Emend

Dosage Forms & Strengths

capsule (aprepitant)

• 40mg
• 80mg
• 125mg

powder for injection (fosaprepitant)

• 150mg

oral suspension

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

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

• 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

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 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)

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)

Capsule: Aged <12 years and weight <30 kg: Safety and efficacy not established

Oral suspension: Aged <6 months: Safety and efficacy not established

Capsule for aged ≥12 years or <12 years and weight ≥30 kg

• 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 and 3: 80 mg PO 1 hr prior to chemotherapy plus dexamethasone 8 mg PO qAM
• Day 4: Dexamethasone 8 mg PO in AM

Oral suspension for aged ≥6 months to <12 years

• Day 1: 3 mg/kg PO 1 hr prior to chemotherapy Days 2 and 3: 2 mg/kg PO 1 hr prior to chemotherapy
• Administer with concomitant dexamethasone and 5-HT3 antagonist (eg, ondansetron)

Dosing Considerations

Children must be able to swallow capsule whole

Has not been studied for treatment of established nausea and vomiting

Chronic continuous administration is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use

Emend is a prescription medicine used in adults to prevent nausea and vomiting:

Capsule:

• prevent nausea and vomiting that may occur within 24 hours after receiving chemotherapy treatment
• prevent delayed nausea and vomiting that may occur several days after receiving chemotherapy medications
• prevent nausea and vomiting caused by surgery

​Injection:

• prevent nausea and vomiting that may occur within 24 hours after receiving chemotherapy treatment
• prevent delayed nausea and vomiting that may occur several days after receiving chemotherapy medications

Emend is not used to treat nausea and vomiting that you already have.

Emend should not be used continuously for a long time (chronic use).

It is not known if Emend is safe and effective in children.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.
 

Emend is part of the drug class:

• Other antiemetics

In people taking Emend capsule to prevent nausea and vomiting caused by chemotherapy, the most common side effects include:

• tiredness
• nausea
• hiccups
• constipation
• diarrhea
• loss of appetite
• headache
• hair loss

In people taking Emend capsule to prevent nausea and vomiting after surgery, the most common side effects are:

• constipation
• nausea
• itching
• fever
• low blood pressure
• headache

In people taking Emend injection to prevent nausea and vomiting caused by chemotherapy, the most common side effects include:

• hiccups
• weakness or tiredness
• changes in liver function blood test results. Your doctor will check you for this.
• headache
• constipation
• loss of appetite
• indigestion
• diarrhea
• belching
• infusion site reactions (pain, hardening, redness, or itching at the site of injection)

This is not a complete list of Emend side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

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

Emend may cause serious side effects, including:

• Serious allergic reactions. Allergic reactions can happen with Emend and may be serious. Stop taking Emend and call your doctor right away if you have any of these signs or symptoms of an allergic reaction:
  • hives
  • rash
  • itching
  • trouble breathing or swallowing.
• Severe skin reactions may occur rarely.

Do not take Emend if you:

• are allergic to any of the ingredients in Emend 
• are taking pimozide (Orap), terfenadine (Seldan), astemizole (Hismanal), or cisapride (Propulsid)

Taking Emend with any of these medicines could cause serious or life-threatening problems.

You should not use aprepitant if you are allergic to it, or if you take another medicine called pimozide (Orap). Aprepitant can cause unwanted or dangerous effects when used with pimozide.

To make sure aprepitant is safe for you, tell your doctor if you have:

• liver disease.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Aprepitant can make birth control pills less effective. Ask your doctor about using a non-hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy, and for 1 month after your last dose.

It is not known whether aprepitant passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

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

Contraindications

• Concomitant use with astemizole (no longer commercially available in the US), cisapride (currently commercially available in the US only under a limited-access protocol), pimozide, or terfenadine (no longer commercially available in the US).1 2 4 12

• Known hypersensitivity to fosaprepitant, aprepitant, polysorbate 80, or any ingredient in the formulations.1 2 4 12

Warnings/Precautions

Sensitivity Reactions

Stevens-Johnson syndrome reported in 1 patient receiving aprepitant with antineoplastic agents.1 4 Hypersensitivity reactions, including anaphylaxis, hives, rash, itching, and urticaria, reported in patients receiving aprepitant or fosaprepitant; may be serious and can cause difficulty in breathing or swallowing.1 2 12 17 Angioedema reported in 1 patient.1 4

General Precautions

Drug-interaction potential could be altered with chronic use (see Interactions); safety of chronic use not established.1

Ensure accuracy of prescription; similarity in spelling and/or pronunciation of Emend (trade name for aprepitant) and Amen (former trade name for medroxyprogesterone acetate) or Vfend (trade name for voriconazole) may result in errors.5

Specific Populations

Category B.1 2 4 12

Aprepitant is distributed into milk in rats; not known whether distributed into human milk.1 2 Discontinue nursing or the drug.1

Safety and efficacy of fosaprepitant and aprepitant not established in children <18 years of age.1 4 6 12

No substantial differences in safety, efficacy, or pharmacokinetics of oral aprepitant relative to younger adults, but increased sensitivity cannot be ruled out.1 4

Oral aprepitant has not been adequately studied in patients with severe hepatic impairment (Child-Pugh score >9); caution advised in these patients.1 4 12

Fosaprepitant metabolized by extrahepatic tissue; hepatic insufficiency not expected to alter conversion of fosaprepitant to aprepitant.12

Common Adverse Effects

Aprepitant capsules: Asthenia and/or fatigue, dizziness, hypoesthesia, nausea, anorexia, diarrhea, constipation, heartburn, abdominal pain, epigastric discomfort, dyspepsia, gastritis, stomatitis, pharyngolaryngeal pain, hiccups, perforating duodenal ulcer, enterocolitis, neutropenia, dehydration, hot flush, pruritus, hypotension, hypertension, sinus tachycardia, neutropenic sepsis, pneumonia, alopecia, bradycardia.1 2

Fosaprepitant injection: Infusion site reactions (e.g., pain, induration), headache.12 13 16 Since fosaprepitant dimeglumine for injection is converted into aprepitant, adverse effects associated with aprepitant also may be expected to occur with the injection.12

• Fosaprepitant is a prodrug; pharmacologically active once metabolized to aprepitant.12 16

• Aprepitant occupies NK1 receptors in the brain.1 3 4 Acts in the CNS to inhibit cancer chemotherapy-induced nausea and vomiting (including both acute and delayed emesis induced by cisplatin) and postoperative nausea and vomiting.1 3 4

• Augments the antiemetic activity of ondansetron and dexamethasone.1 3 4

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

Emend® for oral suspension, in combination with other antiemetic agents, is indicated in patients 6 months of age and older 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.
• nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Emend® capsules, in combination with other antiemetic agents, is indicated in patients 12 years of age and older 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.
• nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Prevention of Postoperative Nausea and Vomiting (PONV)

Emend capsules are indicated in adults for the prevention of postoperative nausea and vomiting.

Limitations of Use

• Emend has not been studied for the treatment of established nausea and vomiting.
• Chronic continuous administration of Emend is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

Adults and Pediatric Patients 12 Years of Age and Older

The recommended oral dosage of Emend capsules, dexamethasone, and a 5-HT3 antagonist in adults and pediatric patients 12 years of age and older who can swallow oral capsules, for the prevention of nausea and vomiting associated with administration of HEC or MEC is shown in Table 1 or Table 2, respectively. For patients who cannot swallow oral capsules, Emend for oral suspension can be used instead of Emend capsules as shown in Table 3.

Pediatric Patients 6 Months to less than 12 Years of Age or Pediatric and Adult Patients Unable to Swallow Capsules

The recommended dose of Emend for oral suspension to be administered with a 5-HT3 antagonist, with or without a corticosteroid, for the prevention of nausea and vomiting associated with administration of HEC or MEC is specified in Table 3. Dosing of Emend for oral suspension is based on weight, to a maximum of 125 mg on Day 1 and 80 mg on Days 2 and 3. Dosing in pediatric patients less than 6 kg is not recommended.

Prevention of Postoperative Nausea and Vomiting (PONV)

The recommended oral dosage of Emend capsules in adults is 40 mg within 3 hours prior to induction of anesthesia.

Preparation Instructions for Emend for Oral Suspension -- for Healthcare Providers

Emend for oral suspension should be prepared by a healthcare provider.

Once prepared, it may be administered either by a healthcare provider, patient, or caregiver.

Before you prepare Emend:

• Do not open the pouch of Emend until ready to prepare the medicine.
• Store the pouch at room temperature [between 68°F-77°F (20°C-25°C)].

Administration Instructions

Emend capsules and Emend for oral suspension can be administered with or without food.

Emend capsules

• Swallow capsules whole.

Emend for oral suspension

• The dose will be prepared by the healthcare provider and dispensed to the patient or caregiver in an oral dispenser.
• Keep the dispenser in the refrigerator until administered to the patient. The dose can be stored at room temperature for up to 3 hours before use.
• When ready to use, take the cap off the dispenser, place the dispenser in the patient's mouth along the inner cheek on either the right or left side. Slowly dispense the medicine.
• The dose must be used within 72 hours of preparation.
• Discard any doses remaining after 72 hours.

Emend capsules:

• 40 mg: white body and mustard yellow cap with "464" and "40 mg" printed radially in black ink on the body.
• 80 mg: white body and cap with "461" and "80 mg" printed radially in black ink on the body.
• 125 mg: white body and pink cap with "462" and "125 mg" printed radially in black ink on the body.

Emend for oral suspension:

• 125 mg as a pink to light pink powder in a single-use pouch with one 1 mL oral dosing dispenser, one 5 mL oral dosing dispenser, one cap and mixing cup.

Emend capsules contain the active ingredient, aprepitant. Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, an antiemetic agent, 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:

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.

Each pouch of Emend for oral suspension 125 mg contains 125 mg of aprepitant and the following inactive ingredients: sucrose, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, red iron oxide, and sodium stearyl fumarate.

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-controlled studies, healthy young men received oral Emend doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily (0.08, 0.24, 0.8, and 2.4 times the maximum recommended single dose, respectively) 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 Emend regimen for CINV produced mean trough plasma aprepitant concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 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 Emend 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. Maximum aprepitant concentrations after a single 200-mg dose of fosaprepitant were 4- and 9-fold higher than that achieved with oral Emend 125 mg and 40 mg, respectively. QT prolongation with the oral Emend dosing regimens for CINV and PONV is 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 to 125 mg, the mean absolute oral bioavailability of Emend 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 were 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) was approximately 70 L in humans.

Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology (12.1)].

Elimination

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 (2.4 times the maximum recommended dose), 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 intravenous 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 half-life ranged from approximately 9 to 13 hours.

Specific Populations

Age: Geriatric Population

Following oral administration of a single 125-mg dose of Emend on Day 1 and 80 mg once daily on Days 2 through 5 (2 additional days of dosing compared to the recommended duration), the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) 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 [see Use in Specific Populations (8.5)].

Age: Pediatric Population

As part of a 3-day regimen, dosing of aprepitant capsules (125-mg/80-mg/80-mg) in 18 pediatric patients (aged 12 through 17 years) achieved a mean AUC0-24hr of 17 mcg∙hr/mL on Day 1 with mean peak plasma concentration (Cmax) at 1.3 mcg/mL occurring at approximately 4 hours. The mean concentrations at the end of Day 2 (N=8) and Day 3 (N=16) were both at 0.6 mcg/mL

As part of a 3-day regimen, weight-based dosing of aprepitant powder for oral suspension (3-mg/kg;2-mg/kg;2-mg/kg) in 18 pediatric patients aged 6 months to less than 12 years achieved a mean AUC0-24hr of 20.9 mcg∙hr/mL on Day 1 with mean peak plasma concentration (Cmax) at 1.8 mcg/mL (N=19), occurring at approximately 6 hours. The mean concentrations at the end of Day 2 (N=18) and Day 3 (N=19) were 0.4 mcg/mL and 0.5 mcg/mL, respectively [see Dosage and Administration (2.1)].

A population pharmacokinetic analysis of aprepitant in pediatric patients (aged 6 months through 17 years) suggests that sex and race have no clinically meaningful effect on the pharmacokinetics of aprepitant.

Sex

Following oral administration of a single dose of Emend ranging from 40 mg to 375 mg (3 times the maximum recommended dose), the AUC0-24hr and Cmax are 9% and 17% higher in females as compared with males. The half-life of aprepitant is approximately 25% lower in females as compared with males and Tmax occurs at approximately the same time. These differences are not considered clinically meaningful.

Race/Ethnicity

Following oral administration of a single dose of Emend ranging from 40 mg to 375 mg (3 times the maximum recommended dose), the AUC0-24hr and Cmax are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC0-24hr and Cmax were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC0-24hr or Cmax between Caucasians and Blacks. These differences are not considered clinically meaningful.

Renal Impairment

A single 240-mg dose of Emend (approximately 1.9 times the maximum recommended dose) was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2 as measured by 24-hour urinary creatinine clearance) 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 (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). 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 [see Use in Specific Populations (8.6)].

Hepatic Impairment

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. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations (8.7)].

Body Mass Index (BMI)

For every 5 kg/m2 increase in BMI, AUC0-24hr and Cmax of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m2 to 36 kg/m2. This change is not considered clinically meaningful.

Drug Interactions Studies

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.

Effects of Aprepitant on the Pharmacokinetics of Other Drugs

CYP3A4 substrates (i.e., midazolam): Interactions between Emend and coadministered midazolam are listed in Table 12 (increase is indicated as "↑", decrease as "↓", no change as "↔").

A difference of less than 2-fold increase of midazolam AUC is not considered clinically important.

Corticosteroids:

Dexamethasone: Emend, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg dexamethasone on Day 1 and 8-mg dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5 [see Dosage and Administration (2.1)]. A single dose of Emend (40 mg) when coadministered with a single dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold, which is not considered clinically significant.

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 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. Although the concomitant administration of methylprednisolone with the single 40-mg dose of Emend 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.

Chemotherapeutic agents:

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.

Oral contraceptives: When Emend was administered as a 3-day regimen (125-mg/80-mg/80-mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment.

When a daily dosage of an oral contraceptive containing ethinyl estradiol and norgestimate was administered on Days 1 through 21, and Emend 40 mg was given on Day 8, the AUC of ethinyl estradiol decreased by 4% and by 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 [see Drug Interactions (7.1)].

CYP2C9 substrates (e.g., 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 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 [see Drug Interactions (7.1)].

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

Emend, when given as a 40-mg single dose on Day 1, decreased the AUC of tolbutamide 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 prior to the administration of Emend 40 mg and on Days 2, 4, 8, and 15. This effect was not considered significant.

P-glycoprotein substrates: 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.

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).

Effect of Other Drugs on the Pharmacokinetics of Aprepitant

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 [see Drug Interactions (7.2)].

Rifampin: When a single 375-mg dose of Emend (3 times the maximum recommended dose) 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 [see Drug Interactions (7.2)].

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 (approximately 1.8 times the recommended dose), 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 [see Drug Interactions (7.2)].

Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation (approximately 0.7 and 1.4 times the maximum recommended dose), 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. This effect was not considered clinically important.

Prevention of Nausea and Vomiting Associated with HEC in Adults

Oral administration of Emend in combination with ondansetron and dexamethasone (Emend regimen) has been shown to prevent acute and delayed nausea and vomiting associated with HEC including high-dose cisplatin, and nausea and vomiting associated with MEC.

In Studies 1 and 2, both multicenter, randomized, parallel, double-blind, controlled clinical studies in adults, Emend in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone alone) in patients receiving a chemotherapy regimen that included cisplatin greater than 50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). See Table 13.

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

Of the 550 patients who were randomized to receive the Emend regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The Emend-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. A total of 170 patients were 65 years or older, with 29 patients being 75 years or older.

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 post-cisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

Primary endpoint:

• complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries)

Other prespecified endpoints:

• complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score less than 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 less than 5 mm on a 0 to 100 mm scale)
• no significant nausea (maximum VAS less than 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 14. In both studies, a statistically significantly higher proportion of patients receiving the Emend 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 Emend 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 Emend regimen, and the incidence of first emesis was reduced in the Emend regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1.

Additional Patient-Reported Outcomes: The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both studies using the Functional Living Index–Emesis (FLIE), a validated nausea- and 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 greater than 108. In each of the 2 studies, a higher proportion of patients receiving the Emend 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 Emend regimen was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

Prevention of Nausea and Vomiting Associated with MEC in Adults

Emend was studied in two randomized, double-blind, parallel-group studies (Studies 3 and 4) in adult patients receiving MEC.

In Study 3, in breast cancer patients, Emend in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving a MEC regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (less than or equal to 60 mg/m2) or epirubicin (less than or equal to 100 mg/m2). See Table 15.

In this study, the most common combinations were cyclophosphamide + doxorubicin (61%); and cyclophosphamide + epirubicin + fluorouracil (22%).

Of the 438 patients who were randomized to receive the Emend regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and less than 1% Other. The Emend-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.

The antiemetic activity of Emend was evaluated based on the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

Primary endpoint:

• complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) 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 less than 5 mm on a 0 to 100 mm scale)
• no significant nausea (maximum VAS less than 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 less than 25 mm on a 0 to 100 mm scale)
• complete response during the acute and delayed phases.

A summary of the key results from Study 3 is shown in Table 16. In Study 3, a statistically significantly (p=0.015) higher proportion of patients receiving the Emend 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 Emend 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.

Additional Patient-Reported Outcomes: In Study 3, in patients receiving MEC, 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 Emend 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: In Study 3, patients receiving MEC were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. The antiemetic effect for patients receiving the Emend regimen was maintained during all cycles.

In Study 4, Emend in combination with ondansetron and dexamethasone was compared with a standard therapy (ondansetron and dexamethasone alone) in patients receiving a MEC regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenous (less than 1500 mg/m2); or cytarabine intravenous (greater than 1 g/m2). See Table 15. Patients receiving the Emend 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.

Of the 430 patients who were randomized to receive the Emend 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 Emend-treated 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.

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 Study 4 is shown in Table 17. In Study 4, a statistically significantly higher proportion of patients receiving the Emend 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 Emend 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 Emend 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 Emend 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 Emend were observed to have no vomiting and complete response compared to patients receiving standard therapy. For sex, the difference in complete response rates between the Emend 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 sex was observed for the no vomiting endpoint.

Prevention of Nausea and Vomiting Associated with HEC or MEC in Pediatric Patients

In a randomized, double-blind, active comparator-controlled clinical study that included 302 pediatric patients aged 6 months to 17 years receiving HEC or MEC, Emend in combination with ondansetron was compared to ondansetron alone (control regimen) for the prevention of CINV (Study 5). Intravenous dexamethasone was permitted as part of the antiemetic regimen in both treatment groups, at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the Emend group, reflecting a dosage adjustment to account for a drug interaction [see Clinical Pharmacology (12.3)]. No dexamethasone dose reduction was required for patients who received the control regimen.

Eligible patients had documented malignancy at either an original diagnosis or relapse and were scheduled to receive emetogenic chemotherapy or a chemotherapy regimen not previously tolerated due to vomiting along with ondansetron as part of their antiemetic regimen.

Of the 152 pediatric patients randomized to receive the Emend regimen, 55% were male, 45% female, 78% White, 7% Asian, 0% Black, 24% Hispanic, and 13% Multi-Racial. The most common primary malignancies in subjects receiving the Emend regimen were osteosarcoma (11%), Ewing's sarcoma (11%), neuroblastoma (9%) and rhabdomyosarcoma (8%). Other concomitant chemotherapy agents commonly administered and the number of Emend patients exposed were: vincristine sulfate (65), etoposide (59), doxorubicin (48), ifosfamide (45), carboplatin (39), and cisplatin (35).

The treatment regimens in Study 5 for pediatric patients are defined in Table 18. Of the pediatric patients, 29% in the Emend regimen and 28% in the control regimen used dexamethasone as part of the antiemetic regimen in Cycle 1.

The antiemetic activity of Emend was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint in Study 5 was complete response in the delayed phase (25 to 120 hours following chemotherapy) in Cycle 1. Patients had the opportunity to receive open-label Emend in subsequent cycles (Optional Cycles 2-6); however efficacy was not assessed in these optional cycles. Overall efficacy was based on the evaluation of the following endpoints:

Primary endpoint:

• complete response (no vomiting, retching and no use of rescue medication) in the delayed phase (25 to 120 hours following initiation of chemotherapy)

Other prespecified endpoints:

• complete response in the acute phase (0 to 24 hours following initiation of chemotherapy)
• complete response in the overall phase (up to 120 hours following initiation of chemotherapy)
• no vomiting (defined as no emesis, retching or dry heaves, regardless of use of rescue medication) in the overall phase
• safety and tolerability

A summary of the key study results are shown in Table 19.

Prevention of PONV in Adults

In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (Studies 7 and 8), Emend was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. These two studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. Study 7 was a multinational study including the U.S., whereas, Study 8 was conducted entirely in the U.S.

In the two studies, patients were randomized to receive 40-mg Emend, 125-mg Emend, or 4-mg ondansetron as a single dose. Emend 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 Emend 125-mg dose did not demonstrate any additional clinical benefit over the 40-mg dose and is not a recommended dosage regimen [see Dosage and Administration (2.2)].

Of the 564 patients who received 40-mg Emend, 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 Emend 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.

Efficacy measures in Study 7 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 Emend and 4-mg ondansetron are described in Table 20:

In Study 7, the use of Emend did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of Emend delayed the time to first vomiting, as depicted in Figure 3.

Efficacy measures in Study 8 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).

Study 8 failed to satisfy its primary hypothesis that Emend 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 40-mg Emend had a clinically meaningful effect with respect to the secondary endpoint "no vomiting" during the first 24 hours after surgery and was associated with a 16% improvement over ondansetron for the no vomiting endpoint.