Drug Interaction:
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.
2.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
.
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.
4. 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.
5. 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.
Nevirapine
No dosage adjustment of bedaquiline is required when co-administered
with nevirapine
Efavirenz
Concomitant administration of bedaquiline and efavirenz, or other moderate
CYP3A inducers, should be avoided
6. 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.
Indication:
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
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.
QT Prolongation
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.
RECENT MAJOR CHANGES
Indications and Usage (1) 05/2015
Drug Name- Sirturo
Active Ingredient - Bedaquiline
As a part of combination therapy to treat adults with multi-drug resistent
pulmonary tuberculosis (TB) when other alternatives are not available
Indication-
Combination to threat adults with multi-drug resistent pulmonary tuberculosis when
other alternatives not available
Approved by FDA on 28-12--2012 (Ref- FDA approved List- 2012)
LIST OF APPROVED DRUG FROM 01-01-2015 To 31-12-2015
ISSUED BY NEW DRUG DIVISION - DRUG CONTROLLER GENERAL- INDIA
Sr.No Name of Drug Indication Date of Issue
2. Bedaquiline Tablet 100mg 14-01-2015
In adults (>/=18years) , as part of Combination therapy
of Combination therapy of pulmonary tuberculosis due
to multi-drug resistent Mycobacterium tuberculosis
when an effective treatment regimen cannot Otherwise
be provided
Approved by DCG INDIA (Ref- DCGI approved List- 01-01-2015 To 31-12-3015)
Adverse Reaction:
The most common adverse reactions reported in 10% or more of patients treated
with SIRTURO were nausea, arthralgia, headache, hemoptysis and chest pain.
Contra-Indications:
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
QT prolongation can occur with SIRTURO. Monitor ECGs and discontinue
SIRTURO if significant ventricular arrhythmia or QTcF interval > 500 ms
develops.
Hepatotoxicity may occur with use of SIRTURO.
Monitor liver-related laboratory tests. Discontinue if evidence of liver injury.
Dosages/ Overdosage Etc:
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).
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.
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
Safety and efficacy of SIRTURO in HIV-infected patients with
MDR-TB have not been established, as clinical data are limited
DOSAGE AND ADMINISTRATION
Emphasize need for compliance with full course of therapy
Prior to administration, obtain ECG, liver enzymes and electrolytes.
Obtain susceptibility information for the background regimen against
Mycobacterium tuberculosis isolate if possible.
DOSAGE FORMS AND STRENGTHS
SIRTURO tablets, 100 mg are uncoated white to almost white round
biconvex
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Serious Adverse Reactions
Advise patients that the following serious side effects can occur with SIRTURO: death,
heart rhythm abnormalities, and/or hepatitis. In addition, advise patients about other
potential side effects: nausea, joint pain, headache, increased blood amylase,
hemoptysis,chest pain, anorexia, and/or rash.
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 antibacterial drugs in the future.
If a dose is missed during the first 2 weeks of treatment, advise patients
not to make up themissed dose but to continue the usual dosing schedule.
From Week 3 onwards, if a 200 mg dose is missed, advise patients to
take the missed dose as soon as possible, and then resume the
3 times a week regimen.
Administration Instructions
Inform patients to take SIRTURO with food.
Use with Alcohol and other Medications
Advise 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.
:
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Bedaquiline is a diarylquinoline antimycobacterial drug
2.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)
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
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.
2. 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.
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.
3. Pediatric Use
The safety and effectiveness of SIRTURO in pediatric patients have not been established.
4. 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.
