Эменд®

General characteristics. Structure:

Active ingredient: 80 mg or 125 mg of an aprepitant.

Excipients: hydroxypropyl cellulose, sodium lauryl sulfate, sucrose, cellulose microcrystallic (in granules), sodium the lauryl sulfate (micronized).

Structure of a solid gelatin capsule: titanium dioxide, gelatin, blackened black SW-9008/9009.

Pharmacological properties:

Pharmacodynamics. Antiemetic drug, the selection high-affine antagonist of receptors of neurokinin-1 (NK1) of substance P. Selectivity of linkng of an aprepitant with NK1 receptors is at least 3000 times higher, than for other enzymes, carriers of ion channels and sites of receptors, including dopamine and serotoninovy receptors which are targets of the drugs existing now which are applied to treatment of the nausea and vomiting connected with chemotherapy.

In preclinical trials it was shown that antagonists of NK1 receptors prevent development of the vomiting caused by chemotherapeutic drugs (for example, Cisplatinum) at the expense of the central mechanism of action.

The Aprepitant gets into a brain and contacts brain NK1 receptors. Possessing long central action, the aprepitant inhibits both the acute, and delayed phases of the vomiting caused by Cisplatinum and also strengthens at the same time antiemetic action of an ondansetron and dexamethasone.

Pharmacokinetics. Absorption. After intake of Cmax in a blood plasma it is reached approximately in 4 h. Absolute bioavailability averages about 60-65%. Reception of the capsule along with meal does not exert clinical significant impact on bioavailability of an aprepitant.

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

After intake of the drug Emend® in a dose of 125 mg in the 1st day and then in a dose of 80 mg/days in the 2nd and 3rd days of AUC during 24 h made about 19.5 мкг×ч/мл in the 1st day and 20.1 мкг×ч/мл for the 3rd day. Cmax made 1.5 mkg/ml and 1.4 mkg/ml in the 1st and 3rd days respectively and was reached approximately in 4 h after administration of drug.

Distribution. Linkng with proteins of plasma makes more than 95%. Vd in an equilibrium state makes about 66 l.

In pilot studies it is shown that the aprepitant gets through a placental barrier at rats and through GEB at rats and polecats.

At the person the aprepitant gets through GEB.

Metabolism. The Aprepitant is exposed to intensive metabolism in a liver by means of oxidation in a morpholine ring and its side chains generally under the influence of CYP3A4 and only a small part of drug is metabolized with the participation of CYP1A2 and CYP2C19 (CYP2D6, CYP2C9 or CYP2E1 do not participate in metabolism of an aprepitant).

Removal. The seeming T1/2 makes from about 9 to 13 h.

The Aprepitant is removed mainly in the form of metabolites through intestines (86%) and kidneys (5%).

The seeming plasma clearance of an aprepitant makes from about 60 to 84 ml/min.

Pharmacokinetics in special clinical cases. The drug Emend® pharmacokinetics at children and teenagers aged up to 18 years is not studied.

At patients at the age of 65 years after intake of the drug Emend® in a single dose 125 mg in the 1st day are also more senior and then in a dose of 80 mg/days in the 2nd and 5th days of AUC during 24 h was 21% more in the 1st day and are 36% more for the 5th day, than at persons 65 years are younger. Cmax at the same time was 10% higher in the 1st day and is 24% higher for the 5th day. These distinctions were not clinically significant.

At patients with a slight liver failure (5-6 points on a scale of Chayld-Pyyu) after intake of the drug Emend® in a dose of 125 mg in the 1st day and then in a dose of 80 mg/days in the 2nd and 3rd days of AUC during 24 h was 11% less in the 1st day and is 36% less for the 3rd day, than at the healthy volunteers who received the same doses of drug. At patients with a moderate liver failure (7-9 points on a scale of Chayld-Pyyu) AUC during 24 h was 10% more in the 1st day and is 18% more for the 3rd day, than at the healthy volunteers who received the same doses. These distinctions are not recognized as clinically significant.

Patients with a renal failure of heavy degree (KK <30 ml/min.) and the patients in an end-stage of a renal failure needing a hemodialysis received Emend® once in a dose of 240 mg. At patients with a renal failure of heavy degree of AUC for a total aprepitant (both connected, and not connected with proteins) it was lowered by 21%, and Cmax was lowered by 32% in comparison with healthy volunteers. At the patients with an end-stage of a renal failure who are on a hemodialysis, AUC for a total aprepitant was 42% less, and Cmax for 32%. Due to the small decrease in linkng of an aprepitant with proteins of plasma at patients with a renal failure of AUC value pharmacological of active untied drug at these patients and at healthy faces authentically did not differ. The hemodialysis which is carried out in 4 and 48 h after administration of drug did not exert significant impact on pharmacokinetics of an aprepitant. In dialyzate less than 0.2% of a dose of an aprepitant were found.

After a single dose in the drug drug Emend® AUC0-24 and Cmax at women were for 9% and 17% respectively above, than at men. T1/2 of an aprepitant at women was 25% less, than at men, and significant distinctions in time of achievement of Cmax between women and men were not noted. These distinctions of pharmacokinetic parameters have no clinical value.

Dose adjustment of the drug Emend® depending on race is not required.

The index of body weight does not influence pharmacokinetics of an aprepitant.

Indications to use:

— for the prevention of the acute and delayed nausea and the vomitings caused highly - or umerennoemetogenny antineoplastic drugs (in a combination with other antiemetic drugs).

Route of administration and doses:

Drug is accepted inside irrespective of meal. ^Эменд® appoint within 3 days in a combination with GKS and antagonists of serotoninovy _{5-HT3-receptors}.

Before an initiation of treatment it is necessary to study the application instruction of the antagonist of serotoninovy _5-HT3 receptors appointed along with ^{the drug Emend®}. The recommended ^{drug Emend®} dose at the three-day mode makes 125 mg for 1 h before reception of chemotherapeutic drugs in the 1st day and 80 mg of 1 times/days in the morning in the 2nd and 3rd days.

The scheme of administration of drugs depending on degree of an emetogennost of antineoplastic therapy is provided in tables.

Vysokoemetogenny chemotherapy.

Umerennoemetogenny chemotherapy.

With a slight or moderate liver failure (from 5 to 9 points on a scale of Chayld-Pyyu) dose adjustment is not required from patients. Clinical data on use of drug for patients with a heavy liver failure (> 9 points on a scale of Chayld-Pyyu) are absent.

At patients with a renal failure of heavy degree (KK <30 ml/min.), and also at the patients in an end-stage of a renal failure who are on a hemodialysis, is not required to dose adjustment.

Dose adjustment depending on a sex, age, race or an index of body weight is not required.

Features of use:

Use at pregnancy and feeding by a breast. Adequate and strictly controlled clinical trials of safety of drug at pregnancy were not conducted therefore use of the drug Emend® at pregnancy is not recommended.

It is unknown whether the aprepitant with breast milk at the person is allocated. In need of use of drug in the period of a lactation it is necessary to resolve an issue of the termination of breastfeeding in connection with risk of undesirable influence on the baby.

Use at abnormal liver functions. With a slight or moderate liver failure (from 5 to 9 points on a scale of Chayld-Pyyu) dose adjustment is not required from patients. Clinical data on use of drug for patients with a heavy liver failure (> 9 points on a scale of Chayld-Pyyu) are absent.

Use at renal failures. With a renal failure of heavy degree (KK less than 30 ml/min.), and also at the patients in an end-stage of a renal failure who are on a hemodialysis, dose adjustment is not required from patients.

Use for children. Safety and efficiency of use of the drug Emend® for children are not established.

Use for elderly patients. Dose adjustment is not required to patients of advanced age (65 years are also more senior).

Special instructions. CYP3A4 inhibition aprepitanty can lead to increase in concentration in a blood plasma of drugs which are metabolized mainly with the participation of CYP3A4 isoenzyme (including some chemotherapeutic drugs).

Use in pediatrics. Safety and efficiency of use of the drug Emend® for children are not established.

Influence on ability to driving of motor transport and to control of mechanisms. Researches on studying of influence of the drug Emend® on ability to manage vehicles or to work with mechanisms were not conducted. However it is necessary to consider a profile of side effects of drug which can affect ability of patients to manage mechanisms. At patients various reactions to Emend® are possible.

Side effects:

Safety of an aprepitant was estimated approximately at 6500 patients.

Prevention of nausea and vomiting, caused by chemotherapy. Vysokoemetogenny therapy. 544 patients receiving vysokoemetogenny therapy and an aprepitant in the first cycle took part in clinical trial. 413 patients from this group continued therapy (the maximum number of courses of chemotherapy - 6). The three-day mode of administration of drug Emend® with ondansetrony and dexamethasone was well transferred to combinations by patients. The majority of the side reactions recorded in clinical trials were defined as reaction easy and moderate severity.

The most frequent side reactions against the background of vysokoemetogenny chemotherapy at the patients receiving an aprepitant in a combination with antagonists of serotoninovy 5-HT3-receptors and dexamethasone (were observed with a bigger frequency, than at therapy by antagonists of serotoninovy 5-HT3-receptors and dexamethasone): hiccups (4.6%), increase in activity of ALT (2.8%), dyspepsia (2.6%), lock (2.4%), headache (2%) and loss of appetite (2%).

In additional clinical trial 1169 patients receiving different types of vysokoemetogenny chemotherapy and the modes of prevention of nausea and vomiting using an aprepitant and antagonists of serotoninovy 5-HT3-receptors and dexamethasone or only antagonists of serotoninovy 5-HT3-receptors and dexamethasone, had an identical profile of side reactions.

Umerennoemetogenny therapy. In clinical trial with participation of 868 patients the most frequent side reaction against the background of umerennoemetogenny chemotherapy the patients receiving an aprepitant in a combination with antagonists of 5-HT3-receptors and dexamethasone (it was observed with a bigger frequency, than at therapy by antagonists of 5-HT3 receptors and dexamethasone), had a fatigue (1.4%).

In the integrated analysis of researches of vysokoemetogenny and umerennoemetogenny chemotherapy at the patients receiving treatment by an aprepitant the following connected with administration of drug side effects and with a bigger frequency was observed, than at standard therapy: often (from ≥1/100 to <1/10), infrequently (from ≥1/1000 to <1/100), it is rare (from ≥1/10 000 to <1/1000).

Infectious and parasitic diseases: seldom - candidiasis, a staphylococcal infection.

From system of a hemopoiesis: infrequently - anemia, a febrile neutropenia.

From a metabolism and food: often - a loss of appetite; seldom - a polydipsia.

Disturbances of mentality: infrequently - uneasiness; seldom - a disorientation, euphoria.

From a nervous system: infrequently - dizziness, drowsiness; seldom - cognitive disturbances, block, a food faddism.

From sense bodys: seldom - conjunctivitis, a sonitus.

From cardiovascular system: infrequently - a cardiopalmus, pristupoobrazny feeling of heat ("inflows"); seldom - bradycardia, warmly vascular disorders.

From respiratory system: often - a hiccups; seldom - a pharyngalgia, sneezing, cough, a post-nasal syndrome, irritation of a throat.

From the alimentary system: often - dyspepsia; infrequently - an eructation, nausea, a gastroesophageal reflux, vomiting, an abdominal pain, dryness in a mouth, a meteorism; seldom - firm kcal, a ruptured ulcer of a duodenum, neytropenichesky colitis, stomatitis, abdominal distention.

From skin and a hypodermic fatty tissue: infrequently - rash, an acne; seldom - a photosensitization, the increased perspiration, seborrhea, increase in fat content of skin, pruritic rash.

From a musculoskeletal system: seldom - muscular spasms, muscular weakness.

From an urinary system: infrequently - a dysuria; seldom - a pollakiuria.

Changes from laboratory indicators: often - increase in activity of ALT; infrequently - increase in activity of nuclear heating plant, increase in activity of ShchF; seldom - increase in a diuresis, existence of erythrocytes in urine, a hyponatremia, a body degrowth, a glucosuria, a neutropenia.

General frustration: often - fatigue; infrequently - an adynamy, an indisposition; seldom - hypostases, a sensation of discomfort in a thorax, gait disturbance.

The profile of side effects at the patients receiving vysokoemetogenny and umerennoemetogenny chemotherapy when carrying out repeated courses (the maximum number of courses - 6) using an aprepitant was comparable to that during the 1st cycle of chemotherapy.

In other research of use of an aprepitant for the prevention of nausea and vomiting induced by chemotherapy the message on serious side effects - Stephens-Johnson's syndrome, a toxic epidermal necrolysis was received (Lyell's disease).

Data of post-registration researches. Because reports arrived from volunteers from groups of the population with an uncertain number, it is impossible to determine authentically expected frequency or a causal relationship with administration of drug.

From skin and skin appendages: an itch, rash, urticaria, it is rare - Stephens-Johnson's syndrome, a toxic epidermal necrolysis (Lyell's disease).

From immune system: hypersensitivity reactions, including anaphylactic reactions.

Interaction with other medicines:

The Aprepitant is substrate, moderate inhibitor and the inductor of an isoenzyme CYP3A4, and also CYP2C9 isoenzyme inductor.

At co-administration the aprepitant can increase concentration in plasma of medicines which metabolism happens with the participation of CYP3A4 isoenzyme. Эменд® it is not necessary to apply along with Pimozidum, terfenadiny, astemizoly, tsizapridy, derivatives of alkaloids of an ergot. CYP3A4 isoenzyme inhibition under the influence of an aprepitant can lead to increase in concentration of these drugs in plasma and to potentially serious and life-threatening reactions.

The Aprepitant induces metabolism of warfarin and Tolbutamidum. Co-administration of the drug Emend® with these or other drugs which are metabolized with the participation of CYP2C9 isoenzyme (for example, with Phenytoinum) can lead to decrease in their concentration in plasma. Influence of the drug Emend® on AUC R is noted (+) - or S (-) - warfarin, however at combined use was observed decrease in the minimum concentration of S (-) - warfarin which was followed by decrease in MNO by 14% in 5 days after the end of administration of drug Emend®.

At the patients receiving therapy by warfarin for a long time it is necessary to monitorirovat carefully the MNO level within 2 weeks, and especially for 7–10 days after the beginning of administration of drug of Emend® according to the 3-day scheme, during each cycle of chemotherapy.

Эменд® reduces AUC of Tolbutamidum which is CYP2C9 isoenzyme substrate by 23% in the 4th day, for 28% in the 8th day and for 15% in the 15th day. At the same time Tolbutamidum in a single dose of 500 mg was appointed before the 3-day scheme of therapy the drug Emend® in the 4th, 8th and 15th days.

Interaction of the drug Emend® with the drugs which are P-glycoprotein carrier substrates is improbable (lack of interaction of the drug Emend® with digoxin). The Aprepitant does not cause clinically significant changes of pharmacokinetics of antagonists of serotoninovy 5HT3-receptors - an ondansetron, a granisetron and a gidrodolasetron (an active metabolite of a dolasetron).

At a concomitant use of the drug Emend® and GKS increase in AUC dexamethasone (is noted at intake) by 2.2 time, Methylprednisolonum entered in/in - by 1.3 time and Methylprednisolonum accepted inside - by 2.5 times. In this regard for achievement of necessary effect the standard dose of dexamethasone at its intake in a combination with an aprepitant is lowered by 50%, Methylprednisolonum at introduction in/in lowered approximately by 25%, at appointment inside - for 50%.

At use of the drug Emend® together with chemotherapeutic drugs which metabolism mainly or partially happens with the participation of CYP3A4 isoenzyme (этопозид, винорелбин, dotsetakset and paklitakset) the dose of these drugs can be not adjusted. However it is recommended to be careful at use for the patients receiving these drugs and to provide additional observation. In post-registration researches neurotoxicity cases which can be considered as possible side effect of the ifosfamid applied together with an aprepitant were recorded.

Influence of the drug Emend® on pharmacokinetics of a dotsetaksel is not revealed.

Efficiency of hormonal contraceptives during reception and within 28 days after the end of administration of drug Emend® can be reduced (during treatment by the drug Emend® and within 1 month after reception of the last dose of the drug Emend® it is necessary to apply alternative or reserve methods of contraception).

At concomitant oral administration of midazolam and the drug Emend® increase in AUC midazolam is noted. Possible increase in concentration in a blood plasma of midazolam or other benzodiazepines which metabolism is carried out with the participation of CYP3A4 isoenzyme (to alprazola, triazoles) should be taken into account at co-administration of these drugs with the drug Emend®.

The concomitant use of the drug Emend® with drugs which inhibit activity of an isoenzyme of CYP3A4 can lead to increase in concentration of an aprepitant in a blood plasma. Therefore, it is necessary to appoint with care Emend® in a combination with strong inhibitors of an isoenzyme CYP3A4 (for example, with ketokonazoly). However the concomitant use of the drug Emend® with moderate inhibitors of an isoenzyme CYP3A4 (for example, with diltiazem, itrakonazoly, vorikonazoly, pozakonazoly, klaritromitsiny, telitromitsiny and protease inhibitors) does not cause clinically significant changes of concentration of an aprepitant in a blood plasma.

The concomitant use of the drug Emend® with drugs which are strong inductors of an isoenzyme CYP3A4 (for example, with rifampicin, Phenytoinum, carbamazepine, phenobarbital) can lead to reduction of concentration of an aprepitant in plasma and, thus, to decrease in efficiency of the drug Emend®. Also simultaneous use of an aprepitant with drugs of the St. John's Wort which is made a hole is not recommended.

Patients with slight and moderate arterial hypertension have a reception of the tablet of an aprepitant containing the dose comparable from 230 mg of drug in capsules in a combination with diltiazem in a dose of 120 mg of 3 times/days within 5 days led to increase in AUC of an aprepitant twice and to simultaneous increase in AUC diltiazem by 1.7 times. These pharmacokinetic effects did not lead to clinically significant changes on an ECG, ChSS or the ABP in comparison with changes of these indicators at reception only diltiazem.

The concomitant use of an aprepitant of 1 times/days in the form of tablets in the dose comparable from 85 mg or 170 mg of drug in capsules, and a paroksetina in a dose of 20 mg of 1 times/days led to AUC reduction approximately for 25% and Cmax approximately for 20% both for an aprepitant, and for a paroksetin.

Contraindications:

— a heavy liver failure (> 9 points on a scale of Chayld-Pyyu);

— simultaneous use with Pimozidum, terfenadiny, astemizoly and tsizapridy;

— hypersensitivity to drug components.

With care it is necessary to apply Emend® at the patients who are at the same time receiving medicines which are metabolized mainly with the participation of CYP3A4 isoenzyme. Co-administration of the drug Emend® with warfarin can lead to clinically significant decrease in MNO. At the patients receiving long therapy by warfarin it is necessary to monitorirovat carefully MNO value within 2 weeks at each cycle of chemotherapy and especially in 7-10 days after the beginning of administration of drug of Emend® according to the 3-day scheme. Efficiency of hormonal contraceptives can decrease in time and within 28 days after treatment by the drug Emend®. During treatment by the drug Emend® and within 1 month after reception of the last dose of the drug Emend® it is necessary to use alternative and reserve methods of contraception.

Overdose:

Symptoms: the available data on use of an aprepitant in high doses without chemotherapy (once to 600 mg or on 375 mg daily within 42 days) confirm good tolerance of drug. At 1 patient who accepted 1440 mg of an aprepitant drowsiness and a headache were observed.

Treatment: therapy by the drug Emend® should be stopped and provided control of a condition of the patient. If necessary carry out symptomatic therapy. Due to the antiemetic action of an aprepitant the medicines causing vomiting, most likely, will not be effective. The antidote to drug is unknown. The hemodialysis is not effective.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 4 years.

Issue conditions:

According to the recipe

Packaging:

1 pieces - blisters (1) - packs cardboard.
1 pieces - blisters (2) - packs cardboard.
1 pieces - blisters (5) - packs cardboard.
2 pieces - blisters (1) - packs cardboard.
2 pieces - blisters (2) - packs cardboard.
2 pieces - blisters (5) - packs cardboard.