Alcohol

Increased risk of hepatotoxicity1

Avoid concomitant use, especially in patients with diminished hepatic reserve1

Clofazimine

Additive or synergistic effects on QT interval prolongation1

Closely monitor ECG1

Cycloserine

No clinically important effect on cycloserine pharmacokinetics1

Efavirenz

Slightly decreased bedaquiline AUC and increased peak concentrations of bedaquiline M2 metabolite; no effect on efavirenz pharmacokinetics9

Not considered clinically important9

Ethambutol

No clinically important effect on ethambutol pharmacokinetics1

Fluoroquinolones

Increased risk of QT interval prolongation1

Ofloxacin: No clinically important effect on ofloxacin pharmacokinetics1

Closely monitor ECG1

Isoniazid

No clinically important effect on AUC of bedaquiline or isoniazid1

Dosage adjustment not needed for either drug1

Kanamycin

No clinically important effect on kanamycin pharmacokinetics1

Ketoconazole

Increased bedaquiline AUC and concentrations; possible increased risk of bedaquiline adverse effects1

Increased risk of QT interval prolongation1

Avoid concomitant use for durations >14 consecutive days, unless benefits outweigh risks;1 monitor for adverse effects1

Lopinavir/ritonavir

Increased bedaquiline AUC; no clinically important effect on bedaquiline peak concentrations1

Use concomitantly with caution and only if benefits outweigh risks1

Macrolides

Increased risk of QT interval prolongation1

Closely monitor ECG1

Nevirapine

No clinically important effect on bedaquiline AUC1

Bedaquiline dosage adjustment not needed1

Pyrazinamide

No clinically important effect on AUC of bedaquiline or pyrazinamide1

Dosage adjustment not needed for either drug1

Rifamycins (rifampin, rifabutin, rifapentine)

Possible decreased bedaquiline concentrations with possible decreased therapeutic effects1

Rifampin: Bedaquiline AUC decreased 52%1

Avoid concomitant use1

Sirturo Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentration attained at approximately 5 hours.1 8

Proportional increases in peak plasma concentration and AUC with single doses up to 700 mg and multiple doses up to 400 mg daily.1 8

Food

Administration with standard meal (22 g fat, 558 calories) results in twofold increase in relative bioavailability compared with fasting conditions.1 8

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

>99.9%.1

Elimination

Metabolism

Metabolized primarily by CYP3A4.1

Major metabolite of bedaquiline, an N-monodesmethyl metabolite (M2), has 4–6 times less antimycobacterial activity compared with parent drug.1

Elimination Route

Primarily eliminated in feces; negligible renal clearance of unchanged drug.1

Unlikely to be substantially removed from plasma by hemodialysis or peritoneal dialysis.1

Half-life

Mean terminal elimination half-lives of bedaquiline and M2 metabolite are similar and are approximately 5.5 months; long half-life probably related to slow release of drug and metabolite from peripheral tissues.1 6

Special Populations

Patients with moderate hepatic impairment (Child-Pugh class B): Mean AUC of bedaquiline and M2 metabolite following single 400-mg dose are approximately 20% lower compared with healthy individuals.1

Pharmacokinetics do not appear to correlate with Clcr.1

No clinically important differences in pharmacokinetics related to age, gender, or race.1

Pharmacokinetics in children not studied to date.1

Stability

Storage

Oral

Tablets

25°C; may be exposed to 15–30°C.1

Dispense in original container; if dispensed outside original container, store in tight, light-resistant container with expiration date ≤3 months.1

Actions

  • Diarylquinoline antimycobacterial; antituberculosis agent.1 5 6 7 8

  • Inhibits mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme essential for generation of energy in M. tuberculosis.1 5 6 7 8 13 15

  • Active in vitro against M. tuberculosis,1 6 8 12 including drug-susceptible M. tuberculosis and multidrug-resistant strains resistant to isoniazid, rifampin, ethambutol, ethionamide, pyrazinamide, streptomycin, and/or ofloxacin.6 7 8 12 MIC of bedaquiline reported for clinical isolates of multidrug-resistant M. tuberculosis generally has ranged from 0.003–0.25 mcg/mL.1 6

  • Also active in vitro against some other mycobacteria (e.g., M. avium,8 12 M. intracellulare,8 12 M. abscessus,8 M. ulcerans).8

  • M. tuberculosis with reduced susceptibility or resistance to bedaquiline (4- to 133-fold increase in MIC) have been produced in vitro,7 14 and strains with reduced susceptibility have emerged during treatment with the drug.1 Mutations in the atpE target gene have been identified as a mechanism of mycobacterial resistance to bedaquiline;1 7 8 14 other mechanisms of resistance also exist.1 14

Advice to Patients

  • Importance of providing patient a copy of the manufacturer's patient information (medication guide).2 Importance of patient reading the medication guide prior to initiation of therapy and each time the prescription is refilled.2

  • Importance of taking bedaquiline exactly as prescribed and completing the full course of therapy with bedaquiline and other antituberculosis drugs.1

  • Advise patients that missed doses may decrease treatment effectiveness and increase the risk of developing resistance to bedaquiline and other antituberculosis drugs.1 If a dose of bedaquiline is missed during the first 2 weeks of therapy, the missed dose should be skipped and the usual dosing schedule continued.1 If a dose of bedaquiline is missed after the first 2 weeks, the missed dose should be taken as soon as possible and the usual 3-times-weekly regimen resumed.1

  • Importance of taking bedaquiline with food.1

  • Importance of storing bedaquiline tablets in original container and protecting from light.2

  • Possibility of serious adverse effects, including increased risk of death, heart rhythm abnormalities, and/or hepatitis.1

  • Importance of informing clinicians of personal or family history of congenital QT interval prolongation or heart failure.1

  • Importance of informing clinicians if symptoms suggestive of hepatotoxicity (e.g., nausea, vomiting, abdominal pain, fever, weakness, pruritus, fatigue, anorexia, jaundice, dark urine, light-colored stools) occur.2

  • Potential for bedaquiline to cause nausea, arthralgia, headache, increased amylase concentrations, hemoptysis, chest pain, anorexia, or rash.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.1 Advise patients to abstain from alcohol and other hepatotoxic drugs or herbal products.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Bedaquiline Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

100 mg (of bedaquiline)

Sirturo

Janssen

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 27, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Janssen Therapeutics. Sirturo (bedaquiline) tablets prescribing information. Titusville, NJ; 2013 June.

2. Janssen Therapeutics. Sirturo (bedaquiline) tablets medication guide. Titusville, NJ; 2012 Dec.

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food Drug and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2005 Jan 10. From FDA website. Accessed 2013 Apr 10.

4. Centers for Disease Control and Prevention. Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep. 2003; 52(No. RR-11):1-77.

5. Diacon AH, Pym A, Grobusch M et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009; 360:2397-405. [PubMed 19494215]

6. Diacon AH, Donald PR, Pym A et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012; 56:3271-6. [PubMed 22391540]

7. Huitric E, Verhasselt P, Koul A et al. Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2010; 54:1022-8. [PubMed 20038615]

8. Matteelli A, Carvalho AC, Dooley KE et al. TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol. 2010; 5:849-58. [PubMed 20521931]

9. Dooley KE, Park JG, Swindells S et al. Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267. J Acquir Immune Defic Syndr. 2012; 59:455-62. [PubMed 22126739]

10. World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis. Interim policy guidance. 2013. From WHO website.

12. Huitric E, Verhasselt P, Andries K et al. In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007; 51:4202-4. [PubMed 17709466]

13. Haagsma AC, Podasca I, Koul A et al. Probing the interaction of the diarylquinoline TMC207 with its target mycobacterial ATP synthase. PLoS One. 2011; 6:e23575.

14. Segala E, Sougakoff W, Nevejans-Chauffour A et al. New mutations in the mycobacterial ATP synthase: new insights into the binding of the diarylquinoline TMC207 to the ATP synthase C-ring structure. Antimicrob Agents Chemother. 2012; 56:2326-34. [PubMed 22354303]

15. Biukovic G, Basak S, Manimekalai MS et al. Variations of subunit {varepsilon} of the Mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207. Antimicrob Agents Chemother. 2013; 57:168-76. [PubMed 23089752]

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