APREPITANT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for APREPITANT (APREPITANT).
Selective high-affinity antagonist of the human substance P/neurokinin 1 (NK1) receptor, inhibiting emesis by blocking the binding of substance P in the central nervous system.
| Metabolism | Primarily metabolized by CYP3A4 (major), with minor contributions from CYP1A2 and CYP2C19. Aprepitant is a moderate inhibitor of CYP3A4 and an inducer of CYP2C9. |
| Excretion | Aprepitant is eliminated primarily by metabolism; less than 5% is excreted unchanged in urine or feces. Approximately 50% of a dose is recovered in feces (mostly metabolites) and 10% in urine. |
| Half-life | Terminal elimination half-life is approximately 9 to 13 hours in adults, allowing once-daily dosing. In pediatric patients, half-life may be shorter (about 5-6 hours). |
| Protein binding | Greater than 95% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution is approximately 70 L (about 1 L/kg for a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 60-65% due to first-pass metabolism. The IV prodrug fosaprepitant is rapidly converted to aprepitant, providing 100% bioavailability of the active moiety. |
| Onset of Action | Oral: onset of antiemetic effect occurs within 1-2 hours. Intravenous (fosaprepitant): onset within 30 minutes, with peak concentrations at end of infusion. |
| Duration of Action | Duration of antiemetic effect is approximately 24 hours, supporting once-daily dosing for 3 days (chemotherapy-induced nausea and vomiting). |
125 mg orally once on day 1, then 80 mg orally once on days 2 and 3 of a 3-day chemotherapy regimen, given 1 hour before chemotherapy. Alternatively, a single 165 mg oral dose for prevention of postoperative nausea and vomiting.
| Dosage form | INJECTABLE |
| Renal impairment | No dosage adjustment required for mild to severe renal impairment (GFR ≥15 mL/min). Not studied in end-stage renal disease (GFR <15 mL/min); use with caution. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: No adjustment. Child-Pugh Class C: Use with caution; no specific dose recommendation due to lack of data. |
| Pediatric use | For patients 6 months and older: Day 1: 3 mg/kg (max 125 mg) orally; Days 2 and 3: 2 mg/kg (max 80 mg) orally. Alternatively, for patients aged 12 years and older: same as adult dosing. |
| Geriatric use | No specific dose adjustment required; elderly patients may be more sensitive to side effects. No pharmacokinetic differences observed in patients >65 years. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for APREPITANT (APREPITANT).
| Breastfeeding | No human data on excretion in breast milk. The M/P ratio is unknown. Aprepitant is highly protein-bound and has a large volume of distribution, suggesting low milk concentration. Caution advised; consider risks and benefits. |
| Teratogenic Risk | Pregnancy Category B1. No evidence of teratogenicity in animal studies; limited human data, but risk cannot be excluded. First trimester: minimal data, no established association with major malformations. Second and third trimesters: no specific fetal risks identified, but use only if clearly needed. |
■ FDA Black Box Warning
None
| Serious Effects |
Concurrent use with pimozide (risk of QT prolongation and torsades de pointes).
| Precautions | CYP3A4-mediated drug interactions (e.g., warfarin, oral contraceptives, pimozide), decreased efficacy with chronic use due to enzyme induction, risk of hypersensitivity reactions, caution in patients with severe hepatic impairment. |
| Food/Dietary | Grapefruit juice should be avoided as it may increase aprepitant exposure. Aprepitant can be taken with or without food. |
| Clinical Pearls |
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| Fetal Monitoring |
| No specific monitoring required beyond standard obstetric care. Monitor for nausea/vomiting control and potential adverse effects (e.g., hypersensitivity, liver function if long-term use). |
| Fertility Effects | No evidence of impaired fertility in animal studies. Human data lacking; unlikely to have significant impact on fertility. |
| Administer aprepitant 1 hour before chemotherapy on day 1 with dexamethasone and a 5-HT3 antagonist. For delayed nausea, give on days 2 and 3 after chemotherapy. Aprepitant is a moderate CYP3A4 inhibitor; reduce doses of oral contraceptives, warfarin, and midazolam. It induces CYP2C9, potentially decreasing efficacy of warfarin and oral hypoglycemics. Use with caution in patients on chronic CYP3A4 substrates. |
| Patient Advice | Take aprepitant exactly as prescribed, usually 1 hour before chemotherapy on day 1, and then once daily on days 2 and 3. · Swallow capsules whole with water, with or without food. · Inform your doctor if you are taking birth control pills, as aprepitant may make them less effective; use additional non-hormonal contraception. · Report any signs of liver problems (yellowing skin/eyes, dark urine) or allergic reactions (rash, difficulty breathing). · Avoid grapefruit juice during treatment as it may increase aprepitant levels. |