Aprepitant

• Emend^®

Mechanism of Action

Substance P/neurokinin 1 (NK1) receptor antagonist

Absorption

Bioavailability: 60-65% (PO)

Peak plasma time

• 125 mg PO once: 4 hr
• 80 mg PO twice: 4 hr
• 40 mg PO once: 3 hr

Peak plasma concentration

• 125 mg PO once: 1.6 mcg/mL
• 80 mg PO twice: 1.4 mcg/mL
• 40 mg PO once: 0.7 mcg/mL
• 150 mg IV once: 4.15 mcg/mL

AUC

• 125 mg PO once: 19.6 mcg·hr/mL
• 80 mg PO twice: 21.2 mcg·hr/mL
• 150 mg IV once: 37.38 mcg·hr/mL

Distribution

Protein bound: >95%

Vd: 70 L

Metabolism

Hepatic CYP3A4 (major); CYP1A2, CYP2C19 (minor)

Fosaprepitant (IV form) rapidly converted to aprepitant in vivo

Enzymes inhibited: CYP3A4

Enzymes induced: CYP2C9

Elimination

Half-life: 9-13 hr

Total body clearance: 62-90 mL/min

Excretion (IV admin): 57% urine; 45% feces

Dialyzable: No

Aprepitant may be found in some form under the following brand names:

• Emend

Take aprepitant exactly as prescribed.

Aprepitant is given for 3 days as part of the chemotherapy induced nausea and vomiting (CINV) regimen that includes a corticosteroid and a 5-HT3 antagonist. 

• The recommended dose of aprepitant 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. 
• The injection may be substituted for oral aprepitant (125 mg) on Day 1 only as part of the CINV regimen. 

High emetogenic cancer (Single Dose Regimen): The injection (150 mg) is administered on Day 1 only as an infusion over 20-30 minutes initiated approximately 30 minutes prior to chemotherapy. No capsules of aprepitant are administered on Days 2 and 3. The injection is part of a regimen to prevent nausea and vomiting induced by chemotherapy that includes a corticosteroid and a 5-HT3 antagonist. 

High and moderate emetogenic cancer (3-Day Dosing Regimen): The injection (115 mg) is administered on Day 1 as an infusion over 15 minutes initiated approximately 30 minutes prior to chemotherapy. Emend capsules (80 mg) are given orally on Days 2 and 3. The injection and capsules are part of a regimen to prevent nausea and vomiting induced by chemotherapy that includes a corticosteroid and a 5-HT3 antagonist. 

For prevention of Postoperative Nausea and Vomiting (PONV): Aprepitant capsules will be given 3 hours prior to administration of anesthesia.

If you take the blood thinner medicine warfarin (Coumadin, Jantoven), your doctor may do blood tests after you take aprepitant to check your blood clotting.

• Storage requirements:
  • Capsule: Store at room temperature, between 68°F and 77°F (20°C and 25°C).
  • Injection: Store at 36-46°F (2-8°C)
• Keep aprepitant and all medicines out of the reach of children.

You should not take aprepitant if you also take pimozide. A serious drug interaction can occur when pimozide is used together with aprepitant.

Clinically Significant CYP3A4 Drug Interactions

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

See Table 8 and Table 9 for a listing of potentially significant drug interactions [see DRUG INTERACTIONS (7.1, 7.2)].

Decrease in INR with Concomitant Warfarin

Coadministration of Aprepitant with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time [see CLINICAL PHARMACOLOGY (12.3)]. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Aprepitant with each chemotherapy cycle, or following administration of a single 40-mg dose of Aprepitant for the prevention of postoperative nausea and vomiting [see DRUG INTERACTIONS (7.1)].

Risk of Reduced Efficacy of Hormonal Contraceptives

Upon coadministration with Aprepitant, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of Aprepitant [see CLINICAL PHARMACOLOGY (12.3)]. Advise patients to use alternative or back-up methods of contraception during treatment with Aprepitant and for 1 month following the last dose of Aprepitant [see DRUG INTERACTIONS (7.1)].

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Emend: 40 mg, 80 mg, 125 mg

Emend Tri-Pack: 80 mg & 125 mg

Generic: 40 mg, 80 mg, 125 mg, 80 mg & 125 mg

Suspension Reconstituted, Oral:

Emend: 125 mg (1 ea)

Following oral administration of aprepitant 125 mg 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 AUC of aprepitant was 11% lower on day 1 and 36% lower on day 3 compared with healthy subjects; in patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC of aprepitant was 10% higher on day 1 and 18% higher on day 3. These differences are not considered clinically meaningful.

Prevention of chemotherapy-induced nausea and vomiting:

Prevention of acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy (initial and repeat courses; in combination with other antiemetics) in patients ≥12 years (capsules) and in patients ≥6 months (oral suspension).

Prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (initial and repeat courses; in combination with other antiemetics) in patients ≥12 years (capsules) and in patients ≥6 months (oral suspension).

Postoperative nausea and vomiting: Prevention of postoperative nausea and vomiting (PONV) in adults.

Limitations of use: Aprepitant has not been studied for the management of existing nausea and vomiting. Chronic, continuous administration is not recommended (has not been studied and chronic use may alter aprepitant’s drug interaction profile).

Refer to adult dosing.

A suspension for oral administration is commercially available.

A 20 mg/mL oral aprepitant suspension may be prepared with capsules and a 1:1 combination of Ora-Sweet and Ora-Plus (or Ora-Blend). Empty the contents of four 125 mg capsules into a mortar and reduce to a fine powder (process will take 10-15 minutes). Add small portions of vehicle and mix to a uniform paste. Add sufficient vehicle to form a liquid; transfer to a graduated cylinder, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 25 mL. Label "shake well" and "refrigerate". Stable for 90 days refrigerated.

Applies to aprepitant: oral capsule, oral powder for suspension

Along with its needed effects, aprepitant may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking aprepitant:

• Black or tarry stools
• chills
• cough
• fever
• lower back or side pain
• painful or difficult urination
• pale skin
• shortness of breath
• sore throat
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

• Blistering, peeling, or loosening of the skin
• confusion about identity, place, and time
• diarrhea
• itching or skin rash
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• redness of the skin
• red, irritated eyes
• red skin lesions, often with a purple center
• slow or irregular heartbeat

Some side effects of aprepitant may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• confusion
• decreased urination
• dizziness
• dry mouth
• fainting
• heartburn
• hiccups
• increase in heart rate
• indigestion
• lack or loss of strength
• lightheadedness
• loss of appetite
• nausea
• rapid breathing
• stomach discomfort upset or pain
• sunken eyes
• swelling or inflammation of the mouth
• thirst
• weight loss
• wrinkled skin

• Burning feeling in the chest or stomach
• hot flashes
• indigestion
• pain or discomfort in the chest, upper stomach, or throat
• tenderness in the stomach area

FDA pregnancy category: B Use aprepitant only if clearly needed. Comments: Reduced efficacy of hormonal contraceptives during and for 28 days following the last dose of aprepitant. Alternative or back-up contraception should be used during treatment and for 1 month following the last dose.

Animal reproduction studies have revealed no evidence of impaired fertility or harm to the fetus. There are no controlled data in human pregnancy. FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Dosage Forms & Strengths

capsule (aprepitant)

• Emend, generic
• 40mg
• 80mg
• 125mg

injection, powder for reconstitution (fosaprepitant)

• Emend, generic
• 150mg/vial

oral suspension (Emend)

• 125mg/pouch (once pouch is mixed with 4.6 mL drinking water, resulting suspension yields 25mg/mL)

injection, emulsion (aprepitant)

• Cinvanti
• 7.2mg/mL (130mg/18mL)

Chemotherapy-Induced Nausea & Vomiting

Indicated for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin; also indicated for nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC)

Use in combination with other antiemetics

IV (fosaprepitant)

• HEC
  • Day 1: 150 mg IV infused over 20-30 minutes ~30 minutes before chemotherapy plus dexamethasone 12 mg PO and a 5-HT3 antagonist
  • Day 2: Dexamethasone 8 mg PO in AM
  • Days 3 and 4: Dexamethasone 8 mg PO BID (morning and evening)
  • Note: A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with aprepitant
• MEC
  • Day 1: 150 mg IV infused over 20-30 minutes ~30 minutes before chemotherapy plus dexamethasone 12 mg PO and a 5-HT3 antagonist

IV emulsion (aprepitant - Cinvanti)

• HEC
  • Day 1: 130 mg IV infused over 30 minutes or as IV push over 2 min; complete infusion or injection ~30 minutes before chemotherapy plus dexamethasone 12 mg PO and a 5-HT3 antagonist
  • Day 2: Dexamethasone 8 mg PO in AM
  • Days 3 and 4: Dexamethasone 8 mg PO BID (morning and evening)
  • Note: A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with aprepitant
• MEC
  • Day 1: 100 mg IV infused over 30 minutes or as IV push over 2 min; complete infusion or injection ~30 minutes before chemotherapy plus dexamethasone 12 mg PO and a 5-HT3 antagonist
  • Days 2-3: 80 mg PO 1 hr prior to chemotherapy
  • Note: A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with aprepitant

Oral

• Day 1: 125 mg PO 1 hr prior to chemotherapy plus dexamethasone 12 mg PO (30 minutes before chemotherapy) and a 5-HT3 antagonist
• Days 2-3: 80 mg PO 1 hr prior to chemotherapy plus dexamethasone 8 mg PO qAM
• Day 4: Dexamethasone 8 mg PO in AM

Postoperative Nausea & Vomiting

Indicated for prevention of PONV

40 mg PO within 3 hr prior to anesthesia induction

Dosage Modifications

Renal impairment

• Severe (CrCl 80 mL/min)
• ESRD undergoing hemodialysis: Decreased AUC of total aprepitant by 42% and Cmax decreased by 32%

Hepatic impairment

• Mild-to-moderate (Child Pugh score 5 to 9): No dosage adjustment necessary
• Severe (Child Pugh score >9): Safety and efficacy has not been established

Dosing Considerations

Limitation of use

• Has not been studied for the treatment of established nausea and vomiting

Dosage Forms & Strengths

capsule (aprepitant)

• 80mg
• 125mg

oral suspension

• 125mg/pouch (once pouch is mixed with 4.6 mL drinking water, resulting suspension yields 25mg/mL)

injection, powder for reconstitution (fosaprepitant)

• Emend, generic
• 150mg/vial

Chemotherapy-Induced Nausea & Vomiting

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, and for moderately emetogenic cancer chemotherapy (MEC)

Oral suspension: Aged

IV Compatibility

Fosaprepitant IV: 0.9% NaCl

Aprepitant IV emulsion: 0.9% NaCl or D5W

IV Incompatibilities

Fosaprepitant: Divalent cation-containing solutions (Ca++, Mg++, Zn++ etc), Hartmann's Solution, LR

Aprepitant emulsion: Do not mix with other drugs

IV Preparation (Fosaprepitant)

Aseptically inject 5 mL 0.9% NaCl into vial along vial wall to prevent foaming

Gently swirl to dissolve; do not shake

Withdraw entire volume from vial and transfer it into a prepared infusion bag of 145 mL 0.9% NaCl to yield a total volume of 150 mL and a final concentration of 1 mg/mL

Gently invert bag 2-3 times to mix

Final volume

• 6 months to