What Is Aprepitant (Emend)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approval: Yes (Initial approval date: March 26, 2003)
• Brand Name: Emend®
• Active Ingredient: Aprepitant
• Route of Administration: Oral capsules or suspension; an IV form (fosaprepitant) is also available
• Class: NK1 (neurokinin-1) receptor antagonist
• Category: Antiemetic (prevents nausea and vomiting)
• Manufacturer: Merck & Co., Inc.
• Distribution in Turkey: MSD İlaçları (Merck Sharp & Dohme)
• Approved Cancer Indications: Prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy; prevention of postoperative nausea and vomiting in certain circumstances

What Is Aprepitant? How Does It Work?

Aprepitant is an antiemetic medicine used to prevent chemotherapy-induced nausea and vomiting. It is generally combined with other antiemetics, such as corticosteroids and serotonin receptor antagonists, in highly emetogenic chemotherapy regimens, which have a high potential to cause vomiting. An oral formulation is available and is usually used before treatment and for several days afterward.

How Does It Work?

Aprepitant targets NK1 (neurokinin-1) receptors in the brain's vomiting center. Chemotherapy triggers release of a neuropeptide called substance P from the intestines and central nervous system. Substance P binds to NK1 receptors, triggering nausea and the vomiting reflex.

By binding to NK1 receptors, aprepitant blocks this effect of substance P. It therefore prevents nausea and vomiting both immediately after chemotherapy (the acute phase) and over the following days (the delayed phase).

Unlike other antiemetics, aprepitant is particularly effective against delayed nausea and vomiting, giving it an important role in combination treatment strategies.

FDA (US Food and Drug Administration) Approval History

• March 26, 2003: Approved for preventing acute and delayed nausea and vomiting caused by highly emetogenic chemotherapy.
• October 28, 2005: The indication was expanded to nausea and vomiting caused by moderately emetogenic chemotherapy.
• June 20, 2006: Approved for preventing postoperative nausea and vomiting.
• January 25, 2008: The intravenous formulation was approved for preventing nausea and vomiting caused by highly emetogenic chemotherapy.
• November 12, 2010: Approved as a single-dose 150 mg regimen.
• August 28, 2015: Approved for patients aged 12–17 and pediatric patients aged <12 weighing ≥30 kg.
• December 17, 2015: The oral suspension was approved for children aged 6 months to 12 years and patients unable to swallow capsules.
• February 1, 2016: The indication was expanded to prevention of nausea and vomiting caused by moderately emetogenic chemotherapy.

Licensing in Turkey

Emend's licensed therapeutic indications in Turkey are listed as follows:

• In adults, together with other antiemetic agents, prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.
• Prevention of nausea or vomiting associated with initial and repeat courses of combination chemotherapy with an anthracycline (doxorubicin or epirubicin) and cyclophosphamide.

Is It Reimbursed?

Emend is reimbursed by the Social Security Institution (SGK), subject to certain conditions. It must be prescribed by a specialist for the relevant therapeutic indications. SGK reimbursement requires a medical board report or specialist physician's report for the patient.

Price: Emend, 3 capsules: 1,049.27 TL

Mechanisms of Resistance

• Activation of Alternative Pathways: Post-chemotherapy nausea and vomiting can be triggered not only by substance P but also by pathways involving serotonin (5-HT3), dopamine, and histamine. If these pathways become dominant, aprepitant, which targets only NK1 receptors, may be insufficient.
• Overexpression of NK1 Receptors: If the number of NK1 receptors in the brain's vomiting center increases, a fixed dose of aprepitant may not block them all, reducing its effect.
• Increased Substance P Levels: If substance P production rises excessively after chemotherapy, available aprepitant doses may be insufficient. The excess neuropeptide can bind to unblocked receptors and continue triggering nausea and vomiting.
• Impaired Drug Absorption or Metabolism: After oral administration, plasma aprepitant levels may fall because of absorption problems, such as impaired gastrointestinal motility, or altered hepatic CYP3A4 enzyme activity. This can reduce effectiveness and create a resistance-like situation.
• Genetic Differences (Pharmacogenetic Effects): Some individuals may have genetic differences in the structure or number of NK1 receptors. These variations may alter aprepitant's binding efficiency and lead to individual resistance.

Absorption

Aprepitant is absorbed rapidly and effectively after oral administration. The rate varies with the formulation and gastrointestinal transit time. Peak plasma levels are generally reached within a few hours of the drug entering the blood. Food does not substantially reduce bioavailability, so it may be taken with or without food.

Distribution

Aprepitant is extensively distributed into tissues. It binds strongly to blood proteins, particularly albumin, at more than 90%. This helps it remain in the circulation longer. Some may also enter cerebrospinal fluid because its target NK1 receptors are in the central nervous system.

Metabolism

The medicine is metabolized in the liver by CYP3A4, which breaks it down into less active metabolites. Aprepitant may also affect the enzyme's activity, for example as a moderate inhibitor, creating a risk of interactions. This is considered particularly when adjusting the doses of concomitant chemotherapy medicines.

Elimination

Aprepitant is eliminated mainly through bile into feces, with very little renal excretion in urine. Dose adjustment is therefore generally unnecessary in renal impairment. Its half-life, described as the time it remains active in the body, is approximately 9–13 hours, indicating an effect that persists throughout the day.

Dosing Schedule

• Emend is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist.
• The recommended Emend dose on day 1 of chemotherapy is 125 mg orally, 1 hour before treatment (day 1), followed by 80 mg once each morning on days 2 and 3. This schedule provides activity in both the acute phase (the first 24 hours) and delayed phase (days 1–3).
• Tablets are taken orally and should be swallowed whole, without chewing or crushing.
• It may be taken with or without food.
• The prescribed doses generally begin on the same day as chemotherapy and continue for several days afterward.
• Although treatment is brief, full adherence to the dosing schedule is important for optimal effectiveness.

Drug Interactions

• Interactions With CYP3A4: Because aprepitant inhibits CYP3A4, blood levels of medicines broken down by this enzyme may increase. Dexamethasone (a corticosteroid): Levels may rise, requiring dose reduction. Chemotherapy medicines such as etoposide, vinorelbine, and paclitaxel: Effects may increase, with a higher risk of adverse effects. Benzodiazepines such as midazolam: Sedation may be prolonged.
• CYP3A4 Inducers (Medicines That Accelerate Aprepitant Breakdown): These may lower plasma aprepitant levels and reduce its effect. Examples include rifampin, carbamazepine, phenytoin, and St. John's wort (Hypericum).
• CYP3A4 Inhibitors (May Increase Aprepitant Levels): Concomitant use may raise blood aprepitant levels and worsen adverse effects. Examples include ketoconazole, clarithromycin, and itraconazole.
• Interactions With CYP2C9: Aprepitant may reduce CYP2C9 activity, altering the levels of medicines broken down by this enzyme. Warfarin (an anticoagulant): INR may fall, increasing the risk of clotting. Tolbutamide (an antidiabetic medicine): Its effect may decrease. Phenytoin (an antiepileptic): Levels may fall, impairing seizure control.
• Interactions With Hormonal Contraception: Aprepitant may reduce the effectiveness of hormonal birth control. Additional contraception is therefore recommended during treatment and for at least 1 month afterward.

Precautions

• Drug Interactions: Aprepitant may interact with many medicines, particularly by affecting hepatic CYP3A4. This may increase or decrease the effects of certain medicines.
• Steroids such as dexamethasone: Their effects may increase, so the dose is reduced. Anticoagulants such as warfarin: Their effect may decrease, so INR should be monitored.
• Birth control pills: Their effectiveness may decrease, requiring additional contraception during and after treatment. No new medicine should be started or existing medicine stopped without consulting a doctor.
• Nervous System Effects: Some patients may experience dizziness, fatigue, or mild headache. Caution is needed, particularly with activities requiring alertness, such as driving.
• Use With Food: Aprepitant may be taken with or without food, but a consistent daily routine is recommended. Food does not substantially affect absorption.
• Use in Children: Special formulations, such as suspension, have been developed for pediatric use. Doses must be calculated according to age and weight. Children should receive it only on medical advice.
• Renal and Hepatic Impairment: Because elimination occurs mainly through the liver rather than the kidneys, dose adjustment is generally unnecessary. Use cautiously in mild-to-moderate hepatic impairment; use may be limited in severe impairment.
• Pregnancy and Breastfeeding: The safety of aprepitant in pregnancy has not been adequately established. Although transfer into human milk is not fully known, breastfeeding is not recommended. Effective contraception should be used by women who could become pregnant. Dose Adherence and Treatment Duration: Aprepitant is generally given as a short 3-day course. Avoiding missed doses and taking them as scheduled is critical to effectiveness.

Adverse Effects

• Fatigue: 13%
• Decreased appetite: 11%
• Headache: 5–7%
• Constipation: 4–6%
• Diarrhea: 3–5%
• Indigestion: 3–4%
• Nausea: 2–4%
• Hiccups: 2–3%
• Dizziness: 2–3%
• Elevated liver enzymes (AST/ALT): 1–4%
• Anxiety: 1–2%
• Insomnia: 1–2%
• Dry mouth
• Taste disturbance
• Rash
• Itching
• Upper respiratory tract infection
• Vomiting
• Back pain
• Muscle pain
• Anaphylactic reaction (allergic shock)
• Severe hepatic dysfunction
• Hypersensitivity reactions with rash
• Confusion