Emend^® (Capsules) Instructions for Use

Marketing Authorization Holder

Merck Sharp & Dohme, B.V. (Netherlands)

Manufactured By

Alkermes Pharma Ireland Ltd. (Ireland)

Packaging and Quality Control Release

MERCK SHARP & DOHME, B.V. (Netherlands)

Contact Information

MSD Pharmaceuticals LLC (Russia)

ATC Code

A04AD12 (Aprepitant)

Active Substance

Aprepitant (Rec.INN registered by WHO)

Dosage Form

Emend®

Capsules 80 mg and 125 mg: 3 pcs. (capsule set: Capsules 125 mg 1 pc. and Capsules 80 mg 2 pcs.)

Dosage Form, Packaging, and Composition

Capsules hard gelatin, with an opaque white cap and an opaque white body, with the inscriptions “461” and “80mg” printed in black ink; capsule contents – white or almost white granules.

Excipients: hydroxypropylcellulose – 16 mg, sodium lauryl sulfate – 0.3097 mg, sucrose – 80 mg, microcrystalline cellulose (in granules) – 39.16 mg, sodium lauryl sulfate (micronized) – 0.3097 mg.

Composition of the hard gelatin capsule titanium dioxide – 1.0434 mg, gelatin – up to 58 mg.
Black ink SW-9008/9009.

Capsules hard gelatin, with an opaque pink cap and an opaque white body, with the inscriptions “462” and “125mg” printed in black ink; capsule contents – white or almost white granules.

Excipients: hydroxypropylcellulose – 25 mg, sodium lauryl sulfate – 0.4839 mg, sucrose – 125 mg, microcrystalline cellulose (in granules) – 61.21 mg, sodium lauryl sulfate (micronized) – 0.6738 mg.

Composition of the hard gelatin capsule titanium dioxide – 1.3672 mg, iron oxide yellow – 0.0182 mg, iron oxide red – 0.1155 mg, gelatin – up to 76 mg .
Black ink SW-9008/9009.

Blister with 2 caps. 80 mg and blister with 1 caps. 125 mg – cardboard folders (1) – cardboard packs.

Clinical-Pharmacological Group

Antiemetic drug. NK₁ receptor antagonist

Pharmacotherapeutic Group

Antiemetic agent – neurokinin receptor blocker

Pharmacological Action

Antiemetic drug, a selective high-affinity antagonist of neurokinin-1 (NK₁) substance P receptors. The selectivity of aprepitant binding to NK₁ receptors is at least 3000 times higher than for other enzymes, ion channel transporters and receptor sites, including dopamine and serotonin receptors, which are targets of currently available drugs used to treat chemotherapy-induced nausea and vomiting.

Preclinical studies have shown that NK₁ receptor antagonists prevent chemotherapy-induced vomiting (e.g., by cisplatin) through a central mechanism of action.

Aprepitant penetrates the brain and binds to brain NK₁ receptors. Possessing a long central action, Aprepitant inhibits both the acute and delayed phases of cisplatin-induced vomiting and enhances the antiemetic effect of ondansetron and dexamethasone in this case.

Pharmacokinetics

Absorption

After oral administration, C_max in plasma is reached in approximately 4 hours. The absolute bioavailability averages about 60-65%. Taking the capsule with food does not have a clinically significant effect on the bioavailability of aprepitant.

The pharmacokinetics of aprepitant in the range of clinical doses is nonlinear.

After oral administration of Emend^® at a dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 3, the AUC over 24 hours was approximately 19.5 µg×h/ml on day 1 and 20.1 µg×h/ml on day 3. C_max was 1.5 µg/ml and 1.4 µg/ml on days 1 and 3, respectively, and was reached approximately 4 hours after drug administration.

Distribution

Plasma protein binding is more than 95%. The geometric mean V_d at steady state is approximately 66 L.

Experimental studies have shown that Aprepitant crosses the placental barrier in rats and the blood-brain barrier in rats and ferrets.

In humans, Aprepitant crosses the blood-brain barrier.

Metabolism

Aprepitant undergoes extensive metabolism in the liver through oxidation of the morpholine ring and its side chains primarily by CYP3A4, and only a small portion of the drug is metabolized by CYP1A2 and CYP2C19 (CYP2D6, CYP2C9 or CYP2E1 are not involved in the metabolism of aprepitant).

Excretion

The apparent terminal T_1/2 is approximately 9 to 13 hours.

Aprepitant is excreted mainly as metabolites through the intestine (86%) and kidneys (5%).

The apparent plasma clearance of aprepitant is approximately 60 to 84 ml/min.

Pharmacokinetics in special clinical cases

Children. The pharmacokinetics of Emend^® in children and adolescents under 18 years of age have not been studied.

Elderly patients. Dose adjustment of Emend^® is not required in elderly patients. After oral administration of Emend^® at a single dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 5, the AUC over 24 hours in elderly patients (≥65 years) was 21% higher on day 1 and 36% higher on day 5 than in persons younger than 65 years. C_max was 10% higher on day 1 and 24% higher on day 5. These differences were not clinically significant.

Patients with hepatic impairment. Dose adjustment of Emend^® is not required in patients with mild and moderate hepatic impairment. In patients with mild hepatic impairment (5-6 points on the Child-Pugh scale) after oral administration of Emend^® at a dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 3, the AUC over 24 hours was 11% lower on day 1 and 36% lower on day 3 than in healthy volunteers who received the same doses of the drug. In patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale), the AUC over 24 hours was 10% higher on day 1 and 18% higher on day 3 than in healthy volunteers who received the same doses. These differences were not considered clinically significant. There is no experience with the use of Emend^® in patients with severe hepatic impairment (>9 points on the Child-Pugh scale).

Patients with renal impairment. Dose adjustment of Emend^® is not required in patients with severe renal impairment and patients with end-stage renal disease on hemodialysis. Patients with severe renal impairment (CrCl<30 ml/min) and patients with end-stage renal disease requiring hemodialysis received Emend^® as a single dose of 240 mg. In patients with severe renal impairment, the AUC for total aprepitant (both bound and unbound) was reduced by 21%, and C_max was reduced by 32% compared to healthy volunteers. In patients with end-stage renal disease on hemodialysis, the AUC for total aprepitant was 42% lower and C_max was 32% lower. Due to a slight decrease in aprepitant binding to plasma proteins in patients with renal impairment, the AUC values of the pharmacologically active unbound drug in these patients and in healthy individuals did not differ significantly. Hemodialysis performed 4 and 48 hours after drug administration did not have a significant effect on the pharmacokinetics of aprepitant. Less than 0.2% of the aprepitant dose was detected in the dialysate.

Gender. Dose adjustment of Emend^® based on gender is not required. After a single oral dose of Emend^®, the AUC_0-24 and C_max of the drug in women were 9% and 17% higher, respectively, than in men. The T_1/2 of aprepitant in women was approximately 25% shorter than in men, and no significant differences in the time to reach C_max between women and men were noted. These differences in pharmacokinetic parameters are not clinically significant.

Race. Dose adjustment of Emend^® based on race is not required.

Body mass index. BMI does not affect the pharmacokinetics of aprepitant.

Indications

• For the prevention of acute and delayed nausea and vomiting caused by highly emetogenic or moderately emetogenic anticancer drugs (in combination with other antiemetic drugs).

ICD codes

Dosage Regimen

Emend^® capsules are taken orally regardless of meals.

Emend^® is taken for 3 days in combination with corticosteroids and serotonin 5-HT₃ receptor antagonists.

Before starting treatment, the instructions for use of the serotonin 5-HT₃ receptor antagonist prescribed concomitantly with Emend^® should be reviewed. The recommended dose of Emend^® for the three-day regimen is 125 mg 1 hour before taking chemotherapeutic drugs on day 1 and 80 mg once/day in the morning on days 2 and 3.

The tables show the drug administration regimen depending on the degree of emetogenicity of anticancer therapy.

Highly emetogenic chemotherapy

Moderately emetogenic chemotherapy

Dose adjustment based on gender, age, race or body mass index is not required.

In patients with mild or moderate hepatic impairment (5 to 9 points on the Child-Pugh scale), dose adjustment is not required. Clinical data on the use of the drug in patients with severe hepatic impairment (>9 points on the Child-Pugh scale) are not available.

In patients with severe renal impairment (CrCl<30 ml/min), as well as in patients with end-stage renal disease on hemodialysis, dose adjustment is not required.

Adverse Reactions

The safety of aprepitant has been evaluated in approximately 6500 patients.

Prevention of chemotherapy-induced nausea and vomiting

Highly emetogenic therapy

A clinical study included 544 patients receiving highly emetogenic therapy and Aprepitant in the first cycle. 413 patients from this group continued therapy (maximum number of chemotherapy courses – 6). The three-day regimen of Emend^® in combination with ondansetron and dexamethasone was well tolerated by patients. Most of the adverse reactions recorded in clinical studies were defined as mild to moderate in severity.

Most common adverse events during highly emetogenic chemotherapy in patients receiving Aprepitant in combination with serotonin 5-HT₃ receptor antagonists and dexamethasone (observed more frequently than with therapy with serotonin 5-HT₃ receptor antagonists and dexamethasone): hiccups (4.6%), increased ALT activity (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2%) and decreased appetite (2%).

In an additional clinical study in 1169 patients receiving various types of highly emetogenic chemotherapy and nausea and vomiting prevention regimens using aprepitant and serotonin 5-HT₃ receptor antagonists and dexamethasone or only serotonin 5-HT₃ receptor antagonists and dexamethasone, the adverse reaction profile was the same.

Moderately emetogenic therapy

In a clinical study involving 868 patients, the most common adverse event during moderately emetogenic chemotherapy in patients receiving Aprepitant in combination with 5-HT₃ receptor antagonists and dexamethasone (observed more frequently than with therapy with 5-HT₃ receptor antagonists and dexamethasone) was fatigue (1.4%).

In a pooled analysis of highly emetogenic and moderately emetogenic chemotherapy studies, the following drug-related side effects were observed in patients treated with aprepitant, and more frequently than with standard therapy: common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000).

Infections and infestations rare – candidiasis, staphylococcal infection.

Blood and lymphatic system disorders uncommon – anemia, febrile neutropenia.

Metabolism and nutrition disorders: common – decreased appetite; rare – polydipsia.

Psychiatric disorders uncommon – anxiety; rare – disorientation, euphoria.

Nervous system disorders uncommon – dizziness, somnolence; rare – cognitive disorders, sluggishness, taste perversion.

Eye and ear disorders rare – conjunctivitis, tinnitus.

Cardiac disorders: uncommon – palpitations, paroxysmal hot sensations (“hot flashes”); rare – bradycardia, cardiovascular disorders.

Respiratory, thoracic and mediastinal disorders common – hiccups; rare – sore throat, sneezing, cough, postnasal drip, pharyngeal irritation.

Gastrointestinal disorders common – dyspepsia; uncommon – belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence; rare – hard feces, perforated duodenal ulcer, neutropenic colitis, stomatitis, abdominal distension.

Skin and subcutaneous tissue disorders uncommon – rash, acne; rare – photosensitivity, hyperhidrosis, seborrhea, oily skin, pruritic rash.

Musculoskeletal and connective tissue disorders rare – muscle spasms, muscle weakness.

Renal and urinary disorders uncommon – dysuria; rare – pollakiuria.

Investigations common – increased ALT activity; uncommon – increased AST activity, increased ALP activity; rare – increased diuresis, erythrocytes in urine, hyponatremia, weight loss, glucosuria, neutropenia.

General disorders and administration site conditions: common – fatigue; uncommon – asthenia, malaise; rare – edema, chest discomfort, gait disturbance.

The profile of adverse events in patients receiving highly emetogenic and moderately emetogenic chemotherapy during repeated courses (maximum number of courses – 6) with aprepitant was comparable to that during the 1st cycle of chemotherapy.

In another study of aprepitant for the prevention of chemotherapy-induced nausea and vomiting, serious side effects were reported – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Post-marketing data

The following side effects have been reported during the post-marketing period. Because reports are from volunteers in a population of uncertain size, it is not possible to reliably determine the expected frequency or causal relationship with drug use.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rare – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Immune system disorders: hypersensitivity reactions, including anaphylactic reactions.

Contraindications

• Severe hepatic impairment (>9 points on the Child-Pugh scale);
• Concomitant use with pimozide, terfenadine, astemizole and cisapride;
• Hypersensitivity to the components of the drug.

With caution Emend^® should be used in patients simultaneously receiving drugs that are metabolized mainly by the CYP3A4 isoenzyme. Concomitant administration of Emend^® with warfarin may lead to a clinically significant decrease in INR. In patients receiving long-term warfarin therapy, INR should be carefully monitored for 2 weeks during each chemotherapy cycle and especially 7-10 days after starting Emend^® on the 3-day regimen. The effectiveness of hormonal contraceptives may be reduced during and for 28 days after treatment with Emend^®. During treatment with Emend^® and for 1 month after taking the last dose of Emend^®, alternative or backup methods of contraception should be used.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies of the drug’s safety during pregnancy have not been conducted, therefore the use of Emend^® during pregnancy is not recommended.

It is not known whether Aprepitant is excreted in human breast milk. If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be decided due to the risk of adverse effects on the breastfed infant.

Use in Hepatic Impairment

In patients with mild or moderate hepatic impairment (5 to 9 points on the Child-Pugh scale), no dose adjustment is required.

Clinical data on the use of the drug in patients with severe hepatic impairment (>9 points on the Child-Pugh scale) are not available.

Use in Renal Impairment

In patients with severe renal impairment (creatinine clearance less than 30 ml/min), as well as in patients with end-stage renal disease on hemodialysis, no dose adjustment is required.

Pediatric Use

The safety and efficacy of Emend^® in children have not been established.

Geriatric Use

Elderly patients (65 years and older) do not require dose adjustment.

Special Precautions

Inhibition of CYP3A4 by aprepitant may lead to an increase in plasma concentrations of drugs that are metabolized primarily by the CYP3A4 isoenzyme (including some chemotherapeutic agents).

Use in Pediatrics

The safety and efficacy of Emend^® in children have not been established.

Effect on Ability to Drive and Operate Machinery

Studies on the effect of Emend^® on the ability to drive vehicles or operate machinery have not been conducted.

However, the side effect profile of the drug, which may affect patients’ ability to operate machinery, should be taken into account.

Patients may have varying reactions to Emend^®.

Overdose

Symptoms available data on the use of aprepitant in high doses without chemotherapy (a single dose of up to 600 mg or 375 mg daily for 42 days) indicate good tolerability of the drug.

In one patient who took 1440 mg of aprepitant, drowsiness and headache were observed.

Treatment administration of Emend^® should be discontinued and the patient’s condition should be monitored.

Symptomatic therapy should be administered if necessary.

Due to the antiemetic effect of aprepitant, drugs that induce vomiting are unlikely to be effective.

There is no known antidote for the drug.

Hemodialysis is not effective.

Drug Interactions

Aprepitant is a substrate, a moderate inhibitor, and an inducer of the CYP3A4 isoenzyme, as well as an inducer of the CYP2C9 isoenzyme.

When co-administered, Aprepitant may increase the plasma concentrations of drugs whose metabolism is mediated by the CYP3A4 isoenzyme.

Emend^® should not be used concomitantly with pimozide, terfenadine, astemizole, cisapride, ergot alkaloid derivatives.

Inhibition of the CYP3A4 isoenzyme by aprepitant may lead to increased plasma concentrations of these drugs and potentially serious and life-threatening reactions.

Aprepitant induces the metabolism of warfarin and tolbutamide.

Concomitant administration of Emend^® with these or other drugs that are metabolized by the CYP2C9 isoenzyme (e.g., phenytoin) may lead to a decrease in their plasma concentrations.

No effect of Emend^® on the AUC of R(+)- or S(-)-warfarin was observed; however, a decrease in the minimum concentration of S(-)-warfarin was observed with concomitant use, accompanied by a 14% decrease in INR 5 days after the end of Emend^® administration.

In patients receiving long-term warfarin therapy, INR should be carefully monitored for 2 weeks, especially on days 7-10 after starting Emend^® on the 3-day regimen, during each chemotherapy cycle.

Emend^® reduces the AUC of tolbutamide, a substrate of the CYP2C9 isoenzyme, by 23% on day 4, by 28% on day 8, and by 15% on day 15.

In this case, a single 500 mg dose of tolbutamide was administered before the start of the 3-day regimen of Emend^® on days 4, 8, and 15.

Interaction of Emend^® with drugs that are substrates of the P-glycoprotein transporter is unlikely (no interaction of Emend^® with digoxin).

Aprepitant does not cause clinically significant changes in the pharmacokinetics of serotonin 5HT₃ receptor antagonists – ondansetron, granisetron and hydrodolasetron (the active metabolite of dolasetron).

When Emend^® and corticosteroids were taken concomitantly, the AUC of oral dexamethasone increased 2.2-fold, intravenous methylprednisolone increased 1.3-fold, and oral methylprednisolone increased 2.5-fold.

Therefore, to achieve the desired effect, the standard dose of oral dexamethasone in combination with aprepitant should be reduced by 50%, intravenous methylprednisolone should be reduced by approximately 25%, and oral methylprednisolone should be reduced by 50%.

When Emend^® is used with chemotherapeutic agents that are metabolized primarily or partially by the CYP3A4 isoenzyme (etoposide, vinorelbine, docetaxel and paclitaxel), the doses of these drugs may not require adjustment.

However, caution is recommended when using in patients receiving these drugs, and additional monitoring should be provided.

In post-marketing studies, cases of neurotoxicity have been reported, which may be considered as a possible adverse reaction of ifosfamide used in combination with aprepitant.

No effect of Emend^® on the pharmacokinetics of docetaxel was found.

The effectiveness of hormonal contraceptives during administration and for 28 days after the end of Emend^® administration may be reduced (during treatment with Emend^® and for 1 month after taking the last dose of Emend^®, alternative or backup methods of contraception should be used).

When midazolam was taken orally concomitantly with Emend^®, an increase in the AUC of midazolam was noted.

The possible increase in plasma concentrations of midazolam or other benzodiazepines metabolized by the CYP3A4 isoenzyme (alprazolam, triazolam) should be taken into account when these drugs are co-administered with Emend^®.

Concomitant administration of Emend^® with drugs that inhibit the activity of the CYP3A4 isoenzyme may lead to an increase in the plasma concentration of aprepitant.

Therefore, Emend^® should be used with caution in combination with strong inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole).

However, concomitant administration of Emend^® with moderate inhibitors of the CYP3A4 isoenzyme (e.g., diltiazem, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin and protease inhibitors) does not cause clinically significant changes in the plasma concentration of aprepitant.

Concomitant administration of Emend^® with drugs that are strong inducers of the CYP3A4 isoenzyme (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital) may lead to a decrease in the plasma concentration of aprepitant and, thus, to a decrease in the effectiveness of Emend^®.

Also, concomitant use of aprepitant with St. John’s wort preparations is not recommended.

In patients with mild to moderate arterial hypertension, administration of an aprepitant tablet containing a dose comparable to 230 mg of the drug in capsules, in combination with diltiazem at a dose of 120 mg 3 times/day for 5 days, led to a 2-fold increase in the AUC of aprepitant and a simultaneous 1.7-fold increase in the AUC of diltiazem.

These pharmacokinetic effects did not lead to clinically significant changes in ECG, heart rate or blood pressure compared to changes in these parameters when taking diltiazem alone.

Concomitant administration of aprepitant once daily in the form of tablets at a dose comparable to 85 mg or 170 mg of the drug in capsules, and paroxetine at a dose of 20 mg once daily, led to a decrease in AUC by approximately 25% and C_max by approximately 20% for both aprepitant and paroxetine.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.