BOSENTAN
Clinical safety rating: avoid
Contraindicated (not allowed)
Endothelin receptor antagonist; blocks endothelin-1 (ET-1) from binding to ETA and ETB receptors, inhibiting vasoconstriction and proliferation.
| Metabolism | Hepatic via CYP2C9 and CYP3A4; forms three metabolites (one active). |
| Excretion | Primarily biliary excretion (≥50% as unchanged drug) with fecal elimination; renal excretion accounts for <3% of unchanged drug. |
| Half-life | Terminal elimination half-life is approximately 5 hours in healthy adults, but prolonged in patients with hepatic impairment (up to 21 hours in Child-Pugh Class A and B). |
| Protein binding | >98% bound to plasma proteins, mainly albumin. |
| Volume of Distribution | Approximately 0.5 L/kg, indicating extensive distribution into tissues. |
| Bioavailability | Oral bioavailability is approximately 50% (range 30-70%) in healthy subjects; not significantly affected by food. |
| Onset of Action | Oral: Onset of pulmonary vasodilation occurs within 30-60 minutes after oral administration. |
| Duration of Action | Duration of hemodynamic effects (e.g., reduction in pulmonary vascular resistance) persists for 6-12 hours; requires twice-daily dosing for continuous effect. |
62.5 mg orally twice daily for 4 weeks, then increase to maintenance dose of 125 mg twice daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥15 mL/min; not studied in GFR <15 mL/min or dialysis; use with caution. |
| Liver impairment | Contraindicated in Child-Pugh class C; no dose adjustment for Child-Pugh class A; for class B, initiate at 62.5 mg once daily or every other day based on clinical judgment. |
| Pediatric use | For pulmonary arterial hypertension in children: 2 mg/kg (up to 62.5 mg) orally twice daily for 4 weeks, then increase to 4 mg/kg (up to 125 mg) twice daily. For other indications, not established. |
| Geriatric use | No specific dose adjustment in elderly based on age alone; monitor hepatic function and fluid retention due to potential increased sensitivity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inducers like rifampin decrease levels and inhibitors like ketoconazole increase levels Requires monthly monitoring of liver enzymes due to risk of hepatotoxicity.
| Breastfeeding | Excreted in rat milk; unknown in humans. M/P ratio not established. Breastfeeding is not recommended due to potential for adverse effects in infant, including hepatotoxicity and hematologic toxicity. |
| Teratogenic Risk | FDA Pregnancy Category X. Boxed warning: bosentan is teratogenic in animals and humans. Avoid in pregnancy. Risk of major birth defects including craniofacial, cardiovascular, and CNS anomalies, especially during first trimester. Contraception is required. |
■ FDA Black Box Warning
Not for use in pregnancy; hepatotoxicity; may cause hepatotoxicity and liver failure; contraindicated in pregnancy (can cause fetal harm); female patients must use reliable contraception.
| Common Effects | Headache |
| Serious Effects |
Pregnancy; pre-existing hepatic impairment (moderate to severe); hypersensitivity to bosentan or any component.
| Precautions | Hepatotoxicity (monitor LFTs monthly); fluid retention; pulmonary veno-occlusive disease; hematologic changes (decreased hemoglobin); sperm count reduction; concomitant use with cyclosporine A and glyburide not recommended. |
| Food/Dietary | Grapefruit juice may increase bosentan exposure; avoid concurrent consumption. No other significant food interactions documented. |
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| Fetal Monitoring | Monthly pregnancy tests during treatment and for 1 month after discontinuation. Liver function tests (ALT, AST) monthly. Hemoglobin and hematocrit every 3 months. Signs of fluid retention and pulmonary edema. |
| Fertility Effects | May impair fertility in females via hormonal contraception interaction (reduces contraceptive efficacy). In males, testicular toxicity (atrophy, impaired spermatogenesis) observed in animal studies; clinical significance unknown. |
| Clinical Pearls | Bosentan is an endothelin receptor antagonist used for pulmonary arterial hypertension (PAH). It requires mandatory monthly liver function tests due to hepatotoxicity risk. Contraindicated in pregnancy (category X). Monitor hemoglobin and hematocrit for anemia. Drug interactions: potent CYP3A4 and CYP2C9 inducer, reducing efficacy of hormonal contraceptives, warfarin, and simvastatin. Avoid in moderate to severe hepatic impairment. May cause fluid retention. |
| Patient Advice | Take bosentan exactly as prescribed, with or without food. · You must have monthly blood tests to check your liver function. · Do not become pregnant while taking this drug; use reliable non-hormonal contraception. · Report signs of liver problems: nausea, vomiting, right upper quadrant pain, jaundice, dark urine. · You may experience headache, flushing, or swelling; report fluid retention or sudden weight gain. · Avoid grapefruit juice as it may increase bosentan levels. · Do not stop taking bosentan abruptly without consulting your doctor. |