Warning
·
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 56 7 8
Uses for SirturoTuberculosis
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
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 AdministrationGeneral
·
Use in conjunction with ≥3
other drugs to which the patient's multidrug-resistant M. tuberculosisisolate
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
AdministrationOral Administration
Administer orally with food.1 Swallow
tablets whole with water.1
Dosage
Available as bedaquiline
fumarate; dosage expressed in terms of bedaquiline.1
AdultsTuberculosisActive 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 PopulationsHepatic 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 SirturoContraindications
·
No known contraindications.1
Warnings/PrecautionsWarningsIncreased 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/PrecautionsHepatic 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 PopulationsPregnancy
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 PharmacokineticsAbsorptionBioavailability
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
DistributionExtent
Distributed into milk in rats;
not known whether distributed into human milk.1
Plasma Protein Binding
>99.9%.1
EliminationMetabolism
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
StabilityStorageOralTablets
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 2018,
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
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