Dosing and uses of Tracleer (bosentan)
Adult dosage forms and strengths
tablet
- 62.5mg
- 125mg
Pulmonary Arterial Hypertension (PAH)
Indicated to improve exercise ability and decrease worsening of PAH; effectiveness shown in NYHA II-IV, idiopathic or heritable PAH, connective tissue diseases that result in PAH, and PAH associated with congenital heart disease with left-to-right shunts
<40 kg: Maintain dose at 62.5 mg PO twice daily with or without food
>40 kg: 62.5 mg PO twice daily for 4 weeks and then increased to maintenance dosage 125 mg PO twice daily
Discontinuation of treatment: Consider a reduction in dosage to 62.5 mg PO twice daily for 3-7 days
Dosage modifications
ALT/AST levels
- >3 and <5 x ULN: Confirm test; if confirmed, reduce dose to 62.5 mg twice daily or interrupt treatment and monitor liver tests q2wk; if levels return to pretreatment values, continue or reintroduce treatment at starting dose
- >5 and <8 x ULN: Confirm test; if confirmed, stop treatment and monitor liver tests at least q2wk; if levels return to pretreatment values, consider reintroduction of the treatment at reduced dose
- >8 x ULN: Stop treatment; reintroduction should not be considered
Liver impairment
- Mild: No dose adjustment required
- Moderate or severe: Avoid use
Coadministration with strong CYP3A4 inhibitor (ie, cobicistat or ritonavir)
- Have been receiving elvitegravir/cobicistat/emtricitabine/tenofovir or ritonavir for at least 10 days: Start bosentan at 62.5 mg qDay or every other day based upon individual tolerability
- Have been receiving bosentan: Discontinue bosentan at least 36 hr prior to initiation of elvitegravir/cobicistat/emtricitabine/tenofovir or ritonavir; after at least 10 days, resume bosentan at 62.5 mg qDay or every other day based upon individual tolerability
Idiopathic Pulmonary Fibrosis (Orphan)
Orphan indication sponsor
- Actelion Pharmaceuticals Ltd; Gewerbestrasse 16, CH-4123; Switzerland
Systemic Sclerosis (Orphan)
Reduction of the number (treatment) of new digital ulcers in patients with systemic sclerosis
Orphan indication sponsor
- Actelion Pharmaceuticals Ltd; Gewerbestrasse 16, CH-4123; Switzerland
Administration
Healthcare professionals who prescribe therapy must enroll in the Tracleer REMS Program and must comply with the required monitoring to minimize the risks associated with therapy
Pediatric dosage forms and strengths
Not recommended
Tracleer (bosentan) adverse (side) effects
>10%
Hgb decreased; >1 g/dL (57%)
Inhibition of spermatogenesis (25%)
Headache (16-22%)
Nasopharyngitis (11%)
Transaminses increased (12%)
Respiratory tract infection (22%)
Increased transaminases (12%)
1-10%
Edema, lower limb (5-8%)
Flushing (7-9%)
Hypotension (7%)
Hepatic abnormalities (4%)
Palpitations (4%)
Anemia (3%)
Dyspepsia (4%)
Edema, general (4%)
Fatigue (2%)
Pruritus (4%)
<1%
Hyperbilirubinemia
Vasculitis
Jaundice
Leukopenia
Thrombocytopenia
Leukocytoplastic
Warnings
Black box warnings
Hepatotoxicity
- 3-fold ULN elevation of ALT and AST in ~11% of patients observed
- Measure serum aminotransferase levels (and bilirubin if aminotransferase levels elevated) at baseline & then monthly
- Rare cases of unexplained hepatic cirrhosis reported after prolonged therapy (>12 mth) Avoid in patients with elevated aminotransferase levels (>3 x ULN) at baseline because monitoring liver injury may be more difficult
- Discontinue drug if liver aminotransferase elevations accompanied by clinical symptoms of liver injury (eg, nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue) or increases in bilirubin >2 x ULN
Pregnancy Contraindication
- Likely to produce serious birth defects if used by pregnant women; this effect has been seen consistently when administered to animals
- Negative pregnancy test result required before initiating & prevention of pregnancy required thereafter by the use of at least 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A IUD or LNg 20 IUD inserted, in which case no other contraception required)
- Obtain monthly pregnancy tests
Restricted Distribution Program
- Because of risks of liver injury and birth defects, available only through restricted distribution program called the Tracleer Access Program (TAP) by calling 1-866-228-3546; only prescribers and pharmacies registered with the program may prescribe and distribute bosentan
- May be dispensed only to patients enrolled in and meet all conditions of TAP
Contraindications
Hypersensitivity
Pregnancy
Concomitant cyclosporine or glyburide use
Cautions
Avoid use with moderate-to-severe hepatic impairment
Monitor LFTs; avoid use if ALT or AST >3 x ULN or bilirubin >2 x ULN (see Black box warnings and Dosage modifications)
Peripheral edema, veno-occlusive disease (discontinue if suspected), decreased sperm count, or decreased Hgb/Hct may occur
Breastfeeding NOT recommended
May interact with many medications
Product requires special handling and disposaL
Reduces efficacy of hormonal contraceptives
Avoid pregnancy; use 2 forms of birth control (hormonal contraceptives alone may not be effective)
Increased risk of worsening HF related to fluid retention and death in HF patients.
Pregnancy and lactation
Pregnancy category: X
Lactation: Not known if excreted in breast milk; not recommended
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 Tracleer (bosentan)
Mechanism of action
Competitive antagonist of endothelin-1; blocks endothelin receptors on vascular endothelium and smooth muscle resulting in inhibition of vasoconstriction
Absorption
Bioavailability: 50%
Peak plasma time: 3-5hr
Duration: 24 hr
Distribution
Protein Bound: >98% (primarily to albumin)
Vd: 18L
Metabolism
Metabolized by hepatic CYP2C9 and CYP3A4
Metabolites: Ro 48-5033 (active metabolite), Ro 47-8634 (inactive metabolite)
Enzymes induced: CYP2C9, CYP3A4
Elimination
Half-Life: 5-8 hr
Excretion: Feces (predominantly); urine (minimal)
