Emend capsules set mg 125/80 3 pieces.

Pharmacodynamic

Antiemetics, selective high affinity antagonist of neurokinin-1 (NK ₁ ) Selectivity binding substance P. aprepitant with NK ₁ receptors at least 3000 times higher than for other enzymes, ion channels and transporter receptor sites, including the dopamine and serotonin receptors that are targets currently existing drugs used to treat nausea and vomiting associated with chemotherapy.

In preclinical studies have demonstrated that antagonists of NK ₁ receptor antagonists prevent the development of emesis induced by chemotherapeutic agents (e.g., cisplatin) from the central mechanism of action.

aprepitant penetrates into the brain and is associated with brain NK ₁ receptor. With prolonged action of central, aprepitant inhibits both the acute and the delayed phases as cisplatin-induced emesis, and also increases with the antiemetic effect of ondansetron and dexamethasone.

pharmacokinetics

absorption

After ingestion C _max in the blood plasma is about 4 hours. The absolute bioavailability is on average about 60-65%. Receiving capsule along with meals has no clinically significant impact on the bioavailability of aprepitant.

Pharmacokinetics aprepitant clinical dose range is nonlinear.

After oral administration of the drug Emend® a dose of 125 mg on day 1 and then at a dose of 80 mg / day in the 2nd and 3rd days AUC for 24 hours was about 19.5 g × h / ml at day 1 and 20.1 g × h / mL on day 3. C _max was 1.5 g / ml and 1.4 .mu.g / ml in the 1st and 3rd days, respectively and was achieved after about 4 hours after dosing.

Distribution

Plasma protein binding is more than 95%. V _d in the equilibrium state is approximately 66 l.

In experimental studies have shown that aprepitant crosses the placental barrier in rats and the BBB in rats and ferrets.

A person aprepitant penetrates the blood-brain barrier.

Metabolism

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

Removing

The apparent T _1/2 is from about 9 to 13 hours.

aprepitant derived mainly as metabolites through the intestines (86%) and kidneys (5%).

The apparent plasma clearance aprepitant is from about 60 to 84 ml / min.

Pharmacokinetics in special clinical situations

Emend® pharmacokinetics of the drug in children and adolescents under the age of 18 years have not been studied.

In patients aged 65 years and older after ingestion of the drug Emend® a single dose of 125 mg on day 1, then 80 mg / day in the 2 nd and 5 th days AUC within 24 hours was a 21% increase in 1-day and a 36% increase on the 5th day than in those younger than 65 years. C _max at the same time was 10% higher than in the 1 st day and 24% higher on Day 5. These differences were not clinically significant.

Patients with mild hepatic impairment (5-6 points on the Child-Pugh) Emend® after ingestion of drug at a dose of 125 mg on day 1 and then at a dose of 80 mg / day during 2 minutes and 3- on days AUC for 24 hours was 11% less than in the 1 st day and 36% less on the third day, than in healthy volunteers receiving the same dose. In patients with moderate hepatic insufficiency (7-9 points on a scale Child-Pugh) AUC at 24 hours was 10% higher in the 1st day and a 18% increase on the third day, than in healthy volunteers who received those same dose. These differences are not considered clinically significant.

Patients with severe renal impairment (creatinine clearance < 30 ml / min) and patients in end stage renal disease requiring hemodialysis Emend® received a single dose of 240 mg. Patients with severe renal insufficiency AUC for total aprepitant (both associated and non-associated proteins) was reduced by 21% and the C _max was reduced by 32% as compared with healthy volunteers. In patients with end-stage renal failure undergoing hemodialysis, the AUC of aprepitant for the total was less than 42%, and the C _max 32%. Due to a slight decrease of binding to plasma proteins of aprepitant in patients with renal insufficiency AUC values ​​of pharmacologically active unbound drug in these patients and healthy subjects did not differ significantly. Hemodialysis carried out after 4 and 48 hours after dosing, no significant effect on the pharmacokinetics of aprepitant. The dialysate was detected less than 0.2% of the dose aprepitant.

After a single oral formulation Emend® AUC _0-24 and C _max of the drug in females were 9% and 17%, respectively, higher than in men. T _1/2 aprepitant in women was 25% less than men, and significant differences in time to achieve C _max between women and men is not mentioned. These differences in the pharmacokinetic parameters have no clinical significance. Correction dose Emend® based on race is required. Body mass index did not affect the pharmacokinetics of aprepitant.

Active substance:
Apreрitant

Manufacturer

Merck Sharp & Dohme BV, USA

Composition

1 capsule contains:

Active substance: 125 mg of aprepitant

.

Excipients: hydroxypropylcellulose, sodium lauryl sulfate, sucrose, microcrystalline cellulose;

Capsules Composition: titanium dioxide, gelatin; 125 mg capsules also contain iron oxide yellow and iron oxide red.

The blister 3 capsules. The carton 1 blister.

Indications

For the prevention of acute and delayed nausea and vomiting caused by high or umerennoemetogennymi anticancer drugs (in combination with other antiemetic drugs).

Contraindications

• Severe hepatic insufficiency (> 9 points on the Child-Pugh);
• simultaneous application pimozide, terfenadine, astemizole and cisapride;
• increased sensitivity to the drug.

C caution: Emend® should be used in patients concomitantly receiving medicinal products that are metabolized primarily with the participation of isoenzyme CYP3A4. Simultaneous use of the drug Emend® with warfarin may result in a clinically significant decrease in INR. Patients receiving long term warfarin therapy should be carefully monitored INR for 2 weeks at each cycle of chemotherapy, and particularly 7-10 days after initiation of drug Emend® 3-day scheme. The efficacy of hormonal contraceptives may be reduced during and for 28 days after treatment Emend®. During treatment Emend® and within 1 month after the last dose of the drug should be used Emend® alternative and backup methods of contraception.

Side effects

Security aprepitant was evaluated in approximately 6500 patients.

Prevention of nausea and vomiting caused by chemotherapy

Vysokoemetogennaya therapy

In a clinical study of 544 patients participated, receiving therapy and vysokoemetogennuyu aprepitant in the first cycle. 413 patients of this group continued therapy (maximum number of cycles of chemotherapy – 6). Three-day dosing regime Emend® in combination with ondansetron and dexamethasone was well tolerated. Most side reactions recorded in clinical studies were defined as mild to moderate the reaction.

The most common adverse reaction to the background vysokoemetogennoy chemotherapy patients receiving aprepitant in combination with antagonists of the serotonin 5-HT3-receptors and dexamethasone (observed with greater frequency than in the treatment of serotonin 5-HT ₃ receptors and dexamethasone): hiccups (4.6%), increased ALT (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2%) and loss of appetite ( 2%).

In a further clinical study in 1169 patients receiving various kinds vysokoemetogennoy chemotherapy and prophylaxis of nausea and vomiting modes using aprepitant and antagonists of serotonin 5-HT ₃ receptor and dexamethasone or only serotonin 5-HT ₃ receptor and dexamethasone profile of adverse reactions was similar.

Umerennoemetogennaya therapy

In a clinical study involving 868 patients with the most common side effect of chemotherapy background umerennoemetogennoy patients receiving aprepitant in combination with antagonists of 5-HT ₃ receptor and dexamethasone (observed with greater frequency than in therapy antagonists 5-HT ₃ receptor and dexamethasone), was fatigue (1,4%).

In the pooled analysis and research vysokoemetogennoy umerennoemetogennoy chemotherapy in patients treated aprepitant, the following were observed associated with administration of the drug side effects, and with greater frequency than with standard therapy:

• often (on ≥1 / 100 to < 1/10);
• infrequently (on ≥1 / 1000 < 1/100);
• rare. (From ≥1 / 10000 to < 1/1000)

Infectious and parasitic diseases: rare – candidiasis, staphylococcal infection

.

From the hematopoietic system: rarely – anemia, febrile neutropenia

.

On the part of metabolism and nutrition: common – loss of appetite; rarely – polydipsia

.

Mental Disorders: Infrequent – anxiety; rarely – disorientation, euphoria

.

From the nervous system: rare – dizziness, drowsiness; rarely – cognitive impairment, sedation, dysgeusia

.

From the sensory organs: rarely – conjunctivitis, tinnitus

.

Since the cardiovascular system: rarely – palpitations, hot flashes ( “hot flushes”); rarely – bradycardia, cardiovascular disorders

.

With the respiratory system: often – a hiccup; seldom – a sore throat, sneezing, cough, postnasal syndrome, throat irritation

.

From the digestive system: often – indigestion; infrequently – belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence; rarely – hard stools, perforated duodenal ulcer, neutropenic colitis, stomatitis, abdominal distension

.

Skin and subcutaneous tissue: rare – rash, acne; rarely – photosensitivity, increased sweating, seborrhea, improving oily skin, itchy rash

.

From the musculoskeletal system: rarely – muscle cramps, muscle weakness

.

From the urinary system: rarely – dysuria; rare – pollakiuria

.

Changes to the laboratory parameters: often – increased ALT; rarely – increased activity of AST, increased alkaline phosphatase activity; rarely – increased diuresis, the presence of red blood cells in the urine, hyponatremia, weight loss, glycosuria, neutropenia

.

General disorders: often – fatigue; rarely – fatigue, malaise; rarely – swelling, discomfort in the chest area, gait disturbance

.

The side effect profile in patients receiving chemotherapy umerennoemetogennuyu vysokoemetogennuyu and, during the repeated courses (maximum number of courses – 6) with the use of aprepitant was comparable to that during the 1st cycle of chemotherapy

.

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

.

These post-marketing studies

Due to the fact that the reports have come from volunteers with an indefinite number of groups, it is impossible to reliably determine the expected frequency or a causal relationship to drug intake.

Skin and skin appendages: pruritus, rash, urticaria, rarely – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome)

.

Immune system: Hypersensitivity reactions, including anaphylactic reactions

.

How to accept, acceptance rate and dosage

The drug is taken orally with or without food.

Emend® administered for 3 days in combination with corticosteroids and antagonists of serotonin 5-HT ₃ receptor.

Before treatment should read the instructions for use of the antagonist of serotonin 5-HT ₃ receptor assigned simultaneously with the preparation Emend®. The recommended dose of the drug during the three-day Emend® mode is 125 mg for 1 h before receiving chemotherapy drugs in 1 day and 80 mg 1 time / day in the morning in the 2nd and 3rd days.

The tables given regimen of drug depending on the degree of anti-tumor therapy emetic.

Vysokoemetogennaya chemotherapy

Umerennoemetogennaya chemotherapy

In patients with mild or moderate hepatic insufficiency (from 5 to 9 points on a scale Child-Pugh) dose adjustment is required. Clinical data on the use of the drug in patients with severe hepatic insufficiency (> 9 points on a scale Child-Pugh) are absent

.

In patients with severe renal impairment (creatinine clearance < 30 ml / min) and in patients in end stage renal disease undergoing hemodialysis, the correction dose is not required

.

No dose adjustment based on gender, age, race or body mass index is not required.

Storage conditions

At a temperature of not higher than 30 ° C

Active substance

Apreрitant

Interaction

Aprepitant is a substrate, a moderate inhibitor and inducer isoenzyme CYP3A4, isozyme inductor and CYP2C9.

When concomitant administration aprepitant may increase the plasma concentration of drugs whose metabolism occurs with the participation of isoenzyme CYP3A4. Emend® should not be used concurrently with pimozide, terfenadine, astemizole, cisapride, ergot alkaloid derivatives. Inhibition of CYP3A4 by aprepitant influence can lead to increased concentrations of these drugs in the plasma and potentially serious and life-threatening reactions.

Aprepitant induces the metabolism of warfarin and tolbutamide. Simultaneous administration of drug Emend® with these or other drugs that are metabolized involving isoenzyme CYP2C9 (e.g., phenytoin), may lead to a reduction in their concentration in the plasma. There was no effect of the drug on Emend® AUC R (+) – or S (-) – warfarin, however, when used together observed reduction in the minimum concentration S (-) – warfarin is accompanied by a decrease INR 14% after 5 days after dosing Emend®.

In patients receiving warfarin therapy for a long time, should be carefully monitored INR for 2 weeks, and especially 7-10 days after receiving the drug Emend® 3-day scheme, during each cycle of chemotherapy. < / p>

Emend® reduces the AUC of tolbutamide, are substrates of CYP2C9 isoenzyme, 23% in the 4 th day, 28% in the 8-day and 15% on the 15th day. In this case, tolbutamide in a single dose of 500 mg was administered before the 3-day regimen drug Emend® 4 th, 8 th and 15 th days.

The interaction of the drug Emend® with drugs that are substrates of P-glycoprotein transporter, it is unlikely (lack of interaction with Emend® drug digoxin). Aprepitant does not cause clinically significant changes in pharmacokinetics antagonists of serotonin 5HT ₃ receptor – ondansetron, granisetron and gidrodolasetrona (the active metabolite of dolasetron)

.

When simultaneous administration of the drug and GCS Emend® an increase AUC dexamethasone (ingestion) by 2.2 times, methylprednisolone administered in / – 1.3 times and methylprednisolone ingestable – 2.5 times. In this regard, to achieve a desired unit dose of dexamethasone effect when administered in combination with aprepitant reduced by 50%, when administered methylprednisolone in / reduced by approximately 25% when assigning inside – 50%

.

When applied Emend® preparation together with chemotherapeutic agents, which primarily or partly way metabolism occurs with the participation of isoenzyme CYP3A4 (etoposide, vinorelbine, paclitaxel and docetaxel) doses of these drugs can not be corrected. However, caution is recommended when used in patients receiving these drugs, and to provide additional observation. In post-marketing studies of cases of neurotoxicity have been recorded, which can be considered as a possible side effect of ifosfamide is used in conjunction with aprepitant.

The effect of the drug on the pharmacokinetics of docetaxel Emend® not found.

The efficacy of hormonal contraceptives during reception and for 28 days after dosing Emend® can be reduced (at the time of treatment and Emend® within 1 month after the last dose of the drug should be used Emend® alternative or backup methods of contraception) .

In an oral midazolam and drug Emend® observed increase in AUC of midazolam. Possible increase in plasma concentrations of midazolam or other benzodiazepines, the metabolism of which is carried out with the participation of isoenzyme CYP3A4 (alprazolam, triazolam) should be taken into account with concomitant administration of these drugs with the drug Emend®.

Emend® Simultaneous treatment with the drugs of the drug that inhibit the activity of the isoenzyme CYP3A4, may increase aprepitant concentration in blood plasma. Therefore, caution should assign Emend® in combination with strong inhibitors isoenzyme CYP3A4 (e.g., ketoconazole). However, simultaneous reception Emend® drug with moderate inhibitors isoenzyme CYP3A4 (for example, diltiazem, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, and protease inhibitors) did not cause clinically significant changes aprepitant plasma concentration.

Simultaneous reception Emend® formulation with drugs that are strong inducers isoenzyme CYP3A4 (for example, rifampicin, phenytoin, carbamazepine, phenobarbital) may lead to a reduction in the plasma concentration of aprepitant and thus reduce the effectiveness of the drug Emend®. Also, the simultaneous use of aprepitant with drugs St. John’s wort is not recommended.

In patients with mild to moderate hypertension reception aprepitant tablet containing a dose comparable to the 230 mg dose capsules, in combination with diltiazem in a dose of 120 mg 3 times / day for 5 days resulted in an increase in AUC of aprepitant 2 times and the simultaneous increase of diltiazem AUC 1.7 fold. These pharmacokinetic effects did not result in clinically significant changes in ECG, heart rate, or blood pressure compared with the changes in these indicators only when taking diltiazem.

Simultaneous reception aprepitant 1 time / day in tablet form in doses comparable to the 85 mg or 170 mg dose capsules, and paroxetine, 20 mg 1 time / day resulted in a decrease in AUC of about 25% and C _max of approximately 20% for both aprepitant and paroxetine.

Special conditions

Inhibition aprepitant CYP3A4 may lead to increased plasma concentrations of drugs which are metabolized mainly involving isoenzyme CYP3A4 (including certain chemotherapeutic drugs).

Use in pediatrics

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

The effect on the ability to drive vehicles and other machines that require high concentration of attention

Studies on the effect of the drug on Emend® ability to drive or operate machinery has not been. However, one should take into account the side-effect profile of the drug, which may affect patients’ ability to operate machinery. Patients may be different reactions to Emend®.

Pregnancy and lactation

There are no adequate and well-controlled clinical studies safety of the drug during pregnancy has not been conducted, therefore, the use of Emend® drug is not recommended during pregnancy.

It is not known whether aprepitant is excreted in breast milk in humans. If necessary, use during lactation should decide the issue of termination of breastfeeding because of the risk of undesirable effects on the infant.

Overdose

Symptoms: data available for the application aprepitant in high doses without chemotherapy (single dose up to 600 mg or 375 mg daily during 42 days) indicate good tolerability. In 1 patient who took 1440 mg of aprepitant were observed drowsiness and headache.

The treatment: drug therapy should be discontinued Emend® and monitor the patient’s condition. If necessary, a symptomatic therapy. Due to the effect of aprepitant antiemetic drugs that cause vomiting, most likely, will not be effective. The antidote to the drug is unknown. Hemodialysis is not effective.