Aprepitant: Effect Against Nausea After Chemotherapy

Aprepitant (brand name Emend, generics, and Fosaprepitant as an intravenous prodrug Ivemend) is a selective antagonist at the Neurokinin 1 receptor (NK1) and has been approved in the USA since 2003 and in Europe since 2003. In Germany, Aprepitant is an integral component of modern antiemetic therapy regimens in oncology. It works primarily on the delayed phase of nausea and vomiting after highly emetogenic chemotherapy such as Cisplatin, anthracycline-containing regimens, or high-dose Cyclophosphamide.

In comparison to classical antiemetics such as Ondansetron or Granisetron, which work primarily in the acute phase, Aprepitant covers the delayed phase over several days. A modern triple combination consisting of 5 HT3 antagonist, glucocorticoid (Dexamethason), and NK1 antagonist (Aprepitant) significantly reduces the incidence of nausea and vomiting in highly emetogenic chemotherapy. In studies, values below 30 percent for complete response are achieved, compared to sometimes 70 percent without effective antiemesis.

Mechanism of Action

Aprepitant selectively blocks the NK1 receptor in the central nervous system, particularly in the vomiting center of the area postrema and in the nucleus tractus solitarius. The NK1 receptor is activated by substance P, a neuropeptide mediator that plays an important role in the delayed phase of chemotherapy-induced nausea. By blocking this receptor, Aprepitant prevents substance P from docking and thereby interrupts signal transmission to the vomiting center.

The selective blockade of the NK1 receptor complements the effects of classical antiemetics. While 5 HT3 antagonists and glucocorticoids work primarily in the first 24 hours after chemotherapy, Aprepitant covers the period from day 2 to 5, for which no optimal therapy was previously available. This complementary effect explains the additive benefit in modern antiemesis protocols.

Pharmacokinetically, Aprepitant shows moderate oral bioavailability of 60 to 65 percent. The half-life is 9 to 13 hours. Elimination occurs primarily hepatically via CYP3A4 and to a lesser extent via CYP1A2 and CYP2C19. Aprepitant itself is a moderate CYP3A4 inhibitor and a moderate CYP3A4 inducer (auto-induction over 14 days), which explains numerous clinically relevant interactions.

Indications

• Prevention of nausea and vomiting during highly emetogenic chemotherapy, particularly Cisplatin-containing regimens, in triple combination with 5 HT3 antagonist and Dexamethason
• Prevention during moderately emetogenic chemotherapy, such as anthracycline-cyclophosphamide regimens in breast cancer
• Postoperative nausea and vomiting (PONV) in patients at high risk, often as a single dose of 40 mg before anesthesia
• Off-label use for prolonged nausea after chemotherapy, in specialized palliative care settings

Aprepitant is not suitable for the treatment of acute nausea from other causes, such as motion sickness, pregnancy-related vomiting, or gastrointestinal infections. Other antiemetics are better established for these conditions.

Dosage and Administration

Highly emetogenic chemotherapy in adults: 125 mg orally 1 hour before chemotherapy, then 80 mg in the morning on day 2 and day 3. Alternatively, Fosaprepitant 150 mg intravenously as a single dose before chemotherapy covers all 3 days.

Moderately emetogenic chemotherapy: same regimen or shortened based on individual assessment.

Postoperative nausea: 40 mg orally within 3 hours before anesthesia as a single dose.

Pediatric: possible from 6 months with weight-adapted dosing. Exact regimens in pediatric oncology according to the product information.

Concomitant antiemetics: Dexamethason in reduced dose (typically 12 mg on day 1, then 8 mg on days 2 to 4, lower dose than without Aprepitant due to CYP3A4 inhibition). 5 HT3 antagonist such as Ondansetron, Granisetron, or Palonosetron in standard dose.

Renal impairment: generally no dose adjustment required. Hepatic impairment: caution with moderate impairment, no established dose adjustment for severe hepatic impairment, use is individual.

Administration: with or without food, swallow capsules whole without chewing.

Adverse Effects

Common: Fatigue, hiccups, headache, constipation, diarrhea, increase in liver transaminases, anorexia.

Occasional: Dizziness, sleep disturbances, allergic skin reactions, neurological symptoms such as tremor or ataxia.

Rare: Stevens Johnson syndrome, anaphylaxis, severe cutaneous reactions, acute pancreatitis.

With intravenous Fosaprepitant: Reactions at the infusion site with pain, redness, thrombophlebitis. Peripheral administration in larger veins with adequate dilution.

Hiccups are a characteristic adverse effect that may stand out to patients. It is typically self-limiting.

Interactions

• Dexamethason: Aprepitant significantly increases Dexamethason levels. Dexamethasan dose must be reduced to avoid Cushing-like effects.
• Methylprednisolone: similar increase as with Dexamethason, dose adjustment necessary.
• Vitamin K antagonists (Warfarin, Phenprocoumon): via CYP2C9 interaction, INR may fall, monitoring in the first few weeks.
• Hormonal contraceptives: reduced efficacy for 28 days after Aprepitant. Additional contraception such as condom or IUD recommended.
• Strong CYP3A4 inhibitors (Itraconazole, Ketoconazole, Ritonavir, Clarithromycin, Posaconazole): increased Aprepitant levels, caution.
• Strong CYP3A4 inducers (Rifampicin, Carbamazepine, Phenytoin, St. John's Wort): reduced Aprepitant levels, efficacy may decrease.
• CYP3A4 substrates with narrow therapeutic index (Pimozide, Cisapride, Astemizole, ergot alkaloids): contraindicated due to risk of severe arrhythmias.
• Anticancer agents metabolized via CYP3A4 (for example, Vinblastine, Vincristine, Etoposide, Tamoxifen, Cyclophosphamide): individual assessment of levels and toxicity.

Special Precautions

Pregnancy: Data limited. For vital indications, risk-benefit assessment required. For necessary chemotherapy during pregnancy (very rare), Aprepitant is decided individually in consultation with oncology and prenatal medicine. Breast-feeding: Use during chemotherapy and breast-feeding not recommended.

Children: approved from 6 months, dosing weight-adapted.

Before starting therapy: Check history and concomitant medications, especially hormonal contraceptives, anticoagulants, and glucocorticoids. Inform patients about possible interactions, hiccups, and treatment duration.

Therapy monitoring: Clinical observation of antiemetic effect, adjust concomitant therapy if needed. With complete antiemesis, Aprepitant can be continued on days 2 and 3; with good efficacy, no further adjustments are necessary.

Lifestyle during chemotherapy: Small, frequent meals, cold foods, avoidance of strong odors, adequate fluid intake, acupressure at point P6 (against nausea), and relaxation exercises complement pharmacological antiemesis.

When to see a doctor: for persistent or breakthrough nausea, dehydration with dizziness or reduced fluid intake, abdominal pain, bloody vomiting, or fever, immediate presentation to oncology.

Ability to drive: Limited if fatigued or dizzy, individual assessment.

You might also be interested in

• Granisetron, 5 HT3 antagonist as standard partner
• Ondansetron, another 5 HT3 antagonist
• Dexamethason, glucocorticoid in antiemesis
• Scopolamine, anticholinergic agent for nausea
• Fluorouracil, cytostatic with emetogenic risk

Frequently Asked Questions

Sources

• EMA, Emend (Aprepitant) EPAR
• Gelbe Liste, Aprepitant active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Oncological Guidelines for Antiemesis
• ESMO, European Society for Medical Oncology