bedaquiline (Rx)

Brand and Other Names:Sirturo
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 100mg

Multidrug Resistant Pulmonary Tuberculosis

Diarylquinoline antimycobacterial indicated as part of combination therapy for pulmonary multidrug resistant tuberculosis (MDR-TB); reserve bedaquiline for when an effective treatment TB regimen cannot otherwise be provided

Weeks 1-2: 400 mg PO qDay for 2 weeks, THEN

Weeks 3-24: 200 mg 3 times/week with at least 48 hr between doses

Use in combination with at least 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible; reserve bedaquiline for when an effective treatment TB regimen cannot otherwise be provided

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

Dosage Modifications

Renal impairment

  • Mild-to-moderate: No dosage adjustment required
  • Severe or end-stage renal disease requiring hemodialysis or peritoneal dialysis: Use with caution; if used, monitor for adverse reactions of bedaquiline

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): No dosage adjustment required
  • Severe (Child-Pugh C): Not studied; use only if benefits outweigh risks

Dosing Considerations

Limitations of use

  • Latent infection due to Mycobacterium tuberculosis
  • Drug-sensitive tuberculosis
  • Extra-pulmonary tuberculosis
  • Infections cause by nontuberculous mycobacteria

Nontuberculosis Mycobacteria Infection (Orphan)

Orphan designation for treatment of nontuberculosis mycobacteria infection

Orphan sponsor

  • Janssen Research & Development, LLC; 125 Trenton-Harbourton Road; Titusville, New Jersey 08560

Dosage Forms & Strengths

tablet

  • 100mg

Multidrug Resistant Pulmonary Tuberculosis

Diarylquinoline antimycobacterial indicated as part of combination therapy for pulmonary multidrug resistant tuberculosis (MDR-TB); reserve bedaquiline for when an effective treatment TB regimen cannot otherwise be provided

<12 years: Safety and efficacy not established

≥12 years with weight ≥30 kg

  • Weeks 1-2: 400 mg PO qDay for 2 weeks, THEN
  • Weeks 3-24: 200 mg 3 times/week with at least 48 hr between doses
  • Use in combination with at least 4 other drugs to which the patient's MDR-TB isolate is likely to be susceptible; reserve bedaquiline for when an effective treatment TB regimen cannot otherwise be provided

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

Dosage Modifications

Renal impairment

  • Mild-to-moderate:: No dosage adjustment required
  • Severe or end-stage renal disease requiring hemodialysis or peritoneal dialysis: Use with caution; if used, monitor for adverse reactions of bedaquiline

Dosing Considerations

Limitations of use

  • Latent infection due to Mycobacterium tuberculosis
  • Drug-sensitive tuberculosis
  • Extra-pulmonary tuberculosis
  • Infections cause by nontuberculous mycobacteria
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Interactions

Interaction Checker

and bedaquiline

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Adults

            • Nausea (38%)
            • Arthralgia (33%)
            • Headache (28%)
            • Chest pain (11%)

            Pediatrics

            • Arthralgia (40%)
            • Nausea (13%)
            • Abdominal pain (13%)

            1-10%

            Adults

            • Anorexia (9%)
            • Rash (8%)

            Adults or children

            • Transaminases increased (9%)
            • Blood amylase increased (3%)

            Frequency Not Defined

            QT prolongation

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            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

            Administered by directly observed therapy (DOT)

            Hepatotoxicity

            • Hepatic-related adverse effects increased when bedaquiline added to multidrug regimen; avoid alcohol and other hepatotoxic drugs, especially in patients with hepatic impairment
            • Monitor symptoms (eg, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, 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

            • 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, congenital long-QT syndrome, uncompensated heart failure, or hypothyroidism with bradyarrhythmias
            • 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

            Drug interaction overview

            • May prolong QT interval; assess thoroughly and if possible, avoid coadministration with other drugs that prolong QT interval
            • Metabolized by CYP3A4; avoid strong CYP3A4 inducers (eg, rifampin, rifapentine, rifabutin) and antiretroviral drugs that are moderate inducers (eg, efavirenz) 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 >14 consecutive days, unless the benefit of treatment outweighs the risk
            • Use bedaquiline with caution when coadministered 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 use in HIV/MDR-TB coinfected patients not receiving antiretroviral therapy
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            Pregnancy & Lactation

            Pregnancy

            Available data from published literature of use in pregnant women are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            Clinical considerations

            • Active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including, maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death

            Animal studies

            • Reproduction studies in rats and rabbits revealed no evidence of harm to fetuses of pregnant rats and rabbits during organogenesis at exposures up to 6x the clinical dose based on AUC comparisons

            Lactation

            No data are available regarding presence in human milk

            Monitor infants exposed for signs of bedaquiline-related adverse reactions (eg, hepatotoxicity)

            Animal studies

            • Bedaquiline concentrations in rat milk were 6-fold to 12-fold higher than the maximum concentration observed in maternal plasma at exposures 1-2x the clinical exposure (based on AUC comparisons)

            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.

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            Pharmacology

            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 time

            • Adults: 5 hr
            • Age 14-18 years: 4 hr

            Plasma concentrations

            • Peak
              • Adults: 1659 ng/mL
              • Age 14-18 years: 1800 ng/mL
            • Minimum
              • Adults: 654 ng/mL
              • Age 14-18 years: 544 ng/mL

            AUC

            Adults: 25,863 ng⋅hr/mL

            Age 14-18 years: 26,300 ng⋅hr/mL

            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 from peripheral tissues)

            Renal clearance: <0.001%

            Excretion: Mainly in feces

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            Administration

            Oral 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

            Storage

            Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.