AMBRISENTAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AMBRISENTAN (AMBRISENTAN).
Endothelin receptor antagonist (ERA) that selectively binds to endothelin type A (ETA) receptors in pulmonary vascular smooth muscle, blocking endothelin-1-mediated vasoconstriction and proliferation.
| Metabolism | Primarily metabolized by CYP3A4 (major) and CYP2C19 (minor) via dealkylation and oxidation; also undergoes glucuronidation. |
| Excretion | Primarily via nonrenal pathways, with fecal excretion accounting for approximately 77% of a radiolabeled dose (as unchanged drug and metabolites) and renal excretion for about 22% (mostly as metabolites). |
| Half-life | Terminal elimination half-life is approximately 9 hours (range 4–20 hours) in healthy subjects; no significant accumulation is observed with once-daily dosing. |
| Protein binding | Highly protein bound (approximately 99%) to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 1.2 L/kg, indicating extensive distribution into tissues. |
| Bioavailability | Oral bioavailability is not determined due to lack of an intravenous formulation; absorption is complete after oral administration with peak plasma concentrations occurring at 3–5 hours. |
| Onset of Action | Oral: Onset of clinical effect (improvement in exercise capacity) is observed within 2–4 weeks of initiating therapy. |
| Duration of Action | Once-daily dosing maintains therapeutic plasma concentrations over 24 hours; clinical effects (e.g., hemodynamic improvements) persist with continued administration. |
10 mg orally once daily, with or without food, for patients not receiving cyclosporine. For patients receiving cyclosporine, reduce dose to 5 mg once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥15 mL/min. Insufficient data for GFR <15 mL/min or dialysis; use with caution. |
| Liver impairment | Contraindicated in Child-Pugh Class B or C hepatic impairment. For Child-Pugh Class A, use with caution; no specific dose adjustment recommended. |
| Pediatric use | Not approved for use in pediatric patients; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment recommended; monitor for tolerability due to potential age-related renal/hepatic impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AMBRISENTAN (AMBRISENTAN).
| Breastfeeding | Ambrisentan is excreted in rat milk; no human data on M/P ratio. Due to potential for adverse effects in the nursing infant, breastfeeding is not recommended during therapy. |
| Teratogenic Risk | Ambrisentan is contraindicated in pregnancy due to teratogenicity based on animal studies and its class effect. There is a high risk of fetal harm including craniofacial defects, cardiac malformations, and fetal death if exposure occurs during the first trimester. The risk extends throughout pregnancy; no trimester is safe. |
■ FDA Black Box Warning
Due to risk of hepatotoxicity, liver function tests (ALT/AST) must be monitored before initiation and monthly thereafter. Not recommended in patients with severe hepatic impairment (Child-Pugh C).
| Serious Effects |
["Pregnancy (FDA Pregnancy Category X; can cause fetal harm)","Concurrent use with cyclosporine A (elevates ambrisentan levels)","Severe hepatic impairment (Child-Pugh C) or clinically significant hepatic dysfunction","Hypersensitivity to ambrisentan or any component of the formulation"]
| Precautions | ["Hepatotoxicity: monitor liver function monthly; discontinue if ALT/AST >3×ULN and bilirubin >2×ULN","Fluid retention: may cause peripheral edema; monitor for signs of heart failure","Pulmonary edema: discontinue if signs of pulmonary veno-occlusive disease","Decreased hemoglobin and hematocrit: monitor for anemia","Fertility impairment: may cause testicular tubular atrophy and reduced spermatogenesis"] |
| Food/Dietary | Grapefruit juice may increase ambrisentan exposure (CYP3A4 inhibition) and should be avoided. No other significant food interactions. Alcohol use is not restricted but moderate consumption is advised due to potential hepatic effects. |
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| Fetal Monitoring |
| Monitor liver function tests (ALT, AST) monthly, hemoglobin/hematocrit at baseline and periodically, and fluid status for signs of fluid retention. In pregnant patients, conduct serial fetal ultrasound for detection of structural anomalies. |
| Fertility Effects | In animal studies, ambrisentan caused testicular tubular atrophy and impaired spermatogenesis in males, and ovarian effects in females, potentially reducing fertility. Human data are lacking; effects may be reversible upon discontinuation. |
| Clinical Pearls | Ambrisentan is an endothelin receptor antagonist (ERA) used for pulmonary arterial hypertension (PAH). It does not require dose adjustment in mild hepatic impairment but is contraindicated in moderate to severe hepatic impairment (Child-Pugh Class B or C). Baseline and monthly liver function tests are mandatory due to risk of hepatotoxicity. Ambrisentan is metabolized by CYP3A4 and UGT1A9; avoid potent CYP3A4 inducers (e.g., rifampin) as they reduce efficacy. Contraindicated in pregnancy (X category); monthly pregnancy tests required. Monitor for fluid retention and peripheral edema; may require diuretic adjustment. |
| Patient Advice | Take exactly as prescribed; do not stop without consulting your doctor. · Ambrisentan can cause serious liver injury; you will need monthly blood tests to check your liver function. · This medication can harm a developing fetus; use effective contraception and have monthly pregnancy tests. · Report any signs of liver problems (nausea, vomiting, fatigue, dark urine, jaundice) or fluid retention (swelling of ankles or legs) immediately. · Avoid drinking grapefruit juice while taking ambrisentan as it may affect the drug levels. |