TRACLEER
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRACLEER (TRACLEER).
Bosentan is a dual endothelin receptor antagonist (ERA) that blocks endothelin-1 (ET-1) from binding to ETA and ETB receptors in pulmonary vascular smooth muscle and endothelium, reducing vasoconstriction and cell proliferation.
| Metabolism | Primarily metabolized by cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4; also a substrate of CYP2C19. Bosentan is also an inducer of CYP2C9 and CYP3A4, which can affect coadministered drugs. |
| Excretion | Primarily hepatic metabolism (CYP2C9 and CYP3A4) with biliary excretion of unchanged drug and metabolites. Renal excretion of unchanged drug is negligible (<1%). Fecal excretion accounts for ~75% of total clearance, with ~25% excreted in urine as metabolites. |
| Half-life | Terminal elimination half-life is approximately 4-5 hours in healthy adults. In patients with pulmonary arterial hypertension, half-life may be slightly prolonged (up to 6-8 hours) due to reduced clearance. |
| Protein binding | Highly protein bound (>98%), primarily to albumin and to a lesser extent alpha1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is 0.3-0.5 L/kg, indicating distribution primarily into extracellular fluid and well-perfused tissues. |
| Bioavailability | Oral bioavailability is approximately 50% (range 30-70%) due to first-pass metabolism. Food increases bioavailability by about 1.2- to 1.5-fold. |
| Onset of Action | Oral: Clinical improvement (e.g., increased 6-minute walk distance) typically observed within 2-4 weeks of starting therapy. |
| Duration of Action | Duration of hemodynamic effect (e.g., reduction in pulmonary vascular resistance) persists for several hours after a single dose. Pharmacodynamic effects (exercise capacity) are maintained with twice-daily dosing. |
Initial: 62.5 mg twice daily orally for 4 weeks, then increase to maintenance: 125 mg twice daily orally.
| Dosage form | TABLET, FOR SUSPENSION |
| Renal impairment | No dose adjustment required for GFR ≥15 mL/min. Not studied in ESRD (GFR <15 mL/min) or dialysis; use caution. |
| Liver impairment | Contraindicated in Child-Pugh Class C. Child-Pugh A or B: no dose adjustment; monitor liver function closely. Initiate at 62.5 mg twice daily and consider slower up-titration. |
| Pediatric use | Approved for children ≥3 years (weight 10-20 kg): initial 31.25 mg (half of 62.5 mg tablet) twice daily for 4 weeks, then 62.5 mg twice daily; weight >20 kg: same as adult dosing (62.5 mg twice daily initial, then 125 mg twice daily). |
| Geriatric use | No specific dose adjustment; use caution due to potential age-related hepatic or renal impairment. Monitor liver function and vital signs. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRACLEER (TRACLEER).
| Breastfeeding | Bosentan is excreted into human breast milk. The milk-to-plasma ratio is unknown. Due to potential adverse effects (e.g., hepatotoxicity, teratogenicity) in breastfed infants, breastfeeding is not recommended during therapy and for at least 3 days after the last dose. |
| Teratogenic Risk | Bosentan (Tracleer) is teratogenic in humans. There is a high risk of fetal harm if administered during pregnancy, including major congenital malformations (e.g., craniofacial, cardiovascular) and fetal death. Pregnancy is contraindicated. Teratogenicity is highest during the first trimester but risks persist throughout gestation due to potential for fetal toxicity. |
■ FDA Black Box Warning
WARNING: HEPATOTOXICITY AND TERATOGENICITY. Bosentan can cause severe liver injury, including acute liver failure. Measure liver aminotransferases prior to initiation and monthly thereafter. Discontinue if transaminases >3x ULN with symptoms or bilirubin >2x ULN. Bosentan is teratogenic; must exclude pregnancy before starting and ensure reliable contraception during treatment.
| Serious Effects |
["Pregnancy (Category X)","Baseline elevated liver aminotransferases >3x ULN","Moderate to severe hepatic impairment (Child-Pugh class B or C)","Concomitant use with cyclosporine A (increases hepatotoxicity risk)","Concomitant use with glyburide (increases risk of elevated liver enzymes)"]
| Precautions | ["Hepatotoxicity: Monitor liver function tests monthly; dose adjustment or discontinuation may be required.","Teratogenicity: Pregnancy category X; contraindicated in pregnancy. Female patients must use effective contraception.","Fluid retention: May cause peripheral edema and fluid overload; monitor for signs of heart failure.","Decreased hemoglobin: May cause dose-dependent anemia; monitor hemoglobin levels.","Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider PVOD and discontinue therapy.","Drug interactions: Bosentan induces CYP2C9 and CYP3A4; may reduce efficacy of hormonal contraceptives, warfarin, statins, and other drugs."] |
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| Fetal Monitoring | Women of childbearing potential require monthly pregnancy tests prior to each dispensation. Hepatic function (ALT, AST) must be monitored monthly in all patients. Use of effective contraception (hormonal plus barrier or non-hormonal IUD) is mandatory. Fetal ultrasound may be considered if inadvertent exposure occurs. |
| Fertility Effects | Bosentan may impair fertility by affecting spermatogenesis in males (oligospermia, azoospermia) and possibly ovarian function. Reversible upon discontinuation. Animal studies show reduced fertility; human data limited. |