Dosing and uses of Sirturo (bedaquiline)
Adult dosage forms and strengths
tablet
- 100mg
Multidrug Resistant Pulmonary Tuberculosis
Diarylquinoline antimycobacterial indicated as part of combination therapy in adults (≥18 years) with pulmonary multidrug resistant tuberculosis (MDR-TB)
Weeks 1-2: 400 mg PO qDay for 2 weeks, THEn
Weeks 3-24: 200 mg 3 times/week for 22 weeks
Take with a multidrug regimen consisting of at least 4 other drugs that the MDR-TB is likely susceptible for the entire 24 week duration
CDC provisional guidelines
- May be used off-label on a case-by-case basis in children, HIV-infected persons, pregnant women, persons with extrapulmonary MDR TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided
- May be used on a case-by-case basis for durations longer than 24 weeks when an effective treatment regimen cannot be provided otherwise
- Reference: MMWR Recommendations and Reports. October 25, 2013/62(rr9);1-12
Dosing Considerations
Reserve for use when an effective treatment regimen cannot otherwise be provided
Not indicated to treat latent, extrapulmonary, or drug-sensitive tuberculosis
Use in combination with at least 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible
Treatment of nontuberculous mycobacteria infections have not been established
Administration
Take with food
Swallow whole with water
Missed dose
- During first 2 weeks of treatment: Do not make up the missed dose but continue the usual dosing schedule
- From week 3 onwards: If a 200 mg dose is missed, patients should take the missed dose as soon as possible, and then resume the 3 times/week regimen
Pediatric dosage forms and strengths
tablet
- 100mg
Multidrug Resistant Pulmonary Tuberculosis (Off-label)
<18 years: Safety and efficacy not established
Diarylquinoline antimycobacterial indicated as part of combination therapy in adults (≥18 years) with pulmonary multidrug resistant tuberculosis (MDR-TB)
CDC provisional guidelines suggest off-label use in children on a case-by-case basis
Weeks 1-2: 400 mg PO qDay for 2 weeks, THEn
Weeks 3-24: 200 mg 3 times/week for 22 weeks
Take with a multidrug regimen consisting of at least 4 other drugs that the MDR-TB is likely susceptible for the entire 24 week duration
Dosing Considerations
Reserve for use when an effective treatment regimen cannot otherwise be provided
Not indicated to treat latent, extrapulmonary, or drug-sensitive tuberculosis;
CDC provisional guidelines suggest off-label uses on a case-by-case basis in children, HIV-infected persons, pregnant women, persons with extrapulmonary MDR TB, and patients with comorbid conditions on concomitant medications when an effective treatment regimen cannot otherwise be provided
Use in combination with at least 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible
Treatment of nontuberculous mycobacteria infections have not been established
Administration
Take with food
Swallow whole with water
Missed dose
- During first 2 weeks of treatment: Do not make up the missed dose but continue the usual dosing schedule
- From week 3 onwards: If a 200 mg dose is missed, patients should take the missed dose as soon as possible, and then resume the 3 times/week regimen
Sirturo (bedaquiline) adverse (side) effects
>10%
Nausea (38%)
Arthralgia (32.9%)
Headache (27.8%)
1-10%
Transaminases increased (8.9%)
Blood amylase increased (2.5%)
Frequency not defined
QT prolongation
Warnings
Black box warnings
An increased risk of death was seen in the bedaquiline treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in 1 clinical triaL
Only use when an effective treatment regimen cannot otherwise be provided
QT prolongation can occur; coadministration with drugs that prolong the QT interval may cause additive QT prolongation
Contraindications
None
Cautions
Increased risk of death in bedaquiline treatment group (see Black box warnings) Metabolized by CYP3A4; avoid strong CYP3A4 inducers (eg, rifampin, rifapentine, rifabutin) that may reduce bedaquiline’s effect
Coadministration with CYP3A4 inhibitors may increase systemic exposure and result in adverse effects; avoid coadministration with strong CYP3A4 inhibitors for more than 14 consecutive days, unless the benefit of treatment outweighs the risk
Use bedaquiline with caution when co-administered with lopinavir/ritonavir and only if the benefit outweighs the risk
There are no clinical data on the combined use of antiretroviral agents and bedaquiline in HIV/MDR-TB coinfected patients and only limited clinical data on the use of SIRTURO in HIV/MDR-TB coinfected patients not receiving antiretroviral therapy
Administered by directly observed therapy (DOT)
Hepatotoxicity
- Hepatic-related adverse effects increased when bedaquiline added to multidrug regimen; avoid alcohol and other hepatotoxic drugs
- 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
- Monitor ALT, AST, Alkaline phosphatase, and bilirubin at baseline, and monthly while on treatment
- Discontinue if
- aminotransferase increases are accompanied by total bilirubin elevation >2x ULN
- aminotransferase elevations >8x ULN
- aminotransferase elevations persist beyond 2 weeks
QT prolongation
- Also see Black box warnings
- Prolongs QT interval; obtain ECG before initiating treatment and at least 2, 12, and 24 weeks after starting treatment
- Obtain baseline serum levels for potassium, calcium, and magnesium and correct if abnormal; follow-up electrolyte monitoring if QT prolongation detected
- Increased risk for QT prolongation with:
- -coadministration with QT prolonging drugs (eg, fluoroquinolones, macrolides, clofazimine)
- -history of Torsade de Pointes
- -history of congenital long QT syndrome
- -history of hypothyroidism and bradyarrhythmias
- -history of uncompensated heart failure
- -serum calcium, magnesium, or potassium levels below the lower limits of normal
- Discontinue bedaquiline and other QT prolonging drugs if the following develops:
- -clinically significant ventricular arrhythmia
- -QTcF interval >500 ms
- Monitor ECG to confirm QT interval returned to baseline
- If syncope occurs, obtain ECG
Pregnancy and lactation
Pregnancy category: B
Lactation: Unknown whether distributed in human breast milk Pharmacology
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Sirturo (bedaquiline)
Mechanism of action
Diarylquinoline; inhibits mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme essential for the generation of energy in Mycobacterium tuberculosis
Absorption
Bioavailability: Increased 2-fold when taken with standard meal compared with fasted conditions
Peak Plasma Concentration: 5 hr
Distribution
Protein Bound: >99.9%
Vd: 164 L
Metabolism
Metabolized primarily by CYP3A4 to form N-monodesmethyl metabolite (M2) which is 4- to 6-times less active
Elimination
Half-life: 5.5 months (mean terminal half-life of bedaquiline and the M2 metabolite)
Renal clearance: <0.001%
Excretion: Mainly in feces
