Ambrisentan

• Pulmonary Arterial Hypertension (PAH): Treatment of WHO Group 1 PAH to improve exercise capacity and delay clinical worsening.
• Functional Class: Approved for patients in WHO Functional Class II and III symptoms.
• Off-label Uses: Occasionally used in PAH related to connective tissue disease or congenital heart defects, as clinically indicated.

• Formulation: Oral tablets, typically 5 mg and 10 mg strengths.
• Adults:
• Initial dose: 5 mg once daily orally.
• Maintenance dose: May be increased to 10 mg once daily based on clinical response and tolerability.
• Elderly: No specific dosage adjustment recommended; monitor for tolerability.
• Pediatrics: Safety and efficacy not established.
• Renal Impairment: No dose adjustment required for mild to moderate impairment; caution advised in severe impairment.
• Hepatic Impairment: Not recommended in moderate to severe hepatic impairment due to limited data and increased exposure.
• Administration: Taken orally once daily, with or without food.

Ambrisentan is a selective endothelin receptor antagonist that specifically blocks the endothelin type A (ETA) receptor, preventing endothelin-1 (ET-1) mediated vasoconstriction and smooth muscle proliferation in the pulmonary vasculature. By selectively antagonizing ETA receptors, ambrisentan reduces pulmonary arterial pressure and vascular resistance, improving blood flow and decreasing right ventricular strain in patients with pulmonary arterial hypertension.

• Absorption: Well absorbed orally, with peak plasma concentrations reached within 2 hours.
• Bioavailability: Approximately 50%, unaffected significantly by food.
• Distribution: Highly protein bound (~99%), mainly to albumin.
• Metabolism: Primarily metabolized by hepatic enzymes CYP3A4 and CYP2C19.
• Elimination: Excreted mainly via feces (~60%) and urine (~22%) as metabolites.
• Half-life: Approximately 9 to 15 hours, allowing once-daily dosing.

• Pregnancy: FDA Pregnancy Category X. Contraindicated in pregnancy due to teratogenicity and fetal toxicity.
• Lactation: Unknown if excreted in human milk; breastfeeding is not recommended during treatment.

• Primary therapeutic class: Endothelin receptor antagonist
• Subclass: Selective ETA receptor antagonist

• Known hypersensitivity to ambrisentan or any component of the formulation.
• Pregnancy due to teratogenic risk.
• Moderate to severe hepatic impairment.
• Use with cyclosporine or glyburide due to significant drug interactions.

• Hepatotoxicity: Monitor liver function tests monthly for the first year and periodically thereafter. Discontinue if significant liver injury occurs.
• Teratogenicity: Strict pregnancy prevention program required; negative pregnancy test before initiation and monthly during treatment.
• Fluid Retention: Monitor for edema and signs of heart failure.
• Anemia: Monitor hemoglobin/hematocrit regularly; dose adjustment may be necessary.
• Hypotension: Caution in patients with low blood pressure.
• Drug Interactions: Avoid strong CYP3A4 inhibitors or inducers.

• Common: Peripheral edema, nasal congestion, flushing, headache, palpitations.
• Hematologic: Anemia, decreased hemoglobin levels.
• Hepatic: Elevated liver enzymes (ALT, AST), rarely clinically significant hepatotoxicity.
• Rare: Hypersensitivity reactions, including angioedema.

• CYP3A4 inhibitors (e.g., ketoconazole): Increase ambrisentan plasma levels; use caution or avoid combination.
• CYP3A4 inducers (e.g., rifampin): Decrease ambrisentan effectiveness; avoid or adjust dose accordingly.
• Cyclosporine: Contraindicated due to increased ambrisentan exposure.
• Glyburide: Contraindicated; risk of increased glyburide toxicity.
• Potential additive hypotensive effects with other vasodilators.

• Recent guidelines emphasize the importance of regular liver function monitoring and strict adherence to pregnancy prevention programs.
• Expanded use recommended in combination with other PAH agents in certain patients for improved outcomes.
• No recent changes to dosing; safety monitoring remains critical.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep in original packaging until use.
• Keep out of reach of children.