آپرپیتانت
Aprepitant Capsules (Emend Capsules)
آپرپیتانت

نام ژنریک

Aprepitant

شکل دارویی

اشكال دارويي:


Capsule: 80,125mg

موارد مصرف

موارد و مقدار مصرف


الف) جهت پيشگيري از تهوع و استفراغ حاد يا تأخيري به دنبال شيمي‌درماني با داروهاي با خاصيت امتوژنيك زياد (شامل سيس‌پلاتين).


بزرگسالان: روز اول شيمي‌درماني، 125 ميلي‌گرم خوراكي، يك ساعت قبل از درمان تجويز شود؛ سپس 80 ميلي‌گرم خوراكي هر روز صبح روز دوم و سوم شيمي‌درماني تجويز شود. دارو همراه آنتاگونيست 5-HT3 و كورتيكواستروئيد مصرف شود.


ب) پيشگيري از تهوع و استفراغ بعد از اعمال جراحي.


بزرگسالان: 40 ميلي‌گرم از راه خوراكي 3 ساعت قبل از القاء بيهوشي استفاده شود.

موارد منع مصرف

موارد منع مصرف و احتياط


موارد منع مصرف: حساسيت به دارو يا ديگر تركيبات فرمولاسيون؛ مصرف همزمان با سيزاپرايد يا پيموزيد.


موارد احتياط: در موارد نارسايي كبدي با احتياط به كار رود. دارو در بيماران با نارسايي شديد كبدي (child-pugh C) مطالعه نشده است.


دارو جهت درمان تهوع و استفراغ نيست،‌ تنها به صورت پروفيلاكسي به كار رود.


دارو نبايد به صورت طولاني مدت نيز استفاده شود.


با توجه به مسير متابوليسم دارو، در مصرف همزمان با داروهايي كه القاء كننده يا مهار كننده CYP3A4 هستند، احتياط كافي به عمل آيد.

عوارض جانبی دارو

عوارض جانبي


اعصاب مرکزي: ضعف، سرگيجه، خستگي، تب، سردرد، بي‌خوابي.


قلبي ـ عروقي: براديكاردي، افت فشارخون، افزايش فشارخون.


چشم، گوش، حلق و بيني: اختلالات غشاهاي موكوسي، وزوز گوش.


دستگاه گوارش: دردهاي شكمي، بي‌اشتهايي، يبوست، اسهال، درد اپي‌گاستر، گاستريت، سوزش سر دل، تهوع، استفراغ.


ادراري ـ تناسلي: عفونت دستگاه ادراري.


خوني: آنمي، نوتروپني.


متابوليك: دهيدراتاسيون.


تنفسي: سكسكه.


پوست: خارش.


مسموميت و درمان


تظاهرات باليني: تك دوز تا 600 ميلي‌گرم دارو به خوبي تحمل شده است. دوزهاي بالاتر باعث خواب‌آلودگي و سردرد مي‌شود.


درمان: درمان حمايتي است، دارو توسط همودياليز برداشت نمي‌شود.

موارد قابل توجه

-

تداخل دارویی

تداخل دارويي


دارو باعث افزايش سطح آلپرازولام، تريازولام و ميدازولام و افزايش اثرات سداتيو آنها مي‌شود. دوز بنزوديازپين‌ها تا 50% كاهش يابد.


مصرف همزمان با كاربامازپين، فني‌توئين، ريفامپين و ساير القاء كننده‌هاي CYP3A4 باعث كاهش سطح پلاسمايي دارو و اثرات آن مي‌شود.


مصرف همزمان با كلاريترومايسين، ديلتيازم، اريترومايسين، ايتراكونازول،‌ كتوكونازول، نفازودون، نلفيناوير،‌ ريتوناوير، ترولاندومايسين و ساير مهار كننده‌هاي CYP3A4 باعث افزايش سطح پلاسمايي دارو و عوارض آن مي‌شود.


متيل پردنيزولون و دگزامتازون باعث افزايش سطح پلاسمايي دارو و عوارض آن مي‌شوند. دوز كورتيكواستروئيد خوراكي 50% و متيل پردنيزولون وريدي، 25% كاهش يابد.


دوستاكسول، اتوپوزيد،‌ ايفوسفاميد، ايماتينيب، ايرينوتكان، پاكلي‌تاكسول، وين‌بلاستين، وين‌كريستين، وينورلبين باعث افزايش سطوح پلاسمايي دارو و عوارض ناشي از آن مي‌شود.


اپرپيتانت باعث كاهش اثر داروهاي پيشگيري از بارداري مي‌شود.


مصرف همزمان پاروگزتين و اپرپيتانت باعث كاهش اثرات هر دو دارو مي‌شود.


اپرپيتانت باعث كاهش سطح پلاسمايي فني‌توئين مي‌شود. بيمار به دقت مانيتور شده و دوز فني‌توئين افزايش يابد. در صورت لزوم همزمان با هم به كار نروند.


دارو باعث افزايش سطح پيموزيد مي‌شود،‌ همزمان با هم به كار نروند.


مصرف همزمان با تولبوتاميد باعث كاهش اثرات آن مي‌شود. قندخون بيمار به دقت مانيتور شود.


دارو باعث كاهش اثر وارفارين مي‌شود. تا دو هفته بعد از استفاده از اپرپيتانت، INR بيمار مانيتور شود.


مصرف همزمان آب گريپ‌فروت نيز باعث افزايش سطح پلاسمايي دارو و عوارض آن مي‌شود.

مکانیزم اثر

تداخل دارويي


دارو باعث افزايش سطح آلپرازولام، تريازولام و ميدازولام و افزايش اثرات سداتيو آنها مي‌شود. دوز بنزوديازپين‌ها تا 50% كاهش يابد.


مصرف همزمان با كاربامازپين، فني‌توئين، ريفامپين و ساير القاء كننده‌هاي CYP3A4 باعث كاهش سطح پلاسمايي دارو و اثرات آن مي‌شود.


مصرف همزمان با كلاريترومايسين، ديلتيازم، اريترومايسين، ايتراكونازول،‌ كتوكونازول، نفازودون، نلفيناوير،‌ ريتوناوير، ترولاندومايسين و ساير مهار كننده‌هاي CYP3A4 باعث افزايش سطح پلاسمايي دارو و عوارض آن مي‌شود.


متيل پردنيزولون و دگزامتازون باعث افزايش سطح پلاسمايي دارو و عوارض آن مي‌شوند. دوز كورتيكواستروئيد خوراكي 50% و متيل پردنيزولون وريدي، 25% كاهش يابد.


دوستاكسول، اتوپوزيد،‌ ايفوسفاميد، ايماتينيب، ايرينوتكان، پاكلي‌تاكسول، وين‌بلاستين، وين‌كريستين، وينورلبين باعث افزايش سطوح پلاسمايي دارو و عوارض ناشي از آن مي‌شود.


اپرپيتانت باعث كاهش اثر داروهاي پيشگيري از بارداري مي‌شود.


مصرف همزمان پاروگزتين و اپرپيتانت باعث كاهش اثرات هر دو دارو مي‌شود.


اپرپيتانت باعث كاهش سطح پلاسمايي فني‌توئين مي‌شود. بيمار به دقت مانيتور شده و دوز فني‌توئين افزايش يابد. در صورت لزوم همزمان با هم به كار نروند.


دارو باعث افزايش سطح پيموزيد مي‌شود،‌ همزمان با هم به كار نروند.


مصرف همزمان با تولبوتاميد باعث كاهش اثرات آن مي‌شود. قندخون بيمار به دقت مانيتور شود.


دارو باعث كاهش اثر وارفارين مي‌شود. تا دو هفته بعد از استفاده از اپرپيتانت، INR بيمار مانيتور شود.


مصرف همزمان آب گريپ‌فروت نيز باعث افزايش سطح پلاسمايي دارو و عوارض آن مي‌شود.

فارماكوكینتیك

فارماكوكينتيك


جذب: دارو به خوبي جذب شده و فراهمي‌زيستي آن حدود 60 تا 65 درصد مي‌باشد. غذا روي جذب دارو تأثيري ندارد. دارو بعد از حدود 4 ساعت به اوج اثر خود مي‌رسد.


پخش: به ميزان 95% به پروتئين‌هاي پلاسما اتصال مي‌يابد. از سد خون و مغز عبور مي‌كند.


متابوليسم: دارو به ميزان زيادي در كبد توسط CYP3A4 و به ميزان كمتر توسط CYP1A2 و CYP2C19متابوليزه مي‌شود. تمام متابوليت‌ها غيرفعال هستند.


دفع: متابوليت‌ها در ادرار و مدفوع دفع مي‌شوند. متوسط نيمه‌عمر دارو بين 9 تا 13 ساعت است.

سایر اطلاعات

طبقه‌بندي فارماكولوژيك: آنتاگونيست رسپتور نوروكينين 1 / ماده P.


طبقه‌بندي درماني : ضد استفراغ با اثر مركزي.


طبقه‌بندي مصرف در بارداري: رده B


نام‌هاي تجاري: Emend


ملاحظات اختصاصي


1- از تجويز دارو بيش از سه روز در هر دوره شيمي‌درماني پرهيز شود.


2- قبل از تجويز دارو، تداخلات دارويي يا گياهي را كاملاً‌ بررسي كنيد.


3- دارو جهت درمان تهوع و استفراغ فعلي بيمار تجويز نشود. از ساير داروهاي ضد استفراغ در اين موارد استفاده شود.


4- ضمن درمان CBC، تست‌هاي عملكرد كبدي و كراتينين سرم به صورت دوره‌اي مانيتور شود.


نكات قابل توصيه به بيمار


1- به بيمار توضيح دهيد كه اپرپيتانت همراه ساير داروهاي ضد تهوع جهت پيشگيري از تهوع و استفراغ ناشي از شيمي‌درماني به كار مي‌رود. و نبايد به تنهايي در اين مورد تجويز شود.


2- در صورت بروز تهوع و استفراغ به بيمار آموزش دهيد كه به جاي استفاده از اپرپيتانت، از ساير داروهاي ضد تهوع و استفراغ استفاده كند.


3- به بيمار توضيح دهيد كه مصرف ساير داروهاي با نسخه و بدون نسخه و گياهي را گزارش دهد.


4- دارو را همزمان با آب گريپ‌فروت استفاده نكنيد.


5- خانمهايي كه از داروهاي ضد بارداري هورموني استفاده مي‌كنند، بايد
يك روش ديگر پيشگيري از بارداري را ضمن مصرف اين دارو استفاده
كنند.


6- به بيماران توضيح دهيد كه لازم است در كساني كه وارفارين
مصرف مي‌كنند، PT، INR تا 2 هفته بعد از مصرف اپرپيتانت به دقت مانيتور شود.


مصرف در سالمندان: ايمني و اثربخشي دارو بين افراد با سن
بالاتر يا كمتر از 65 سال يكسان است. در اين گروه سني، تنظيم دوز لازم نيست.


مصرف در كودكان: ايمني و اثربخشي دارو در كودكان اثبات نشده است.


مصرف در شيردهي: ترشح دارو در شير مشخص نيست. ضمن مصرف دارو شيردهي صورت نگيرد.


مصرف در بارداري: اثرات تراتوژنيك دارو در انسان بررسي نشده است.


اثر بر آزمايشهاي تشخيصي


دارو باعث افزايش سطح كراتينين، AST، ALT، آلكالين فسفتاز، BUN، گلوكز و پروتئين ادرار مي‌شود. ممكن است سطح سديم كاهش يابد.


ميزان RBC و WBC افزايش يافته و تعداد نوتروفيل‌ها كاهش مي‌يابد.

Aprepitant Capsules (Emend Capsules)

Emend
(aprepitant) Capsules

DRUG DESCRIPTION

EMEND (aprepitant) is a substance P/neurokinin 1 (NK1) receptor antagonist, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.

Its empirical formula is C23H21F7N4O3, and its structural formula is:

EMEND (aprepitant)  Structural Formula Illustration

Aprepitant is a white to off-white crystalline solid, with a molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.

Each capsule of EMEND for oral administration contains either 40 mg, 80 mg, or 125 mg of aprepitant and the following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 40-mg capsule shell also contains yellow ferric oxide, and the 125-mg capsule also contains red ferric oxide and yellow ferric oxide.

What are the possible side effects of aprepitant (Emend, Emend 2-Day, Emend 3-Day)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • feeling like you might pass out;
  • feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin; or
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat.

Less serious side effects may include:

  • nausea, vomiting, heartburn, stomach...

Read All Potential Side Effects and See Pictures of Emend Capsules »

What are the precautions when taking aprepitant capsules (Emend Capsules)?

Before using aprepitant, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this drug passes into breast milk. Consult your doctor before...

Read All Potential Precautions of Emend Capsules »

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

EMEND®, in combination with other antiemetic agents, is indicated for the:

  • prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin
  • prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) [see DOSAGE AND ADMINISTRATION].

Prevention of Postoperative Nausea and Vomiting (PONV)

EMEND is indicated for the prevention of postoperative nausea and vomiting [see DOSAGE AND ADMINISTRATION].

Limitations of Use

EMEND has not been studied for the treatment of established nausea and vomiting.

Chronic continuous administration is not recommended [see WARNINGS AND PRECAUTIONS].

DOSAGE AND ADMINISTRATION

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

Capsules of EMEND (aprepitant) are given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of EMEND is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3.

EMEND may be taken with or without food.

EMEND (fosaprepitant dimeglumine) for Injection (115 mg) is a prodrug of aprepitant and may be substituted for oral EMEND (125 mg), 30 minutes prior to chemotherapy, on Day 1 only of the CINV regimen as an intravenous infusion administered over 15 minutes.

In clinical studies with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:

  Day 1 Day 2 Day 3 Day 4
EMEND* 125 mg orally 80 mg orally 80 mg orally none
Dexamethasone** 12 mg orally 8 mg orally 8 mg orally 8 mg orally
Ondansetront 32 mg I.V. none none none
*EMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.
**Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The dose of dexamethasone was chosen to account for drug interactions.
†Ondansetron was administered 30 minutes prior to chemotherapy treatment on Day 1.

In a clinical study with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy:

  Day 1 Day 2 Day 3
EMEND* 125 mg orally 80 mg orally 80 mg orally
Dexamethasone** 12 mg orally none none
Ondansetront 2 x 8 mg orally none none
*EMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.
**Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone was chosen to account for drug interactions.
†Ondansetron 8-mg capsule was administered 30 to 60 minutes prior to chemotherapy treatment and one 8-mg capsule was administered 8 hours after the first dose on Day 1.

Prevention of Postoperative Nausea and Vomiting (PONV)

The recommended oral dosage of EMEND is 40 mg within 3 hours prior to induction of anesthesia.

EMEND may be taken with or without food.

Geriatric Patients

No dosage adjustment is necessary for the elderly.

Patients with Renal Impairment

No dosage adjustment is necessary for patients with renal impairment or for patients with end stage renal disease (ESRD) undergoing hemodialysis.

Patients with Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic impairment (Child-Pugh score > 9).

Coadministration with Other Drugs

For additional information on dose adjustment for corticosteroids when coadministered with EMEND, see DRUG INTERACTIONS.

Refer to the full prescribing information for coadministered antiemetic agents.

HOW SUPPLIED

Dosage Forms And Strengths

  • Capsules EMEND 40 mg are opaque, hard, gelatin capsules, with white body and mustard yellow cap with “464” and “40 mg” printed radially in black ink on the body.
  • Capsules EMEND 80 mg are white, opaque, hard, gelatin capsules, with “461” and “80 mg” printed radially in black ink on the body.
  • Capsules EMEND 125 mg are opaque, hard, gelatin capsules, with white body and pink cap with “462” and “125 mg” printed radially in black ink on the body.

Storage And Handling

No. 3854 — 80 mg capsules: White, opaque, hard gelatin capsule with “461” and “80 mg” printed radially in black ink on the body. They are supplied as follows:

NDC 0006-0461-02 unit-of-use BiPack of 2
NDC 0006-0461-06 unit-dose package of 6.

No. 3855 — 125 mg capsules: Opaque, hard gelatin capsule with white body and pink cap with “462” and “125 mg” printed radially in black ink on the body. They are supplied as follows:

NDC 0006-0462-06 unit-dose package of 6.

No. 3862 — Unit-of-use TriPack containing one 125 mg capsule and two 80 mg capsules.

NDC 0006-3862-03.

No. 6741 — 40 mg capsules: Opaque, hard gelatin capsule with white body and mustard yellow cap with “464” and “40 mg” printed radially in black ink on the body. They are supplied as follows:

NDC 0006-0464-10 unit-of-use package of 1
NDC 0006-0464-05 unit-dose package of 5.

Storage

Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature].

Distributed by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Revised: 05/2012

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

The overall safety of aprepitant was evaluated in approximately 5300 individuals.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience

Chemotherapy Induced Nausea and Vomiting

Highly Emetogenic Chemotherapy

In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone.

In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Table 1 shows the percent of patients with clinical adverse experiences reported at an incidence ≥ 3%.

Table 1: Percent of Patients Receiving Highly Emetogenic Chemotherapy with Clinical Adverse Experiences (Incidence ≥ 3%) — Cycle 1

  Aprepitant Regimen
(N = 544)
Standard Therapy
(N = 550)
Body as a Whole/ Site Unspecified
  Asthenia/Fatigue 17.8 11.8
  Dizziness 6.6 4.4
  Dehydration 5.9 5.1
  Abdominal Pain 4.6 3.3
  Fever 2.9 3.5
  Mucous Membrane Disorder 2.6 3.1
Digestive System
  Nausea 1 2.7 11.8
  Constipation 10.3 12.2
  Diarrhea 10.3 7.5
  Vomiting 7.5 7.6
  Heartburn 5.3 4.9
  Gastritis 4.2 3.1
  Epigastric Discomfort 4.0 3.1
Eyes, Ears, Nose, and Throat
  Tinnitus 3.7 3.8
Hemic and Lymphatic System
  Neutropenia 3.1 2.9
Metabolism and Nutrition
  Anorexia 10.1 9.5
Nervous System 
  Headache 8.5 8.7
  Insomnia 2.9 3.1
Respiratory System
  Hiccups 10.8 5.6

In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies.

Moderately Emetogenic Chemotherapy

During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy.

In the combined analysis of Cycle 1 data for these 2 studies, the adverse experience profile in both moderately emetogenic chemotherapy studies was generally comparable to the highly emetogenic chemotherapy studies. Table 2 shows the percent of patients with clinical adverse experiences reported at an incidence ≥ 3%.

Table 2: Percent of Patients Receiving Moderately Emetogenic Chemotherapy with Clinical Adverse Experiences (Incidence ≥ 3%) — Cycle 1

  Aprepitant Regimen
(N = 868)
Standard Therapy
(N = 846)
Blood and Lymphatic System Disorders
  Neutropenia 5.8 5.6
Metabolism and Nutrition Disorders
  Anorexia 6.2 7.2
Psychiatric Disorders
  Insomnia 2.6 3.7
Nervous System Disorders
  Headache 13.2 14.3
  Dizziness 2.8 3.4
Gastrointestinal Disorders
  Constipation 10.3 15.5
  Diarrhea 7.6 8.7
  Dyspepsia 5.8 3.8
  Nausea 5.8 5.1
  Stomatitis 3.1 2.7
Skin and Subcutaneous Tissue Disorders
  Alopecia 12.4 11.9
General Disorders and General Administration Site Conditions
  Fatigue 15.4 15.6
  Asthenia 4.7 4.6

In a combined analysis of these two studies, isolated cases of serious adverse experiences were similar in the two treatment groups.

Highly and Moderately Emetogenic Chemotherapy

The following additional clinical adverse experiences (incidence > 0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen in either HEC or MEC studies:

Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection.

Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant neoplasm, nonsmall cell lung carcinoma.

Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia.

Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia.

Psychiatric disorders: anxiety disorder, confusion, depression.

Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor.

Eye disorders: conjunctivitis.

Cardiac disorders: myocardial infarction, palpitations, tachycardia.

Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance.

Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased.

Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash.

Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia.

Renal and urinary disorders: dysuria, renal insufficiency.

Reproductive system and breast disorders: pelvic pain.

General disorders and administrative site conditions: edema, malaise, pain, rigors.

Investigations: weight loss.

Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study.

Laboratory Adverse Experiences

Table 3 shows the percent of patients with laboratory adverse experiences reported at an incidence ≥ 3% in patients receiving highly emetogenic chemotherapy.

Table 3: Percent of Patients Receiving Highly Emetogenic Chemotherapy with Laboratory Adverse Experiences (Incidence ≥ 3%) — Cycle 1

  Aprepitant Regimen
(N = 544)
Standard Therapy
(N = 550)
Proteinuria 6.8 5.3
ALT Increased 6.0 4.3
Blood Urea Nitrogen Increased 4.7 3.5
Serum Creatinine Increased 3.7 4.3
AST Increased 3.0 1.3

The following additional laboratory adverse experiences (incidence > 0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia.

The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

Postoperative Nausea and Vomiting

In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron IV.

Clinical adverse experiences were reported in approximately 60% of patients treated with 40 mg aprepitant compared with approximately 64% of patients treated with 4 mg ondansetron IV. Table 4 shows the percent of patients with clinical adverse experiences reported at an incidence ≥ 3% of the combined studies.

Table 4 : Percent of Patients Receiving General Anesthesia with Clinical Adverse Experiences (Incidence ≥ 3%)

  Aprepitant 40 mg
(N = 564)
Ondansetron
(N = 538)
Infections and Infestations
Urinary Tract Infection 2.3 3.2
Blood and Lymphatic System Disorders
Anemia 3.0 4.3
Psychiatric Disorders
Insomnia 2.1 3.3
Nervous System
Disorders Headache 5.0 6.5
Cardiac Disorders
Bradycardia 4.4 3.9
Vascular Disorders
Hypotension 5.7 4.6
Hypertension 2.1 3.2
Gastrointestinal Disorders
Nausea 8.5 8.6
Constipation 8.5 7.6
Flatulence 4.1 5.8
Vomiting 2.5 3.9
Skin and Subcutaneous Tissue Disorders
Pruritus 7.6 8.4
General Disorders and General Administration Site
Conditions Pyrexia 5.9 10.6

The following additional clinical adverse experiences (incidence > 0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant:

Infections and infestations: postoperative infection

Metabolism and nutrition disorders: hypokalemia, hypovolemia.

Nervous system disorders: dizziness, hypoesthesia, syncope.

Vascular disorders: hematoma

Respiratory, thoracic and mediastinal disorders: dyspnea, hypoxia, respiratory depression.

Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia.

Skin and subcutaneous tissue disorders: urticaria

General disorders and administrative site conditions: hypothermia, pain.

Investigations: blood pressure decreased

Injury, poisoning and procedural complications: operative hemorrhage, wound dehiscence.

Other adverse experiences (incidence ≤ 0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included:

Nervous system disorders: dysarthria, sensory disturbance.

Eye disorders: miosis, visual acuity reduced.

Respiratory, thoracic and mediastinal disorders: wheezing

Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort.

There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40 mg aprepitant.

Laboratory Adverse Experiences

One laboratory adverse experience, hemoglobin decreased (40 mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥ 3% in a patient receiving general anesthesia.

The following additional laboratory adverse experiences (incidence > 0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present.

The adverse experience of ALT increased occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%).

Other Studies

In addition, two serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus.

Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions.

Read the Emend Capsules (aprepitant capsules) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.

Effect of Aprepitant on the Pharmacokinetics of Other Agents

CYP3A4 Substrates

Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect.

As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see CONTRAINDICATIONS]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg).

5-HT3 antagonists

In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Corticosteroids

Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125 mg/80 mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone [see DOSAGE AND ADMINISTRATION]. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended.

Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125 mg/80 mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40 mg dose of aprepitant has not been studied, a single 40 mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended.

Chemotherapeutic agents

[see WARNINGS AND PRECAUTIONS]

Docetaxel: In a pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

CYP2C9 Substrates (Warfarin, Tolbutamide)

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.

Warfarin: A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with EMEND. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting.

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important.

Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone.

The coadministration of EMEND may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND.

Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important.

In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.

An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (e.g., elderly patients) and degree of monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with EMEND for the chemotherapy induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3).

Effect of Other Agents on the Pharmacokinetics of Aprepitant

Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND.

Ketoconazole

When a single 125-mg dose of EMEND was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin

When a single 375-mg dose of EMEND was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold.

Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND.

Additional Interactions

EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study.

Diltiazem

In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone.

Paroxetine

Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine.

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

CYP3A4 Interactions

EMEND (aprepitant), a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125 mg/80 mg regimen, could result in elevated plasma concentrations of these concomitant medications.

Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree.

When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of EMEND [see DRUG INTERACTIONS].

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, EMEND (125 mg/80 mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125 mg/80 mg regimen) was co-administered.

Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see DRUG INTERACTIONS].

Coadministration with Warfarin (a CYP2C9 substrate)

Coadministration of EMEND with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting [see DRUG INTERACTIONS].

Coadministration with Hormonal Contraceptives

Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see DRUG INTERACTIONS].

Patients with Severe Hepatic Impairment

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score > 9). Therefore, caution should be exercised when EMEND is administered in these patients [see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION].

Chronic Continuous Use

Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use.

Patient Counseling Information

[See FDA-Approved Patient Labeling.]

Instructions

Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed.

Patients should be instructed to take EMEND only as prescribed. For the prevention of chemotherapy induced nausea and vomiting (CINV), patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For the prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40 mg capsule of EMEND) within 3 hours prior to induction of anesthesia.

Allergic reactions, which may be serious, and may include hives, rash and itching and cause difficulty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely.

EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products.

Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting.

Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0-24hr) of 0.7 to 1.6 times the human exposure (AUC0-24hr = 19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.

Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test.

Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).

Use In Specific Populations

Pregnancy

Teratogenic effects

Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0-24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0-24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of EMEND in pediatric patients have not been established.

Geriatric Use

In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. In wellcontrolled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with EMEND, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

No specific information is available on the treatment of overdosage.

Drowsiness and headache were reported in one patient who ingested 1440 mg of aprepitant.

In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective.

Aprepitant cannot be removed by hemodialysis.

CONTRAINDICATIONS

EMEND is contraindicated in patients who are hypersensitive to any component of the product.

EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see DRUG INTERACTIONS].

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV).

Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

Pharmacodynamics

NK1 Receptor Occupancy

In two single-blind, multiple-dose, randomized, and placebo control studies, healthy young men received oral aprepitant doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of ~10 ng/mL and ~100 ng/mL, the NK1 receptor occupancies were ~50% and ~90%, respectively. The oral aprepitant regimen for CINV produces mean trough plasma aprepitant concentrations > 500 ng/mL, which would be expected to, based on the fitted curve with the Hill equation, result in > 95% brain NK1 receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of aprepitant has not been established.

Cardiac Electrophysiology

In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant had no effect on the QTc interval. QT prolongation with the oral dosing regimens for CINV and PONV are not expected.

Pharmacokinetics

Absorption

Following oral administration of a single 40 mg dose of EMEND in the fasted state, mean area under the plasma concentration-time curve (AUC0-∞) was 7.8 mcg•hr/mL and mean peak plasma concentration (Cmax) was 0.7 mcg/mL, occurring at approximately 3 hours postdose (Tmax). The absolute bioavailability at the 40-mg dose has not been determined.

Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr was approximately 19.6 mcg•hr/mL and 21.2 mcg•hr/mL on Day 1 and Day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively. At the dose range of 80-125 mg, the mean absolute oral bioavailability of aprepitant is approximately 60 to 65%. Oral administration of the capsule with a standard high-fat breakfast had no clinically meaningful effect on the bioavailability of aprepitant.

The pharmacokinetics of aprepitant are non-linear across the clinical dose range. In healthy young adults, the increase in AUC0-∞ was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.

Distribution

Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) is approximately 70 L in humans.

Aprepitant crosses the placenta in rats and rabbits and crosses the blood brain barrier in humans.

Metabolism

Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.

Excretion

Following administration of a single IV 100-mg dose of [14C]-aprepitant prodrug to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces. A study was not conducted with radiolabeled capsule formulation. The results after oral administration may differ.

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent plasma clearance of aprepitant ranged from approximately 62 to 90 mL/min. The apparent terminal halflife ranged from approximately 9 to 13 hours.

Special Populations

Gender

Following oral administration of a single 125-mg dose of EMEND, no difference in AUC0-24hr was observed between males and females. The Cmax for aprepitant is 16% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and Tmax occurs at approximately the same time. These differences are not considered clinically meaningful. No dosage adjustment for EMEND is necessary based on gender.

Geriatric

Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 through 5, the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly ( ≥ 65 years) relative to younger adults. The Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dosage adjustment for EMEND is necessary in elderly patients.

Pediatric

EMEND has not been evaluated in patients below 18 years of age.

Race

Following oral administration of a single 125-mg dose of EMEND, the AUC0-24hr is approximately 25% and 29% higher in Hispanics as compared with Whites and Blacks, respectively. The Cmax is 22% and 31% higher in Hispanics as compared with Whites and Blacks, respectively. These differences are not considered clinically meaningful. There was no difference in AUC0-24hr or Cmax between Whites and Blacks. No dosage adjustment for EMEND is necessary based on race.

Hepatic Insufficiency

Following administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC0-24hr are not considered clinically meaningful; therefore, no dosage adjustment for EMEND is necessary in patients with mild to moderate hepatic impairment.

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score > 9) [see WARNINGS AND PRECAUTIONS].

Renal Insufficiency

A single 240-mg dose of EMEND was administered to patients with severe renal impairment (CrCl < 30 mL/min) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing hemodialysis, the AUC0-∞ of total aprepitant decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.

No dosage adjustment for EMEND is necessary for patients with renal impairment or for patients with ESRD undergoing hemodialysis.

Clinical Studies

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

Oral administration of EMEND in combination with ondansetron and dexamethasone (aprepitant regimen) has been shown to prevent acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy including high-dose cisplatin, and nausea and vomiting associated with moderately emetogenic chemotherapy.

Highly Emetogenic Chemotherapy (HEC)

In 2 multicenter, randomized, parallel, double-blind, controlled clinical studies, the aprepitant regimen (see Table 6) was compared with standard therapy in patients receiving a chemotherapy regimen that included cisplatin > 50 mg/m² (mean cisplatin dose = 80.2 mg/m²). Of the 550 patients who were randomized to receive the aprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The aprepitant-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. 170 patients were 65 years or older, with 29 patients being 75 years or older.

Patients (N = 1105) were randomized to either the aprepitant regimen (N = 550) or standard therapy (N = 555). The treatment regimens are defined in Table 5.

Table 5: Treatment Regimens in Highly Emetogenic Chemotherapy Trials

Treatment Regimen Day 1 Days 2 to 4
Aprepitant Aprepitant 125 mg PO Dexamethasone 12 mg PO Ondansetron 32 mg I.V. Aprepitant 80 mg PO Daily (Days 2 and 3 only) Dexamethasone 8 mg PO Daily (morning)
Standard Therapy Dexamethasone 20 mg PO Ondansetron 32 mg I.V. Dexamethasone 8 mg PO Daily (morning) Dexamethasone 8 mg PO Daily (evening)
Aprepitant placebo and dexamethasone placebo were used to maintain blinding.

During these studies 95% of the patients in the aprepitant group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of aprepitant patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11).

The antiemetic activity of EMEND was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours postcisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints:

Primary endpoint:

  • complete response (defined as no emetic episodes and no use of rescue therapy)

Other prespecified endpoints:

  • complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score < 25 mm on a 0 to 100 mm scale)
  • no emesis (defined as no emetic episodes regardless of use of rescue therapy)
  • no nausea (maximum VAS < 5 mm on a 0 to 100 mm scale)
  • no significant nausea (maximum VAS < 25 mm on a 0 to 100 mm scale)

A summary of the key study results from each individual study analysis is shown in Table 6 and in Table 7.

Table 6 : Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase for Study 1 — Cycle 1

ENDPOINTS Aprepitant Regimen
(N = 260)† %
Standard Therapy
(N = 261)† + %
p-Value
PRIMARY ENDPOINT
Complete Response
Overall‡ 73 52 < 0.001
OTHER PRESPECIFIED ENDPOINTS
Complete Response
Acute phase§ 89 78 < 0.001
Delayed phase|| 75 56 < 0.001
Complete Protection
Overall 63 49 0.001
Acute phase 85 75 NS*
Delayed phase 66 52 < 0.001
No Emesis
Overall 78 55 < 0.001
Acute phase 90 79 0.001
Delayed phase 81 59 < 0.001
No Nausea
Overall 48 44 NS**
Delayed phase 51 48 NS**
No Significant Nausea
Overall 73 66 NS**
Delayed phase 75 69 NS**
†N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation.
‡Overall: 0 to 120 hours post-cisplatin treatment.
§Acute phase: 0 to 24 hours post-cisplatin treatment.
||Delayed phase: 25 to 120 hours post-cisplatin treatment.
*Not statistically significant when adjusted for multiple comparisons.
**Not statistically significant.
Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm = nausea as bad as it could be.

Table 7: Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase for Study 2 — Cycle 1

ENDPOINTS Aprepitant Regimen
(N = 261)† %
Standard Therapy
(N = 263)† %
p-Value
PRIMARY ENDPOINT
Complete Response
Overall* 63 43 < 0.001
OTHER PRESPECIFIED ENDPOINTS
Complete Response
Acute phase§ 83 68 < 0.001
Delayed phase|| 68 47 < 0.001
Complete Protection
Overall 56 41 < 0.001
Acute phase 80 65 < 0.001
Delayed phase 61 44 < 0.001
No Emesis
Overall 66 44 < 0.001
Acute phase 84 69 < 0.001
Delayed phase 72 48 < 0.001
No Nausea
Overall 49 39 NS*
Delayed phase 53 40 NS*
No Significant Nausea
Overall 71 64 NS**
Delayed phase 73 65 NS**
†N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation.
‡Overall: 0 to 120 hours post-cisplatin treatment.
§Acute phase: 0 to 24 hours post-cisplatin treatment.
||Delayed phase: 25 to 120 hours post-cisplatin treatment.
*Not statistically significant when adjusted for multiple comparisons.
**Not statistically significant.
Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm = nausea as bad as it could be.

In both studies, a statistically significantly higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately.

In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen, and the incidence of first emesis was reduced in the aprepitant regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1.

Figure 1: Percent of Patients Receiving Highly Emetogenic Chemotherapy Who Remain Emesis Free Over Time — Cycle 1

Percent of Patients Receiving Highly Emetogenic Chemotherapy Who Remain Emesis Free Over Time - Illustration

Patient-Reported Outcomes: The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both Phase III studies using the Functional Living Index–Emesis (FLIE), a validated nauseaand vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients' daily lives is defined as a FLIE total score > 108. In each of the 2 studies, a higher proportion of patients receiving the aprepitant regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%).

Multiple-Cycle Extension: In the same 2 clinical studies, patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic effectiveness for the patients receiving the aprepitant regimen is maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

Figure 2: Proportion of Patients Receiving Highly Emetogenic Chemotherapy with No Emesis and No Significant Nausea by Treatment Group and Cycle

Proportion of Patients Receiving Highly Emetogenic Chemotherapy with No Emesis and No Significant Nausea - Illustration

Moderately Emetogenic Chemotherapy (MEC)

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, the aprepitant regimen (see Table 9) was compared with a standard of care therapy in patients receiving a moderately emetogenic chemotherapy regimen that included cyclophosphamide 750-1500 mg/m²; or cyclophosphamide 500-1500 mg/m² and doxorubicin ( ≤ 60 mg/m²) or epirubicin ( ≤ 100 mg/m²).

In this study, the most common combinations were cyclophosphamide + doxorubicin (60.6%); and cyclophosphamide + epirubicin + fluorouracil (21.6%).

Of the 438 patients who were randomized to receive the aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and < 1% Other. The aprepitant-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years.

Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in Table 8.

Table 8: Treatment Regimens in Moderately Emetogenic Chemotherapy Trials

Treatment Regimen Day 1 Days 2 to 3
Aprepitant Aprepitant 125 mg PO† Dexamethasone 12 mg PO‡ Ondansetron 8 mg PO x 2 doses§ Aprepitant 80 mg PO Daily
Standard Therapy Dexamethasone 20 mg PO Ondansetron 8 mg PO x 2 doses Ondansetron 8 mg PO Daily (every 12 hours)
Aprepitant placebo and dexamethasone placebo were used to maintain blinding.
†1 hour prior to chemotherapy.
‡30 minutes prior to chemotherapy.
§30 to 60 minutes prior to chemotherapy and 8 hours after first ondansetron dose.

The antiemetic activity of EMEND was evaluated based on the following endpoints:

Primary endpoint

  • Complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy)

Other prespecified endpoints

  • no emesis (defined as no emetic episodes regardless of use of rescue therapy)
  • no nausea (maximum VAS < 5 mm on a 0 to 100 mm scale)
  • no significant nausea (maximum VAS < 25 mm on a 0 to 100 mm scale)
  • complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score < 25 mm on a 0 to 100 mm scale)
  • complete response during the acute and delayed phases.

A summary of the key results from this study is shown in Table 9.

Table 9: Percent of Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment Group and Phase — Cycle 1

ENDPOINTS Aprepitant Regimen
(N = 433)† %
Standard Therapy
(N = 424)† %
p-Value
PRIMARY ENDPOINT*
Complete Response 51 42 0.015
OTHER PRESPECIFIED ENDPOINTS*
No Emesis 76 59 NS*
No Nausea 33 33 NS
No Significant Nausea 61 56 NS
No Rescue Therapy 59 56 NS
Complete Protection 43 37 NS
†N: Number of patients included in the primary analysis of complete response.
‡Overall: 0 to 120 hours post-chemotherapy treatment.
*NS when adjusted for prespecified multiple comparisons rule; unadjusted p-value < 0.001.

In this study, a statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant regimen (51%) in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the “No Emesis Endpoint”, a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.

Patient-Reported Outcomes: In a phase III study in patients receiving moderately emetogenic chemotherapy, the impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the aprepitant regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the “No Vomiting Domain” of this composite endpoint.

Multiple-Cycle Extension: Patients receiving moderately emetogenic chemotherapy were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. Antiemetic effect for patients receiving the aprepitant regimen is maintained during all cycles.

Postmarketing Trial: In a postmarketing, multicenter, randomized, double-blind, parallel-group, clinical study in 848 cancer patients, the aprepitant regimen (N=430) was compared with a standard of care therapy (N=418) in patients receiving a moderately emetogenic chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV ( < 1500 mg/m²); or cytarabine IV ( > 1 g/m²).

Of the 430 patients who were randomized to receive the aprepitant regimen, 76% were women and 24% were men. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. The aprepitanttreated patients in this clinical study ranged from 22 to 85 years of age, with a mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years. Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers.

The antiemetic activity of EMEND was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period.

A summary of the key results from this study is shown in Table 10.

Table 10 :Percent of Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment Group for Study 2 — Cycle 1

ENDPOINTS Aprepitant Regimen
(N = 430)† %
Standard Therapy
(N = 418)†%
p-Value
No Vomiting Overall 76 62 < 0.0001
Complete Response Overall 69 56 0.0003
†N = Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation.

In this study, a statistically significantly higher proportion of patients receiving the aprepitant regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the aprepitant regimen (69%) in Cycle 1 had a complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively).

In a subgroup analysis by tumor type, a numerically higher proportion of patients receiving aprepitant were observed to have no vomiting and complete response compared to patients receiving standard therapy. For gender, the difference in complete response rates between the aprepitant and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. A similar difference for gender was observed for the no vomiting endpoint.

Prevention of Postoperative Nausea and Vomiting (PONV)

In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (PONV Studies 1 and 2), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. Patients were randomized to receive 40 mg aprepitant, 125 mg aprepitant, or 4 mg ondansetron. Aprepitant was given orally with 50 mL of water 1 to 3 hours before anesthesia. Ondansetron was given intravenously immediately before induction of anesthesia. A comparison between the 125 mg dose and the 40 mg dose did not demonstrate any additional clinical benefit. The remainder of this section will focus on the results in the 40 mg aprepitant dose recommended for PONV.

Of the 564 patients who received 40 mg aprepitant, 92% were women and 8% were men; of these, 58% were White, 13% Hispanic American, 7% Multi-Racial, 14% Black, 6% Asian, and 2% Other. The age of patients treated with 40 mg aprepitant ranged from 19 to 84 years, with a mean age of 46.1 years. 46 patients were 65 years or older, with 13 patients being 75 years or older.

The antiemetic activity of EMEND was evaluated during the 0 to 48 hour period following the end of surgery. The two pivotal studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. PONV Study 1 was a multinational study including the U.S., whereas, PONV Study 2 was conducted entirely in the U.S.

Efficacy measures in PONV Study 1 included:

  • no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
  • complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
  • no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary)
  • time to first use of rescue medication in the 0 to 24 hours following the end of surgery (exploratory)
  • time to first emesis in the 0 to 48 hours following the end of surgery (exploratory).

A closed testing procedure was applied to control the type I error for the primary endpoints.

The results of the primary and secondary endpoints for 40 mg aprepitant and 4 mg ondansetron are described in Table 11:

Table 11: PONV Study 1 Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population)

Treatment n/m (%) Aprepitant vs Ondansetron
Δ Odds ratio† Analysis
Primary Endpoints
No Vomiting 0 to 24 hours (Superiority) (no emetic episodes)
Aprepitant 40 mg 246/293 (84.0) 12.6% 2.1 P<0.001*
Ondansetron 200/280 (71.4)      
Complete Response (Non-inferiority: If LB‡ > 0.65) (no emesis and no rescue therapy, 0 to 24 hours)
Aprepitant 40 mg 187/293 (63.8) 8.8% 1.4 LB=1.02
Ondansetron 154/280 (55.0)      
Complete Response (Superiority: If LB > 1.0) (no emesis and no rescue therapy, 0 to 24 hours)
Aprepitant 40 mg 187/293 (63.8) 8.8% 1.4 LB=1.02+
Ondansetron 154/280 (55.0)      
Secondary Endpoint
No Vomiting 0 to 48 (Superiority) (no emetic episodes)
Aprepitant 40 mg 238/292 (81.5) 15.2% 2.3 P < 0.001*
Ondansetron 185/279 (66.3)      
n/m = Number of responders/number of patients in analysis.
Δ Difference (%): Aprepitant 40 mg minus Ondansetron.
‡ LB= lower bound of 1-sided 97.5% confidence interval for the odds ratio.
* P-value of two-sided test < 0.05.
+ Based on the prespecified fixed sequence multiplicity strategy, Aprepitant 40 mg was not superior to Ondansetron.
† Estimated odds ratio for Aprepitant versus Ondansetron. A value of > 1 favors Aprepitant over Ondansetron.

The use of aprepitant did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of aprepitant delayed the time to first vomiting, as depicted in Figure 3.

Figure 3: Percent of Patients Who Remain Emesis Free During the 48 Hours Following End of Surgery

Percent of Patients Who Remain Emesis Free During the 48 Hours Following End of Surgery - Illustration

Efficacy measures in PONV Study 2 included:

  • complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
  • no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (secondary)
  • no use of rescue therapy in the 0 to 24 hours following the end of surgery (secondary)
  • no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary).

PONV Study 2 failed to satisfy its primary hypothesis that aprepitant is superior to ondansetron in the prevention of PONV as measured by the proportion of patients with complete response in the 24 hours following end of surgery.

The study demonstrated that both dose levels of aprepitant had a clinically meaningful effect with respect to the secondary endpoint “no vomiting” during the first 24 hours after surgery and showed that the use of 40 mg aprepitant was associated with a 16% improvement over ondansetron for the no vomiting endpoint.

Table 12 : PONV Study 2 (Modified-Intention-to-Treat Population)

Treatment n/m (%) Aprepitant vs Ondansetron n
Δ Odds ratio† p-Value
Primary Endpoint
Complete Response (no emesis and no rescue therapy, 0 to 24 hours)
Aprepitant 40 mg 111/248 (44.8) 2.5% 1.1 0.61
Ondansetron 104/246 (42.3)      
Secondary Endpoints
No Vomiting (no emetic episodes, 0 to 24 hours)
Aprepitant 40 mg 223/248 (89.9) 16.3% 3.2 < 0.001*
Ondansetron 181/246 (73.6)      
No Use of Rescue Medication (for established emesis or nausea, 0 to 24 hours)
Aprepitant 40 mg 112/248 (45.2) -0.7% 1.0 0.83
Ondansetron 113/246 (45.9)      
No Vomiting 0 to 48 (Superiority) (no emetic episodes, 0 to 48 hours)
Aprepitant 40 mg 209/247 (84.6) 17.7% 2.7 < 0.001*
Ondansetron 164/245 (66.9)      
n/m = Number of responders/number of patients in analysis.
Δ Difference (%): Aprepitant 40 mg minus Ondansetron.
† Estimated odds ratio: Aprepitant 40 mg versus Ondansetron.
* Not statistically significant after pre-specified multiplicity adjustment.

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

No information provided. Please refer to the PRECAUTIONS section.

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

No information provided. Please refer to the PRECAUTIONS section.

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Emend Capsules Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

APREPITANT - ORAL

(a-PRE-pi-tant)

COMMON BRAND NAME(S): Emend

USES: Aprepitant is used with other medications to help prevent nausea and vomiting caused by cancer drug treatment (chemotherapy). This medication is also used to prevent nausea and vomiting after surgery. Aprepitant works by blocking one of the body's natural substances (substance P/neurokinin 1) that causes vomiting.

This medication will not treat nausea or vomiting if you already have it. Contact your doctor for further instructions if you are experiencing nausea or vomiting.

HOW TO USE: Read the Patient Information Leaflet available from your pharmacist before you start taking this medication and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth, with or without food. To prevent nausea and vomiting caused by cancer chemotherapy, you will usually take the first dose 1 hour before treatment. On the following 2 days, you will usually take the dose once daily in the morning or as directed by your doctor. If you are taking this medication to prevent nausea and vomiting after surgery, you will usually take one dose of 40 milligrams before surgery.

Dosage is based on your medical condition (depending on whether you are taking this medication before cancer chemotherapy or surgery) and response to treatment. It is important to follow your doctor's instructions for when to take each dose, how long to keep taking it, and the strength (number of milligrams) of each dose. If you have any questions, consult your doctor or pharmacist.

Tell your doctor if you develop nausea or vomiting.

Disclaimer

Emend Capsules Consumer (continued)

SIDE EFFECTS: Tiredness and hiccups may occur. If either of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Emend Capsules (aprepitant capsules) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using aprepitant, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this drug passes into breast milk. Consult your doctor before breast-feeding.

Disclaimer

Emend Capsules Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: cisapride, pimozide.

If you are currently using either of these medications listed above, tell your doctor or pharmacist before starting aprepitant.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs affecting liver enzymes that remove aprepitant from your body (such as azole antifungals including itraconazole, macrolide antibiotics including erythromycin, cimetidine, rifamycins including rifabutin, St. John's wort, certain anti-seizure medicines including carbamazepine/phenytoin, certain cancer chemotherapy drugs including ifosfamide/vinblastine/vincristine).

Aprepitant can both speed up and slow down the removal of other drugs from your body, thereby affecting how they work. These affected drugs include (not a complete list): benzodiazepines (e.g., alprazolam, midazolam, triazolam), simvastatin, drugs to treat male sexual function problems (e.g., sildenafil).

If you take warfarin, this drug may affect how well warfarin works in your body. Therefore, your doctor should test your blood during the 2 weeks after your aprepitant treatment to measure how well warfarin is working.

This medication may decrease the effectiveness of hormonal birth control such as pills, patch, or ring. This could cause pregnancy. Discuss with your doctor or pharmacist if you should use additional reliable birth control methods while using this medication and for 1 month after stopping this medication. Also tell your doctor if you have any new spotting or breakthrough bleeding, because these may be signs that your birth control is not working well.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

MISSED DOSE: It is important that you take each dose according to the prescribed schedule. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule.

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised June 2011. Copyright(c) 2011 First Databank, Inc.

Emend Capsules Patient Information Including Side Effects

Brand Names: Emend, Emend 2-Day, Emend 3-Day

Generic Name: aprepitant (Pronunciation: a PREP i tant)

What is aprepitant (Emend Capsules)?

Aprepitant blocks the actions of chemicals in the body that trigger nausea and vomiting.

Aprepitant is used together with other medications to prevent nausea and vomiting that may be caused by surgery or cancer chemotherapy.

Aprepitant is given ahead of time and will not treat nausea or vomiting that you already have.

Aprepitant may also be used for other purposes not listed in this medication guide.

Emend 125 mg

pink/white, imprinted with 462 125 mg

Emend 80 mg

white, imprinted with 461 80 mg

What are the possible side effects of aprepitant (Emend Capsules)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • feeling like you might pass out;
  • feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin; or
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat.

Less serious side effects may include:

  • nausea, vomiting, heartburn, stomach pain;
  • diarrhea or constipation;
  • loss of appetite;
  • hiccups;
  • hair loss;
  • headache;
  • dizziness;
  • tired feeling;
  • mild skin rash;
  • ringing in your ears; or
  • sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Emend Capsules (aprepitant capsules) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about aprepitant (Emend Capsules)?

Do not take aprepitant if you are taking any of the following drugs: cisapride (Propulsid) or pimozide (Orap). These drugs may cause life-threatening interactions when taken together with aprepitant.

If you have liver disease, you may need an aprepitant dose adjustment or special tests.

Aprepitant can make birth control pills less effective, resulting in pregnancy. This effect can last for up to 28 days after your last dose of this medication. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking aprepitant and for at least 1 month after your treatment ends.

There are many other drugs that can interact with aprepitant. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Side Effects Centers

Emend Capsules Patient Information including How Should I Take

What should I discuss with my health care provider before taking aprepitant (Emend Capsules)?

You should not use aprepitant if you are allergic to it.

  • cisapride (Propulsid); or
  • pimozide (Orap).

If you have liver disease, you may need an aprepitant dose adjustment or special tests.

FDA pregnancy category B. Aprepitant is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether aprepitant passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take aprepitant (Emend Capsules)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Aprepitant can be taken with or without food. If you take aprepitant before surgery, follow your doctor's instructions about any restrictions on food or beverages.

The first dose of aprepitant is usually taken 1 hour before treatment with chemotherapy, or 3 hours before a surgery. You may also need additional doses for a couple days after your chemotherapy treatment. Follow your doctor's instructions.

You may also be given other medicines with aprepitant to further help prevent nausea and vomiting.

Aprepitant is not for long-term use.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Store at room temperature away from moisture and heat.

Side Effects Centers

Emend Capsules Patient Information including If I Miss a Dose

What happens if I miss a dose (Emend Capsules)?

Call your doctor for instructions if you forget to take your medicine within the prescribed length of time before your chemotherapy or surgery.

What happens if I overdose (Emend Capsules)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include drowsiness and headache.

What should I avoid while taking aprepitant (Emend Capsules)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

What other drugs will affect aprepitant (Emend Capsules)?

Aprepitant can make birth control pills less effective, resulting in pregnancy. This effect can last for up to 28 days after your last dose of this medication. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking aprepitant and for at least 1 month after your treatment ends.

Tell your doctor about all other medicines you use, especially:

  • tolbutamide (Orinase);
  • a blood thinner such as warfarin (Coumadin);
  • midazolam (Versed) or similar medicines such as Valium, Xanax, or Tranxene;
  • an antidepressant such as nefazodone (Serzone) or paroxetine (Paxil);
  • an antibiotic such as clarithromycin (Biaxin) or rifampin (Rifater, Rifamate);
  • an antifungal medication such as itraconazole (Sporanox) or ketoconazole (Extina, Ketozole, Nizoral, Xolegal);
  • certain cancer medicines such as ifosfamide (Ifex), vinblastine (Velban), or vincristine (Oncovin, Vincasar);
  • HIV medicines such as nelfinavir (Viracept), lopinavir/ritonavir (Kaletra), or ritonavir (Norvir);
  • seizure medication such as carbamazepine (Tegretol, Carbatrol) or phenytoin (Dilantin); or
  • steroid medicine such as dexamethasone (Decadron, Hexadrol) or methylprednisolone (Medapred, Solu-Medrol).

There are many other drugs that may interact with aprepitant. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Where can I get more information?

Your pharmacist can provide more information about aprepitant.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 3.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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