1. Clinical Overview
Aprepitant is a selective, high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. This specific combination of a 125mg capsule on Day 1 followed by an 80mg capsule on Days 2 and 3 is a standard regimen for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy (HEC). It is used in combination with a corticosteroid and a 5-HT3 antagonist. It works centrally in the brainstem vomiting center and peripherally in the gastrointestinal tract.
| Onset | Duration | Bioavailability |
|---|---|---|
| Oral absorption is rapid; antiemetic effect begins within the first 24 hours post-dose. | The regimen provides coverage for the acute (0-24 hours) and delayed (24-120 hours) phases of CINV following HEC. | Approximately 60-65%. |
2. Mechanism of Action
Aprepitant is a selective, high-affinity antagonist of the human substance P/neurokinin 1 (NK1) receptor. Substance P is involved in the final common pathway of emesis. By blocking NK1 receptors in the brainstem's vomiting center (area postrema and nucleus tractus solitarius) and in the gastrointestinal tract, aprepitant inhibits emesis signals triggered by chemotherapy.
3. Indications & Uses
- Prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy (HEC), including cisplatin-based chemotherapy.
- Prevention of postoperative nausea and vomiting (PONV) - though the 125mg/80mg regimen is specifically for CINV.
4. Dosage & Administration
Adult Dosage: For prevention of CINV with HEC: Day 1: 125 mg orally 1 hour prior to chemotherapy. Days 2 and 3: 80 mg orally each morning. Must be given with a 5-HT3 antagonist (e.g., ondansetron) on Day 1 and a corticosteroid (e.g., dexamethasone) on Days 1-4 (dexamethasone dose must be reduced by approximately 50% when co-administered with aprepitant).
Administration: Administer orally with or without food. Swallow the capsule whole with a glass of water. For patients unable to swallow capsules, the contents can be mixed in a small amount of soft food (e.g., applesauce) and consumed immediately without chewing. The Day 1 dose must be given 1 hour before chemotherapy. The Days 2 and 3 doses are given in the morning.
5. Side Effects
Common side effects may include:
- Headache
- Constipation
- Diarrhea
- Anorexia/Loss of appetite
- Fatigue/Asthenia
- Hiccups
- Elevated ALT/AST (transaminases)
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Warfarin | Aprepitant induces CYP2C9, decreasing warfarin levels. INR can decrease by ~14% over 2 weeks. Requires close INR monitoring for 2 weeks after aprepitant regimen. | Major |
| Dexamethasone, Methylprednisolone | Aprepitant is a moderate CYP3A4 inhibitor, increasing corticosteroid AUC by ~2-3 fold. Dexamethasone dose must be reduced by approximately 50%. | Major |
| Midazolam, Triazolam | Increased plasma concentrations and sedation due to CYP3A4 inhibition. | Major |
| Pimozide | Increased pimozide levels, risk of QT prolongation and serious arrhythmias. Contraindicated. | Contraindicated |
| Oral Contraceptives (Ethinyl Estradiol, Norethindrone) | Decreased contraceptive efficacy during and for 28 days after aprepitant regimen due to CYP3A4 induction. Alternative non-hormonal contraception must be used. | Major |
| Chemotherapy agents metabolized by CYP3A4 (e.g., Docetaxel, Paclitaxel, Etoposide, Irinotecan, Vinblastine, Vincristine) | Potential increase in chemotherapeutic agent exposure and toxicity. Monitor for adverse effects. | Moderate |
| Rifampicin, Carbamazepine, Phenytoin | Strong CYP3A4 inducers decrease aprepitant plasma levels, reducing efficacy. Concomitant use not recommended. | Major |
| Ketoconazole, Itraconazole, Clarithromycin | Strong CYP3A4 inhibitors increase aprepitant plasma levels. Use with caution. | Moderate |
7. Patient Counselling
- DO take the 125mg capsule 1 hour before your chemotherapy on Day 1.
- DO take the 80mg capsule each morning on Days 2 and 3, even if you feel well.
- DO inform your doctor about ALL other medications you are taking, including prescription, over-the-counter, vitamins, and herbal products.
- DO use an alternative, non-hormonal method of contraception (e.g., condoms) during and for 1 month after taking aprepitant if you are using oral contraceptives.
- DONT take with pimozide. Inform your doctor if you are on this medication.
- DONT consume grapefruit or grapefruit juice while on this medication.
8. Toxicology & Storage
Overdose: Limited data. In clinical trials, single doses up to 375 mg were administered. Symptoms may be an exaggeration of known adverse effects: severe drowsiness, headache, dizziness, gastrointestinal disturbances.
Storage: Store at room temperature (15°C to 30°C). Protect from moisture and light. Keep in the original blister pack or container until use. Keep out of reach of children.