skill [18:14 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 hepatotoxicity 1 Avoid concomitant use, especially in patients with diminished hepatic reserve 1 Clofazimine Additive or synergistic effects on QT interval prolongation 1 Closely monitor ECG 1 Cycloserine No clinically important effect on cycloserine pharmacokinetics 1 Efavirenz Slightly decreased bedaquiline AUC and increased peak concentrations of bedaquiline M2 metabolite; no effect on efavirenz pharmacokinetics 9 Not considered clinically important 9 Ethambutol No clinically important effect on ethambutol pharmacokinetics 1 Fluoroquinolones Increased risk of QT interval prolongation 1 Ofloxacin: No clinically important effect on ofloxacin pharmacokinetics 1 Closely monitor ECG 1 Isoniazid No clinically important effect on AUC of bedaquiline or isoniazid 1 Dosage adjustment not needed for either drug 1 Kanamycin No clinically important effect on kanamycin pharmacokinetics 1 Ketoconazole Increased bedaquiline AUC and concentrations; possible increased risk of bedaquiline adverse effects 1 Increased risk of QT interval prolongation 1 Avoid concomitant use for durations >14 consecutive days, unless benefits outweigh risks; 1 monitor for adverse effects 1 Lopinavir/ritonavir Increased bedaquiline AUC; no clinically important effect on bedaquiline peak concentrations 1 Use concomitantly with caution and only if benefits outweigh risks 1 Macrolides Increased risk of QT interval prolongation 1 Closely monitor ECG 1 Nevirapine No clinically important effect on bedaquiline AUC 1 Bedaquiline dosage adjustment not needed 1 Pyrazinamide No clinically important effect on AUC of bedaquiline or pyrazinamide 1 Dosage adjustment not needed for either drug 1 Rifamycins (rifampin, rifabutin, rifapentine) Possible decreased bedaquiline concentrations with possible decreased therapeutic effects 1 Rifampin: Bedaquiline AUC decreased 52% 1 Avoid concomitant use 1 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 Cl cr . 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. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Bedaquiline Fumarate Routes Dosage Forms Strengths Brand Names Manufacturer Oral Tablets 100 mg (of bedaquiline) Sirturo Janssen AHFS DI Essentials. Copyright 2017, Selected Revisions September 27, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, 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. [PubMed 12549898] 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] Next Interactions Print this page Add to My Med List More about Sirturo (bedaquiline) Side Effects During Pregnancy Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: diarylquinolines Consumer resources Sirturo Sirturo (Advanced Reading) Professional resources Bedaquiline Fumarate (AHFS Monograph) Related treatment guides Tuberculosis, Resistant]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only B Pregnancy Category No proven risk in humans N/A CSA Schedule Not a controlled drug 4 years Approval History FDA approved 2012 Manufacturers Janssen Pharmaceuticals, Inc. Johnson & Johnson Drug Class Diarylquinolines Related Drugs Tuberculosis, Resistant bedaquiline , Paser , aminosalicylic acid , More... Sirturo Rating No Reviews - Be the first! No Reviews - Be the first! 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