Emend V / V - instructions for use, dose, side effects, contraindications

Active substanceFosaprepitantFosaprepitant

Similar drugsTo uncover

lyophilizate d / infusion

Dosage form: & nbsplIofilizate for solution for infusion

Composition:per one vial:

active substance: 257.6 mg of fmospapitate dimeglumina is equivalent to 157.5 mg of fosaprepitant;

Excipients: disodium edetate 19.7 mg, polysorbate 80 78.8 mg, lactose anhydrous 393.8 mg, sodium hydroxide or hydrochloric acid to pH 9.2.

Description:Lyophilizate bleached to almost white

Pharmacotherapeutic group:antiemetics - neurokinin receptor blocker

ATX: & nbsp

A.04.A.D Other antiemetic drugs

Pharmacodynamics:

Active metabolite of fosaprepitant is an aprepitant selective high affinity receptor antagonist Neurokinin 1 (NK1) substance R.

Isotope studies have shown that selective binding of aprepitant with NK1 -receptors of at least 3000 times higher than with other enzymes, transport proteins, ionic channels and receptors, including dopamine and serotonin receptors, which are targets existing drugs for prevention of nausea and vomiting during chemotherapy.

Pre-clinical studies have shown that antagonists NK1-receptors prevent vomiting caused by chemotherapeutic drugs, such as cisplatin, due to the central mechanism of action. According to the data obtained in studies with positron emission tomography (PET), aprepitant penetrates into the brain and binds to NK1receptors of the brain. The central effect of aprepitant has a long duration, and it inhibits both acute and delayed phases of vomiting caused by cisplatin, and also increases the antiemetic activity of 5-HT3 receptor antagonists (for example, ondansetron) and glucocorticosteroid dexamethasone.

Electrophysiology of the heart In a randomized, double-blind, positively-controlled study QTc interval, a single dose of fosaprepitant 200 mg did not affect the amount QTc interval.

Share of related cerebral NK1-receptor, assessed by positron emission tomography

With a single intravenous dose of fosapreptanta 150 mg in healthy young volunteers, binding NK1 -receptors of the brain was 100% after 24 hours, at least 97% after 48 hours and 75% after 120 hours. Share of related: NK1- receptors correlated with the concentration of aprepitant in plasma.

Pharmacokinetics:

Introduction

After a single intravenous 20-minute infusion of 150 mg of fosaprepitant to healthy volunteers, the mean AUCo-∞ (the area under the concentration-time curve) of aprepitant is 35.0 μg / hr / ml and the mean maximum concentration (FROM_max) of aprepitant is equal to 4.01 μg / ml.

Distribution

Fosaprepitant is rapidly metabolized to aprepitant.

Aprepitant binds to plasma proteins by more than 95%. The geometric mean of the apparent volume of the distribution in the equilibrium state (Vd_ss) in humans it is approximately 66 liters.

Data from PET studies showed that aprepitant penetrates through blood-brain barrier (see, "Farmakodinamika").

Metabolism

The conversion of fosaprepitant into aprepitant can occur in a variety of tissues. Fosaprepitant is converted into aprepitant after intravenous administration within 30 minutes after the end of the infusion. Aprepitant is subject to active metabolism. In the human plasma, seven metabolites of aprepitant have been identified, which have a weak activity. The metabolism of aprepitant occurs to a greater extent by oxidationmorpholine ring and side chains. Research in vitro from using a human liver microsome show that aprepitant is metabolized predominantly through isoenzyme CYP3A4, slightly through isozymes CYP1A2 and CYP2C19 and not metabolized through isoenzymes CYP2D6, CYP2C9 or CYP2E1.

All metabolites that were observed in urine, feces and plasma after intravenous administration of 100 mg of [¹⁴C] -phosaprepitate were also observed after oral administration reception [¹⁴C] -aprepitant. After conversion of 245.4 mg of fosaprepitant dimeglumine (equivalent to 150 mg of free acid fosapreptate) in aprepitant 23.9 mg of phosphoric acid and 95.3 mg of meglumine are released.

Excretion

After a single intravenous administration of 100 mg of [¹⁴C] -phosaprepitate 57% of radioactivity was detected in healthy volunteers in urine and 45% - in the feces.

Aprepitant is excreted in the main as metabolites, unchanged aprepitant not excreted by the kidneys. Finite period half-life of aprepitant is approximately 9 to 13 hours.

Pharmacokinetics in special groups patients

Floor

After a single oral admission aprepitant AUC0.-24h. and Cmax for aprepitant were 9% and 17% respectively, higher in women, than at men. The half-life of aprepitant in women was 25% less than at men, and Tmax was noted in about one and the same time. This difference was not clinically significant. Correction of the dose based on sexual accessory is not required.

Race

After a single oral admission aprepitant, AUC0-24h. about 27% and 31% higher in Hispanics compared with Caucasians and African Americans, respectively. Cmax by 19% and 29% higher than Latin Americans in comparison with patients of the Caucasoid race and Afro-Americans, respectively. After single oral perepitant use in Asians showed an increase AUCo-24h. and FROM_max by 74% and 47%, respectively, compared with patients of the Caucasoid race. Correction of dose based on race is not required.

Elderly patients

After a single oral intake of 125 mg of aprepitant on the first day and 80 mg / day from day 2 to day 5 AUC0-24h. aprepitant in elderly patients (65 years and older) was 21% more on the first day and 36% more on the 5th day than in younger adults. In elderly patients Cmax was 10% higher on the first day and 24% higher on the 5th day than in younger adults. These differences were not clinically significant. Dose adjustments in elderly patients are not required.

Children

The use of fosaprepitant in patients under the age of 18 years has not been studied.

Body mass index (BMI)

BMI does not affect the pharmacokinetics of aprepitant.

Liver failure

Fosaprepitant is not metabolized in the liver, therefore, it is not expected that hepatic insufficiency will affect the conversion of fosaprepitant into aprepitant. Patients with mild to moderate hepatic impairment tolerated oral administration aprepitant. In patients with mild hepatic insufficiency (5-6 points on the Child-Pugh scale) after a single oral intake of 125 mg of aprepitant on the first day and 80 mg once a day on the 2nd and 3rd days AUC0-24h. aprepitant was 11% fewer on the first day and 36% lower on the third day than in healthy volunteers who received the drug in the same regimen. In patients with moderate hepatic insufficiency (7-9 on the Child-Pugh scale) AUC0-24h. aprepitant was 10% more on the first day and 18% more on the third day than in healthy volunteers who received the drug in the same regimen. These differences in AUC0-24h. were not considered clinically significant, so dose adjustment in patients with mild and moderate hepatic insufficiency is not required.

For patients with severe hepatic impairment (more than 9 on the Child-Pugh scale), clinical and pharmacokinetic data are not available.

Renal insufficiency Patients with severe renal insufficiency (creatinine clearance less than 30 ml / min) and patients with terminal renal failure requiring hemodialysis received a single dose of aprepitant 240 mg. In patients with severe renal disease insufficiency AUCo-∞ for summary aprepitant (unrelated and associated with proteins) was reduced by 21%, and Cmax was reduced by 32% compared to healthy volunteers. In patients with ESRD on hemodialysis, AUCo-oo for the total aprepitant was reduced by 42%, and Cmax was reduced by 32%. In connection with a slight decrease in the binding of aprepitant to proteins in patients with renal insufficiency AUC for pharmacologically active unbound epoxypin in such patients did not significantly differ from that of healthy volunteers.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 detected in the dialysate. Dose adjustments in patients with severe renal failure and patients with ESRD on hemodialysis are not required.

Indications:

Preparation Emend® I / O (fosaprepitant) in combination with other antiemetic agents is indicated to prevent acute and delayed nausea and vomiting due to highly emetic or moderately emeticogenic antitumor chemotherapy.

Contraindications:

Hypersensitivity to fosaprepitanu, aprepitant, polysorbate-80 or any other of the components of the drug;
The drug should not be used concurrently with pimozide, terfenadine, astemizole and cisapride;
Severe hepatic insufficiency (more than 9 on the Child-Pugh scale);
Pregnancy;
Childhood.

Carefully:

Due to the fact that fosaprepitant rapidly metabolized in aprepitant (is a weak or moderate isoenzyme inhibitor CYP3A4), it should be used with caution in patients who are simultaneously receiving medications that are metabolized mainly with the participation of the isoenzyme CYP3A4; some chemotherapeutic drugs are metabolized with the participation of isoenzyme CYP3A4. Weak inhibitory effect of fosaprepitant 150 mg on isoenzyme CYP3A4 may lead to an increase in the concentrations of these co-administered oral medications (see Interactions with Other Drugs). There are isolated data on allergic reactions of immediate type, such as reddening, erythema and dyspnea, which occurred during infusion of fosaprepitant. These allergic reactions usually disappeared after discontinuation of the infusion and the use of appropriate therapy. It is not recommended to resume the infusion of the drug to patients who have had these allergic reactions.

Simultaneous administration of fosapreptant orally with warfarin may result in a clinically significant decrease in the International Normalized Ratio (MNO) of prothrombin time. In patients receiving long-term therapy with warfarin, INR should be carefully monitored for 2 weeks, especially 7-10 days after the initiation of fosaprepitant administration for each cycle of chemotherapy (see Interactions with Other Drugs).

EThe effectiveness of hormonal contraceptives may decrease during and for 28 days after taking fosaprepitant. During treatment with fosaprepitanom and within 1 month after taking fosaprepitanta should use alternative or additional methods of contraception (see Interaction with other medicinal products).

Pregnancy and lactation:

USE DURING PREGNANCY AND LACTATION

There have been no controlled clinical trials on the use of the drug in pregnant women and women during breastfeeding. The drug should be used during pregnancy only if the intended benefit to the mother exceeds the potential risk to the fetus.

There is no data on the isolation of the drug with human breast milk. In view of the fact that many drugs are excreted in breast milk and due to the risk of side effects on the infant, the issue of stopping breastfeeding or stopping the drug should be addressed in the light of the need for the drug for the mother.

APPLICATION FOR CHILDREN

Safety and effectiveness of the drug in children have not been studied.

Dosing and Administration:

Preparation Emend® I / O (fosaprepitant) apply on the first day of chemotherapy in the form of intravenous infusion lasting from 20 to 30 minutes approximately 30 minutes before the chemotherapy. Emend® V / B should be used in conjunction with corticosteroids and 5-HTs antagonists.

The recommended dosing regimen for nnausea and vomiting, related to the application moderately emetogenic antitumor chemotherapy:

	1st day	2nd day	3rd day	4th day
Emend * B / W	150 mg intravenously	-	-	-
Dexamethasone **	12 mg orally	8 mg orally	8 mg orally 2 times a day	8 mg orally 2 times a day
Antagonists 5- HT₃ receptors	AT according to the section "Method of administration and dose" appropriate antagonist of 5-HT3 receptors	-	-	-

** Dexamethasone should be taken 30 minutes prior to chemotherapy on the 1st day and in the morning on the 2nd, 3rd and 4th days. Dexamethasone should be taken in the evening of the 3rd and 4th days. The dose of dexamethasone is indicated taking into account the drug interaction. The recommended dosing regimen to prevent nausea and vomiting associated with the use of moderately emetogenic antitumor chemotherapy:

	1st day
Emend * I / O	150 mg intravenously
Dexamethasone *	12 mg orally
Antagonists 5-HTZ receptors	AT according to the "Method of administration and dosage" section of a suitable antagonist 5-HTZ receptors

* Dexamethasone should be taken 30 minutes prior to chemotherapy on the first day. The dose of dexamethasone was chosen fromby the drug interaction.

Preparation of a solution for infusion of Emend® I / B 150 mg

The contents of the vial must be dissolved in 5 ml of 0.9% sodium chloride solution (to avoid foaming, the solution is directed along the wall of the vial). Carefully rotate the bottle (do not shake!).
The resulting solution must be added to the infusion bag or vial containing 145 ml of 0.9% sodium chloride solution to obtain a final volume of 150 ml. Mix the contents of the bag or vial gently. The solution for infusion should be inspected before administration for sediment or discoloration. The prepared solution should be stored at a temperature of up to 25 ° C and used within 24 hours.

All medications for parenteral administration should be carefully examined before use for the presence of mechanical inclusions and discoloration in all cases,when the properties of the solution and the material of the container permit. Fosaprepitant It is incompatible with solutions containing divalent cations (for example, Ca²⁺, Mg²⁺), including Hartmann's solution and Ringer's solution with lactate. Emend® I / O preparation can not be diluted or mixed with solutions that have not been physically and chemically compatible with them. Additional information on the joint administration of the drug with corticosteroids is described in the section "Interaction with other medicinal products".

When prescribing Emend® I / B in combination with other antiemetics, follow the instructions for using these drugs.

No dosage adjustment is required depending on age, gender, race, body mass index (BMI).

Side effects:

Due to the fact that fosaprepitant is metabolized to aprepitant, with the administration of the drug the same undesirable phenomena as for aprepitant are possible.

Aprepitant for oral administration

The most common adverse events associated with highly emetogenic chemotherapy in patients who received aprepitant (4.6%), increased ALT activity (2.8%), dyspepsia (2.6%), constipation (2.4%), headache pain (2.0%) and a decrease in appetite (2.0%). The most common undesirable phenomenon associated with moderately emetogenic chemotherapy in patients who received aprepitant, and marked with a greater frequency than with standard therapy was fatigue (1.4%).

In a combined analysis of studies of highly emetic and moderately emeticogenic chemotherapy in patients treated with aprepitant in a three-day regimen, the following adverse events were observed, with a greater frequency than with standard therapy:

[Frequently (> 1/100, <1/10), Not often (> 1/1000, <1/100), Rarely (> 1/10000, <1/1000)]

Infectious and parasitic diseases:

Rarely: candidiasis, staphylococcal infection.

Violations from the blood and lymphatic system:

Infrequently: anemia, febrile neutropenia.

Disorders from the metabolism and nutrition:

Often: loss of appetite

Rarely: polydipsia.

Disorders of the psyche:

Infrequently: anxiety

Rarely: euphoria, disorientation.

Impaired nervous system:

Infrequently: dizziness, drowsiness

Rarely: cognitive impairment, inhibition, perversion of taste.

Disorders from the side of the organ of vision:

Rarely: conjunctivitis

Hearing disorders and labyrinthine disturbances:

Rarely: noise in ears

Heart Disease:

Infrequently: cardiopalmus

Rarely: bradycardia, cardiovascular disorders

Vascular disorders:

Infrequently: paroxysmal sensations of heat (hot flashes)

Disturbances from the respiratory system, chest and mediastinal organs:

Often: hiccough

Rarely: sore throat, sneezing, cough, postnasal swelling syndrome, throat irritation.

Disorders from the gastrointestinal tract:

Often: dyspepsia

Infrequently: belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence

Rarely: hard stool, perforated duodenal ulcer, neutropenic colitis, stomatitis, bloating.

Disturbances from the skin and subcutaneous tissues:

Infrequently: rash, acne

Rarely: photosensitization, excessive sweating, seborrhea, increased skin fat, an itchy rash.

Disturbances from the musculoskeletal and connective tissue:

Rarely: muscle spasms, muscle weakness.

Disorders from the kidneys and urinary tract:

Infrequently: dysuria

Rarely: pollakiuria.

General disorders and disorders at the site of administration:

Often: fatigue Infrequently: weakness, discomfort

Rarely: swelling, a feeling of discomfort in the chest, a violation of gait.

Laboratory and instrumental data:

Often: increased ALT activity

Not often: increased activity ACT, increased activity of alkaline phosphatase

Rcaustic: increased diuresis, the presence of erythrocytes in the urine, hyponatremia, weight loss, glucosuria, a decrease in the number of neutrophils.

The profile of adverse events in 6 cycles of chemotherapy in studies of highly emetic and moderately emeticogenic chemotherapy with aprepitant was comparable to that during the first cycle of chemotherapy.

In another study using aprepitant to prevent nausea and vomiting induced by chemotherapy, a serious adverse event, the Stevens-Johnson syndrome, was reported.

Fosaprepitant for intravenous administration

In a controlled clinical trial in patients receiving highly emetogenic chemotherapy, the safety profiles of the Emend® B / B preparation (fosaprepitant), administered on the first day, were comparable to those obtained in the study of the use of aprepitant orally in a three-day regimen.

Further, additional, clinically significant, associated with the use of fosaprepitant at a dose of 150 mg adverse events, and not noted in the above clinical studies with the use of perepitent orally (three-day regimen):

Common disorders and disorders together:

Infrequently: erythema, itching, pain at the injection site

Rarely: compaction at injection site

Laboratory and instrumental data:

Infrequently: increase in blood pressure

Disturbances from the skin and subcutaneous tissues:

Infrequently: erythema

Vascular disorders:

Infrequently: paroxysmal sensations of heat (hot flashes), thrombophlebitis (mainly, thrombophlebitis at the site of administration)

Other studies

One-time administration of 40 mg of Emend® preparation (aprepitant) was studied to prevent postoperative nausea and vomiting in patients (not receiving chemotherapy) after general anesthesia.In these studies, the following adverse reactions were observed, the number of which was greater than when taking the reference drug (ondansetron): increased ALT activity, pain in the upper abdomen, atypical noise in the intestine, dysarthria, dyspnoea, hypoesthesia, insomnia, miosis, nausea, sensitivity disorders, bowel discomfort, visual acuity, wheezing.

There were reports of 2 serious adverse events in the study of the use of aprepitant at higher doses to prevent postoperative nausea and vomiting-1 case of constipation and 1 case of partial intestinal obstruction.

One report of angioneurotic edema and urticaria was received as a serious undesirable phenomenon when examining the use of aprepitant not to prevent post-operative or chemotherapy-induced nausea and vomiting.

Post-registration research data

During the post-marketing period, the side effects described below were reported. Due to the fact that the reports came from volunteers from population groups with an undetermined number, it is impossible to reliably determine the expected frequency or causal relationship with taking the drug.

From the skin and skin appendages:

itching, rashes, hives, rarely Stevens-Johnson syndrome (toxic epidermal necrosis).

From the immune system:

hypersensitivity reactions, including anaphylactic reactions.

Reports were received of allergic reactions of immediate type, such as redness, erythema and dyspnea, that occurred during infusion of fosaprepitant (see Caution).

Overdose:

There is no specific information on overcoming the symptoms of an overdose with Emend® B / B. With a single administration of fosaprepitant to volunteers up to 200 mg intravenously or the addition of aprepitant to 600 mg orally, a good tolerance was shown. Three of the 33 volunteers who received fosaprepitant in a dose of 200 mg, there were thromboses at the injection site of a weak degree of severity. In studies not related to the study of chemotherapy-induced nausea and vomiting, a good tolerability of aprepitant was shown in the appointment of patients with aprepitant at a dose of 375 mg once a day for 42 days. In 33 cancer patients, a good tolerability of aprepitant was shown with a single dose of 375 mg on the first day and 250 mg once a day from the 2nd to the 5th day.

There was reported the occurrence of drowsiness and headache in one patient who took 1,440 mg of aprepitant.

In case of an overdose, the drug should be discontinued and provide general supportive therapy and monitoring of the patient's condition. In connection with the antiemetic effect of aprepitant, medications that cause vomiting may not be effective.

In case of an overdose of aprepitant, hemodialysis is not effective.

Interaction:

Drug interactions after the use of fosaprepitant most likely occur with drugs that interact with aprepitant. Further information was obtained from studies performed with aprepitant for oral administration and studies on the joint use of fosaprepitant with dexamethasone, midazolam or diltiazem.

Aprepitant is a substrate, a weak or moderate inhibitor and isoenzyme inducer CYP3A4. Aprepitant is also an isoenzyme inducer CYP2C9. With a single dose, Emend® B / B 150 mg is a mild inhibitor of the isoenzyme CYP3A4 and does not induce induction of the isoenzyme CYP3A4. It is assumed,that the Emend® B / B preparation of 150 mg in the form for intravenous administration will cause less or no greater induction of the isoenzyme CYP2C9 by Oral perepitant intake.

The effect of fosaprepitation / aprepitant on pharmacokinetics of other drugs

Due to the fact that aprepitant is a weak or moderate isoenzyme inhibitor CYP3A4, a fosaprepitant is a weak isoenzyme inhibitor CYP3A4, with the simultaneous administration of medications, the metabolism of which occurs with the participation of the isoenzyme CYP3A4, their concentration in the blood plasma can increase. Fosaprepitant should not be used concomitantly with pimozide, terfenadine, astemizole or cisapride. Inhibition of isoenzyme CYP3A4 under the influence of aprepitant may lead to an increase in the concentration of these drugs in the plasma and to potentially serious or life-threatening reactions (see Contraindications).

It was shown that aprepitant induces metabolism S (-) warfarin and tolbutamide, which are metabolized by the isoenzyme CYP2C9. Simultaneous administration of fosapreptant with these or other drugs that are metabolized by isoenzyme CYP2C9 (for example, with phenytoin), can lead to a decrease in plasma concentrations of these drugs. Interaction of fosaprepitant with drugs that are substrates of the P-glycoprotein carrier, is unlikely in view of the lack of interaction of aprepitant with digoxin in oral administration in clinical studies.

Antagonist Isti 5-HT3

In clinical trials of drug interactions, it was shown that aprepitant, with 125 mg on the first day and 80 mg on the 2nd and 3rd days, does not cause clinically significant changes in the pharmacokinetics of serotonin 5T antagonists₃-receptors - ondansetron, granisetron and hydrodolasetron (active metabolite of dolasetron).

Corticosteroids

Dexamethasone: with joint admission fosaprepitanta 150 mg and dexamethasone taken orally at a dose of 8 mg on the 1 st, 2 nd and 3 rd days, the administration fosaprepitanta in the first day caused an increase AUC dexamethasone approximately 2 times on the 1 st and 2 nd days. The standard dose of dexamethasone (when administered orally) in combination with fosaprepitanom 150 mg (intravenously on the 1st day) should be reduced by approximately 50% to achieve exposure to dexamethasone similar to thatwhen administered without fosaprepitant 150 mg intravenously in the first day (see Dosage and Administration).

Methylprednisolone: with simultaneous oral administration of aprepitant at a dose of 125 mg on the first day and at a dose of 80 mg / day in the 2 nd and 3 rd days, there was an increase AUC methylprednisolone, substrate isoenzyme CYP3A4, 1.3 times the first day and 2.5 times on the third day, with intravenous methylprednisolone 125 mg on the first day and oral intake of 40 mg in the 2 nd and 3- th days.

Chemotherapy drugs

In clinical studies after Oral administration of aprepitant chemotherapy drugs whose metabolism mainly or partially occurs with the participation of the isoenzyme CYP3A4: etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan and paclitaxel. Doses of these drugs were not adjusted taking into account potential drug interactions. Care should be taken to carefully monitor the patient's condition when using chemotherapy drugs, the metabolism of which mainly or partially occurs with the participation of the isoenzyme CYP3A4. AT Post-registration studies recorded cases of neurotoxicity,

Warfarin

Aprepitant was prescribed healthy subjects who received long-term therapy with warfarin, once a dose of 125 mg orally on the first day and at a dose of 80 mg / day on the 2nd and 3rd days. Despite the absence of any influence on the AUC R (+) or S (-) warfarin on the 3rd day with oral reception aprepitanta, a decrease in the minimum concentration S (-) warfarin (substrate isoenzyme CYP2C9) by 34%, which was accompanied by a decrease prothrombin time by 14% (INR) 5 days after the end of the oral administration of aprepitant. Patients receiving long-term therapy with warfarin should be carefully treated monitor prothrombin time (INR) for 2 weeks with each cycle of chemotherapy and especially after 7-10 days after starting the application of fosaprepitant.

Tolbutamide

Aprepitant when administered orally at a dose of 125 mg on the first day and 80 mg on the 2nd and 3rd days causes a decrease AUC tolbutamide (substrate isoenzyme CYP2C9) 23% on the 4th day, 28% on the 8th day, and 15% on the 15th day, with tolbutamide in a single dose of 500 mg prescribed before the start of the three-day regimen of peroral administration of aprepitant and in the 4th and in the 8th, and in the 15th days.

Oral contraceptives With simultaneous administration of aprepitant capsules of 100 mg once a day for 14 days and an oral contraceptive containing 35 μg of ethinylestradiol and 1 mg of norethindrone, a decrease AUC ethinylestradiol by 43% and reduction AUC norethindrone by 8%.

In another study, single administration of an oral contraceptive containing ethinyl estradiol and norethindrone, appointed from days 1 to 21, was combined with simultaneous administration of aprepitant for oral administration of 125 mg on day 8 and 80 mg / day on days 9 and 10, ondansetron in a dose of 32 mg intravenously on the 8th day and dexamethasone administered orally at a dose of 12 mg on the 8th day and 8 mg / day for 9, 10, 11 days. In the study AUC ethinyl estradiol was reduced by 19% on the 10th day, and a decrease in the minimum concentration of ethinylestradiol by 64% was noted from the 9th to the 21st days. Despite the lack of influence of aprepitant for oral administration on AUC norethindrone on the 10th day, there was a decrease in the minimum concentration of norethindrone to 60% from the 9th to the 21st days.

Efficacy of hormonal contraceptives during the period of admission and within 28 days after the end of the fosaprepitant intake can be reduced.During treatment with fosaprepitanom and within 1 month after taking fosaprepitanta should use alternative or additional methods of contraception.

Midazolam

With the simultaneous administration of fosaprepitant at a dose of 150 mg intravenously and midazolam once orally 2 mg on the first day there was an increase AUCo-co midazolam approximately 1.8 times. With a similar dosing regimen, on the 4th day there was no effect on AUC. Fosaprepitant in a dose of 150 mg intravenously is a weak inhibitor of isoenzyme CYP3A4, since its use in a single dose on the first day did not lead to either inhibition or induction of the isoenzyme CYP3A4, in contrast to the results obtained on the 4th day.

Impact other medicinal preparations for pharmacokinetics of aprepitant

Aprepitant is a substrate of isoenzyme CYP3A4, as a result of which the simultaneous reception of fosaprepitant with preparations that inhibit isoenzyme activity CYP3A4, can lead to an increase in the concentration of aprepitant in the blood plasma. Therefore, it is necessary to appoint with caution fosaprepitant in combination with strong inhibitors of isoenzyme CYP3A4 (eg, with ketoconazole), but simultaneous administration of aprepitant with moderate isoenzyme inhibitors CYP3A4 (for example, with diltiazem) does not cause clinically significant changes in the concentration of aprepitant in the blood plasma.

Aprepitant is a substrate of isoenzyme CYP3A4, as a result of which simultaneous reception of fosaprepitant with drugs that are strong isoenzyme inducers CYP3A4 (for example, with rifampicin), can lead to a decrease in its concentration in the plasma and to a decrease in efficacy.

Ketoconazole In the appointment of aprepitant, once orally at a dose of 125 mg on the 5th day of a 10-day regimen of treatment with ketoconazole (400 mg / day), a potent inhibitor of the isoenzyme CYP3A4, AUC aprepitant increased approximately 5-fold, and the final half-life of aprepitant increased approximately 3-fold. It is necessary to appoint with caution fosaprepitant in combination with strong inhibitors of isoenzyme CYP3A4.

Rifampicin

In the appointment of aprepitant, once orally at a dose of 375 mg on the 9th day of the 14-day treatment regimen rifampicin, which is a strong isoenzyme inducer CYP3A4, AUC aprepitant decreased approximately 11-fold, and the final half-life of aprepitant decreased approximately 3-fold. Simultaneous reception of fosaprepitant with drugs that are strong inducers of isoenzyme CYP3A4, may lead to a decrease in plasma concentration and a decrease in efficacy.

Additional data about interaction

Diltiazem

In patients with mild and moderate arterial hypertension, infusion of 100 mg of fosapreptant for 15 minutes in combination with diltiazem in a dose of 120 mg 3 times a day resulted in an increase AUC aprepitant in 1,5 times and increase AUC diltiazem in 1,4 times.

Pharmacokinetic effects led to a small but clinically significant decrease in diastolic pressure (a decrease of 16.8 mm Hg with fosaprepitant and 10.5 mm Hg without fosaprepitant) and a small but clinically significant decrease in systolic pressure ( a reduction of 24.4 mm Hg in the appointment of fosaprepitant and 18.8 mm Hg without fosaprepitant), but did not cause clinically significant changes in heart rate, interval PR compared with the change in these indicators when taking only diltiazem.

In the same study aprepitant was administered once a day in the form of tablets in a dose comparable to 230 mg of the drug in capsules, and diltiazem in a dose of 120 mg 3 times a day for 5 days, which led to an increase AUC aprepitant in 2 times and simultaneous increase AUC diltiazem in 1,7 times. These pharmacokinetic effects did not lead to clinically significant changes in the ECG, heart rate or blood pressure compared with changes in these parameters when taking only diltiazem.

Paroxetine Simultaneous reception of aprepitant 1 time in day in the form of tablets in dose, comparable to 85 mg or 170 mg of the drug in capsules, and paroxetine at a dose of 20 mg 1 time per day resulted in a decrease AUC by about 25% and Сmах by about 20% as for aprepitant, and paroxetine.

Special instructions:

USE DURING PREGNANCY AND LACTATION

There is no data on the isolation of the drug with human breast milk.In view of the fact that many drugs are excreted in breast milk and due to the risk of side effects on the infant, the issue of stopping breastfeeding or stopping the drug should be addressed in the light of the need for the drug for the mother.

APPLICATION FOR CHILDREN

Safety and effectiveness of the drug in children have not been studied.

APPLICATION IN ELDERLY PATIENTS

According to the data obtained in clinical studies, the efficacy and safety of aprepitant in elderly patients (age> 65 years) were comparable with those in younger patients (<65 years). Dosage adjustment in elderly patients is not required

Effect on the ability to drive transp. cf. and fur:

Studies on the effect of the Emend® W / B drug on the ability to drive and work with machinery have not been carried out. However, some of the side effects associated with the use of the Emend® I / B preparation may affect the ability to drive and work with machinery. Individual reactions when using the drug may be different (see Side Effects).

Form release / dosage:

Lyophilizate for the preparation of a solution for infusions of 150 mg.

Packaging:

The lyophilizate is placed in a 10 ml glass type I (EF) bottle sealed with a rubber stopper, crimped with an aluminum cap and with a plastic lid type "flip-off".

One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

2 years. Do not use after the expiration date printed on the package.

Shelf life:

At a temperature of 2 to 8 ° C.

The prepared solution should be stored at a temperature of up to 25 ° C and used within 24 hours.

Keep out of the reach of children.

Terms of leave from pharmacies:On prescription

Registration number:LP-002076

Date of registration:24.05.2013

The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands

Manufacturer: & nbsp

DSM Pharmaceuticals, Inc. USA

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp28.10.2015

Illustrated instructions

Instructions

Emend® I / O (Emend® V / V)