Эменд® In/in

General characteristics. Structure:

Active ingredient: 257,6 mg of a fosaprepitant of a dimeglumin that is equivalent to 157,5 mg of a fosaprepitant in 1 bottle.

Excipients: dinatrium эдетат, polysorbate 80, lactose anhydrous, sodium hydroxide or Acidum hydrochloricum.

Pharmacological properties:

Pharmacodynamics. Antiemetic drug. An active metabolite of a fosaprepitant is the aprepitant - the selection high-affine antagonist of receptors of neurokinin 1 (NK1) of substance P. Isotope researches showed that selectivity of linkng of an aprepitant with NK1 receptors is at least 3000 times higher, than with other enzymes, transport proteins, ion channels and receptors, including dopamine and serotoninovy receptors which are targets of the existing drugs for prevention of nausea and vomiting at chemotherapy.

In preclinical trials it is shown that antagonists of NK1 receptors prevent the vomiting caused by chemotherapeutic drugs such as Cisplatinum at the expense of the central mechanism of action. According to the data obtained in researches by the positron emission tomography (PET), the aprepitant gets into a brain and contacts brain NK1 receptors. The central action of an aprepitant has big duration, and he inhibits both the acute, and delayed phases of the vomiting caused by Cisplatinum and also increases antiemetic activity of antagonists of 5-HT3-retseptorov (for example, an ondansetrona) and GKS (dexamethasone).

In randomized double blind placebo - a controlled research of an interval of QTc single introduction of a fosaprepitant in a dose of 200 mg did not influence the interval size QTc.

At single in introduction of a fosaprepitant in a dose of 150 mg at healthy volunteers binding of NK1 receptors of a brain made 100% in 24 h, not less than 97% - in 48 h and 75% - in 120 h. The share of the connected NK1 receptors correlated with concentration of an aprepitant in plasma.

Pharmacokinetics. After single average AUC0-∞ an aprepitant is equal to healthy volunteers in 20-minute infusion of 150 mg of a fosaprepitant 35 мкг×ч/мл and average Cmax of an aprepitant is equal to 4.01 mkg/ml.

Distribution. The Aprepitant contacts proteins of plasma more than for 95%. The average geometrical the seeming Vd in an equilibrium state at the person makes about 66 l.

Data of researches PET showed that the aprepitant gets through GEB.

Metabolism. The Fosaprepitant is quickly metabolized to an aprepitant (at in introduction within 30 min. after the end of infusion). Transformation of a fosaprepitant in an aprepitant can happen in various fabrics.

The Aprepitant is exposed to active metabolism. In plasma of the person seven metabolites of an aprepitant which have weak activity are identified. Metabolism of an aprepitant happens more by oxidation of a morpholine ring and its side chains. The researches in vitro with use of microsomes of a liver of the person show that the aprepitant is metabolized preferential CYP3A4, is insignificant - with the participation of CYP1A2 and CYP2C19, and CYP2D6, CYP2C9 and CYP2E1 do not participate in his metabolism.

All metabolites which were defined in urine to Calais and plasma in/in introductions of 100 mg [14C] - a fosaprepitant were also defined later after use [14C] - an aprepitant inside. After transformation of 245.4 mg of a fosaprepitant of a dimeglumin (150 mg of a fosaprepitant of free acid are equivalent) in an aprepitant 23.9 mg of phosphoric acid and 95.3 mg of a meglumin are released.

Removal. After single in/in introductions of 100 mg [14C] - a fosaprepitant to healthy volunteers of 57% of radioactivity also 45% — in Calais were defined in urine.

The Aprepitant is removed generally in the form of metabolites, not changed aprepitant is not removed by kidneys. Final T1/2 of an aprepitant makes from about 9 to 13 h.

Pharmacokinetics at special groups of patients. After a single dose of an aprepitant in AUC0-24ch and Cmax for an aprepitant were for 9% and 17% respectively above at women, than at men. T1/2 of an aprepitant at women was 25% shorter, than at men, and Tmax was noted approximately at the same time. This distinction was not recognized as clinically significant. Dose adjustment depending on a sex is not required.

After single use of an aprepitant inside, AUC0-24ch approximately for 27% and 31% is higher at Latin Americans in comparison with patients of Caucasian race and the Afro-Americans, respectively. Cmax for 19% and 29% is higher at Latin Americans in comparison with patients of Caucasian race and the Afro-Americans, respectively. After single oral administration of an aprepitant at patients of Asian race increase in AUC0-24ch and Cmax by 74% and 47%, respectively, in comparison with patients of Caucasian race is noted. Dose adjustment depending on race is not required.

After single use of an aprepitant inside in a dose of 125 mg in the 1st day and 80 mg/days with 2nd for the 5th days of AUC0-24ch of an aprepitant at patients of advanced age (of 65 years is also more senior) was 21% more in the 1st day and is 36% more in the 5th day, than at younger adults. At patients of advanced age of Cmax was 10% higher in the 1st day and is 24% higher in the 5th day, than at younger adults. These distinctions were not recognized as clinically significant. Dose adjustment is not required from patients of advanced age.

Use of a fosaprepitant for patients aged up to 18 years was not studied.

The Body Weight Index (BWI) does not influence pharmacokinetics of an aprepitant.

The Fosaprepitant is not metabolized in a liver, therefore, influence of a liver failure on transformation of a fosaprepitant in an aprepitant is not expected. Patients with a liver failure of easy and average degree well transferred an aprepitant at oral administration. At patients with a liver failure of easy degree (5-6 points on a scale of Chayld-Pyyu) after a single dose of an aprepitant inside in a dose of 125 mg in the 1st day and 80 mg of 1 times/days in the 2nd and 3rd days of AUC0-24ch of an aprepitant was 11% less in the 1st day and is 36% lower in the 3rd day, than at the healthy volunteers receiving drug in the same mode. At patients with a liver failure of average degree (7 — 9 points on a scale of Chayld-Pyyu) AUC0-24ch of an aprepitant was 10% more in the 1st day and is 18% more in the 3rd day, than at the healthy volunteers receiving drug in the same mode. These distinctions in AUC0-24ch were not considered clinically significant therefore dose adjustment with a liver failure of easy and average degree is not required from patients. For patients with a liver failure of heavy degree (more than 9 points on a scale of Chayld-Pyyu) clinical and pharmacokinetic data are not available.

Patients with a renal failure of heavy degree (KK less than 30 ml/min.) and the patients with an end-stage of a renal failure needing a hemodialysis received an aprepitant in a single dose 240 mg. At patients with a renal failure of heavy degree of AUC0-∞ for a total aprepitant (not connected and 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, AUC0-∞ for a total aprepitant it was lowered by 42%, and Cmax was lowered by 32%. Due to the small decrease in linkng of an aprepitant with proteins at patients with a renal failure of AUC for pharmacological active untied aprepitant at such patients considerably did not differ from that at healthy volunteers. The hemodialysis which is carried out in 4 or 48 h after administration of drug did not exert considerable impact on pharmacokinetics of an aprepitant: in dialyzate less than 0.2% of a dose were found. Dose adjustment with a renal failure of heavy degree and the patients with an end-stage of a renal failure who are on a hemodialysis is not required from patients.

Indications to use:

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

Route of administration and doses:

^{The drug Emend® In/in} (fosaprepitant) is used in the 1st day of chemotherapy in a look in/in infusion lasting from 20 up to 30 min. approximately in 30 min. prior to carrying out chemotherapy. ^{The drug Emend® In/in} should be used in a combination with corticosteroids and _{5-HT3-antagonistami}.

The recommended dosing mode for the prevention of nausea and vomiting connected using vysokoemetogenny antineoplastic chemotherapy:

* Dexamethasone should be accepted in 30 min. prior to the beginning of chemotherapy in the 1st day and in the morning in the 2nd, 3rd and 4th days. Dexamethasone should be accepted in the evening in the 3rd and 4th days. The dose of dexamethasone is specified taking into account medicinal interaction.

The recommended dosing mode for the prevention of nausea and vomiting connected using umerennoemetogenny antineoplastic chemotherapy:

* Dexamethasone should be accepted in 30 min. prior to chemotherapy in the 1st day. The dose of dexamethasone was chosen taking into account medicinal interaction.

Dose adjustment depending on age, sex is not required, to race, and also the body weight index (BWI).

Preparation of solution for infusion ^{of the drug Emend® In/in} of 150 mg:

1. Contents of a bottle it is necessary to dissolve in 5 ml 0.9% of solution of sodium of chloride (in order to avoid foaming solution should be directed on a bottle wall). It is necessary to rotate a bottle carefully (not to stir up!).

2. The received solution needs to be added to a bag for infusion or the bottle containing 145 ml of 0.9% of solution of sodium of chloride for obtaining the final volume of 150 ml. It is necessary to mix contents of a bag or a bottle carefully. Before introduction solution for infusion needs to be examined on existence of a deposit or discoloration. The prepared solution should be stored at a temperature up to 25 °C and to use during 24 h.

All medicines for parenteral administration should be examined carefully before use regarding existence of mechanical inclusions and change of coloring in all cases when it properties of solution and material of a container allow.

Incompatibility. The Fosaprepitant is incompatible with the solutions containing bivalent cations (for example, Sa, Mg), including with Hartman's solution and Ringer's solution with a lactate. ^{The drug Emend® In/in} cannot be parted or mixed with solutions, physical and chemical compatibility with which was not proved.

Features of use:

Use at pregnancy and feeding by a breast. Adequate and strictly controlled clinical trials on use of drug for pregnant women and women in the period of a lactation it was not carried out. Use of drug at pregnancy is possible only in that case when the estimated advantage for mother surpasses potential risk for a fruit.

Data about release of drug with breast milk are absent. In view of the fact that many medicines are emitted with breast milk and in connection with risk of undesirable influence on the baby, the question of the termination of breastfeeding or phase-out of drug should be solved taking into account need of drug for mother.

Use at abnormal liver functions. Use of drug at a liver failure of heavy degree is contraindicated (more than 9 points on a scale of Chayld-Pyyu).

Use at renal failures. Dose adjustment with a renal failure of heavy degree and the patients with an end-stage of a renal failure who are on a hemodialysis is not required from patients.

Use for children. Use of drug for patients age up to 18 years is contraindicated (safety and efficiency of use were not studied).

Use for elderly patients. According to the data obtained in клиничесикх researches, efficiency and safety of an aprepitant at patients of advanced age (≥65 years) were comparable to those at younger patients (<65 years). Dose adjustment is not required from patients of advanced age.

Special instructions. At use of the drug Emend® In/in in a combination with other antiemetic drugs it is necessary to follow the application instruction of these drugs.

According to the data obtained in clinical trials, efficiency and safety of an aprepitant at patients of advanced age (≥65 years) were comparable to those at younger patients (<65 years). Dose adjustment is not required from patients of advanced age.

Use in pediatrics. Safety and efficiency of use of drug for children were not studied.

Influence on ability to driving of motor transport and to control of mechanisms. Researches about influence of the drug Emend® In/in on ability to drive the car and to work with mechanisms were not conducted. However some side effects connected using the drug Emend® In/in can affect ability to control of motor transport and performance of other types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

In view of the fact that the fosaprepitant is metabolized to an aprepitant, at use of drug the same undesirable reactions, as for an aprepitant are possible.

Aprepitant for use inside. The most often met undesirable phenomena connected with vysokoemeteogenny chemotherapy, at the patients receiving an aprepitant in the three-day mode and, than at standard therapy, were observed with a bigger frequency: hiccups (4.6%), increase in activity of ALT (2.8%), dyspepsia (2.6%), lock (2.4%), headache (2%) and loss of appetite (2%). The most often met undesirable phenomenon connected with umerennoemeteogenny chemotherapy, the patients receiving an aprepitant, and noted with a bigger frequency, than at standard therapy, had a fatigue (1.4%).

In the integrated analysis of researches of vysokoemetogenny and umerennoemetogenny chemotherapy at the patients receiving treatment by an aprepitant in the three-day mode the following connected using drug the undesirable phenomena and with a bigger frequency was observed, than at standard therapy.

Frequency was defined as follows: often (> 1/100, <1/10), infrequently (≥1/1000, <1/100), it is rare (≥1/10 000, <1/1000).

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

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

Mental disturbances: infrequently - uneasiness; seldom - euphoria, a disorientation.

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

From an organ of sight: seldom - conjunctivitis.

From an acoustic organ and labyrinth disturbances: seldom - a sonitus.

From cardiovascular system: infrequently - a cardiopalmus, pristupoobrazny feelings of heat (inflows); seldom - bradycardia, cardiovascular disturbances.

From respiratory system: often - a hiccups; seldom - a pharyngalgia, sneezing, cough, a syndrome of post-nasal flowing, 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 - a firm chair, a ruptured ulcer of a duodenum, neytropenichesky colitis, stomatitis, abdominal distention.

From skin and hypodermic fabrics: 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.

The general frustration and disturbance in an injection site: often - fatigue, a loss of appetite; infrequently - weakness, discomfort; seldom - a polydipsia, hypostases, a sensation of discomfort in a thorax, gait disturbance.

Laboratory and tool data: often - increase in activity of ALT; infrequently - increase in activity of ACT, ShchF; seldom - increase in a diuresis, existence of erythrocytes in urine, a hyponatremia, a body degrowth, a glucosuria, reduction of number of neutrophils.

The profile of the undesirable phenomena when carrying out 6 cycles of chemotherapy in researches of vysokoemetogenny and umerennoemetogenny chemotherapy using an aprepitant was comparable to that during the first cycle of chemotherapy.

In other research using an aprepitant for the prevention of nausea and vomiting induced by chemotherapy the message on the serious undesirable phenomenon - Stephens-Johnson's syndrome was received.

Fosaprepitant for in/in introductions. During controlled clinical trial at the patients receiving vysokoemetogenny chemotherapy, profiles of safety of the drug Emend® In/in (fosaprepitant) appointed in the 1st day were comparable to those when carrying out researches of use of an aprepitant inside in the three-day mode.

Further the additional, clinically significant, connected using a fosaprepitant in a dose 150 mg by-effects, and not noted in the clinical trials described above using an aprepitant inside are presented (the three-day mode).

General frustration and disturbances together introductions: infrequently - an erythema, an itch, pain in an injection site; seldom - consolidation in an injection site.

From skin and hypodermic fabrics: infrequently - an erythema.

From cardiovascular system: infrequently - increase in the ABP, pristupoobrazny feelings of heat (inflows), thrombophlebitises (preferential, thrombophlebitises in an injection site).

Other researches. Single use of the drug Emend® (aprepitant) in a dose of 40 mg for prevention of postoperative nausea and vomiting at the patients (who are not receiving chemotherapy) after carrying out the general anesthesia was studied. In these researches the following side reactions which number was more, than at comparison drug use (ондансетрон) were observed: increase in activity of ALT, pain in an upper part of a stomach, atypical noise in intestines, a dysarthtia, диспноэ, a hypesthesia, sleeplessness, a miosis, nausea, sensitivity disturbances, the discomfort in intestines, decrease in visual acuity, goose breathing (got hoarse).

Messages on 2 serious undesirable phenomena when studying use of an aprepitant in higher doses for prevention of postoperative nausea and vomiting were received — 1 case of a lock and 1 case of partial intestinal obstruction.

One message on a Quincke's disease and urticaria was received as the serious undesirable phenomenon at a research of use of an aprepitant not for prevention by the postoperative or caused chemotherapy of nausea and vomiting.

Data of post-registration researches. During the post-registration period messages on the side effects given below were received. 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 using drug.

From skin and hypodermic fabrics: an itch, rash, urticaria, it is rare - Stephens-Johnson's syndrome.

From immune system: hypersensitivity reactions, including anaphylactic reactions.

Messages on allergic reactions of immediate type, such as reddening, an erythema and диспноэ which arose during infusion of a fosaprepitant were received.

Interaction with other medicines:

Medicinal interaction after use of a fosaprepitant most possibly happens to drugs which interact with an aprepitant. Further information is obtained according to the researches executed with an aprepitant for intake and researches of the combined use of a fosaprepitant together with dexamethasone, midazolam or diltiazem.

The Aprepitant is substrate, weak or moderate inhibitor and the inductor CYP3A4. The Aprepitant is also the inductor CYP2C9. At single use the drug Emend® In/in of 150 mg is weak CYP3A4 inhibitor and does not cause induction of CYP3A4. It is supposed that the drug Emend® In/in of 150 mg at in introduction will cause smaller or similar induction of CYP2C9 in comparison with an aprepitant for intake.

Influence of a fosaprepitanta/aprepitant on pharmacokinetics of other medicines. In view of the fact that the aprepitant is weak or moderate CYP3A4 inhibitor, and the fosaprepitant is weak CYP3A4 inhibitor, at simultaneous use of medicines which metabolism happens with the participation of CYP3A4, their concentration in a blood plasma can increase.

Fosaprepitant it is not necessary to apply along with Pimozidum, terfenadiny, astemizoly or tsizapridy. CYP3A4 inhibition under the influence of an aprepitant can lead to increase in concentration of these drugs in plasma and to potentially serious or life-threatening reactions.

It was established that the aprepitant induces metabolism of S (-) of warfarin and Tolbutamidum which are metabolized by CYP2C9. Simultaneous use of a fosaprepitant with these or other drugs which are also metabolized with the participation of CYP2C9 (for example, with Phenytoinum) can lead to decrease in concentration in plasma of these drugs.

Interaction of a fosaprepitant with the drugs which are R-glycoprotein carrier substrates is improbable in view of the fact that in clinical trials lack of interaction of an aprepitant with digoxin at intake was noted.

Antagonists of serotoninovy 5-HT3-retseptorov. During clinical trials of medicinal interaction it was established that the aprepitant at use in a dose of 125 mg in the 1st day and 80 mg in the 2nd and 3rd days does not cause clinically significant changes of pharmacokinetics of antagonists of serotoninovy 5-HT3-retseptorov — an ondansetron, a granisetron and a gidrodolasetron (an active metabolite of a dolasetron).

Corticosteroids. Dexamethasone: at simultaneous use of a fosaprepitant in a dose of 150 mg and dexamethasone for intake in a dose of 8 mg in the 1st, 2nd and 3rd days, introduction of a fosaprepitant in the 1st day caused increase in AUC dexamethasone approximately twice in the 1st and 2nd days. The standard dose of dexamethasone (at its oral administration) in combination with a fosaprepitant of 150 mg (in/in in the 1st day) should be lowered approximately by 50% for achievement of exposure of dexamethasone similar that at appointment without fosaprepitant of 150 mg in/in in the 1st day.

Methylprednisolonum: at simultaneous use of an aprepitant for intake in a dose of 125 mg in the 1st day and in a dose of 80 mg/days in the 2nd and 3rd days increase in AUC of Methylprednisolonum, CYP3A4 substrate, by 1.3 times in the 1st day and by 2.5 times in the 3rd day was noted, at in introduction of Methylprednisolonum in a dose of 125 mg in the 1st day and at oral administration in a dose of 40 mg in the 2nd and 3rd days.

Chemotherapeutic drugs. In clinical trials after reception of an aprepitant chemotherapeutic drugs which metabolism mainly or partially happens with the participation of CYP3A4 were inside appointed: этопозид, винорелбин, dotsetakset, ифосфамид, cyclophosphamide, иринотекан and paklitakset. Doses of the specified drugs were not adjusted taking into account potential medicinal interaction. It is necessary to be careful and to carefully control a condition of the patient at use of chemotherapeutic drugs which metabolism mainly or partially happens with the participation of CYP3A4. In post-registration researches neurotoxicity cases as possible side effect of an ifosfamid, primenyamy along with an aprepitant were recorded.

Dotsetaksel: in a separate research of pharmacokinetics at oral administration of an aprepitant (for the prevention of nausea and vomiting induced by chemotherapy) any influence on pharmacokinetics of a dotsetaksel was not noted.

Vinorelbin: in a separate research of pharmacokinetics at oral administration of an aprepitant (for the prevention of nausea and vomiting induced by chemotherapy) any influence on pharmacokinetics of a vinorelbin was not noted.

Warfarin. The Aprepitant was appointed to the healthy volunteers receiving long therapy by warfarin, once in a dose of 125 mg orally in the 1st day and in a dose of 80 mg/days in the 2nd and 3rd days. Despite the lack of any influence on AUC R (+) or S (-) of warfarin in the 3rd day at oral administration of an aprepitant, was noted reduction of the minimum concentration of S (-) of warfarin (CYP2C9 substrate) for 34% which was followed by reduction of a prothrombin time by 14% (MHO) in 5 days after the end of oral administration of an aprepitant. At the patients receiving long therapy by warfarin it is necessary to control carefully a prothrombin time (MHO) within 2 weeks at each cycle of chemotherapy and especially in 7-10 days after the beginning of use of a fosaprepitant.

Tolbutamidum. The Aprepitant at use inside in a dose of 125 mg in the 1st day and 80 mg in the 2nd and 3rd days causes reduction of AUC of Tolbutamidum (CYP2C9 substrate) for 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 three-day mode of oral administration of an aprepitant both in the 4th, and in the 8th, and in the 15th by days.

Oral contraceptives. At simultaneous use of an aprepitant in capsules on 100 mg of 1 times/days within 14 days and the oral contraceptive containing 35 mkg of ethinylestradiol and 1 mg of norethindrone reduction of AUC ethinylestradiol by 43% and reduction of AUC norethindrone by 8% was noted. In other research use of the oral contraceptive containing ethinylestradiol and norethindrone, appointed with 1st on the 21st days was combined using an aprepitant for intake according to the scheme of 125 mg for the 8th day and 80 mg/days for the 9th and 10th days, an ondansetron - in/in in a dose of 32 mg for the 8th day and dexamethasone for intake in a dose of 12 mg for the 8th day and 8 mg/days for the 9th, 10th, 11th days. In the research AUC of ethinylestradiol decreased by 19% for the 10th day, and decrease in the minimum concentration of ethinylestradiol by 64% with 9th on the 21st was noted days. Despite the lack of influence of an aprepitant for intake on AUC norethindrone for the 10th day, decrease in the minimum concentration of norethindrone to 60% with 9th on the 21st was noted days. Efficiency of hormonal contraceptives during use and within 28 days after the end of reception of a fosaprepitant can be reduced. During treatment by a fosaprepitant and within 1 month after the end of use of a fosaprepitant it is necessary to apply alternative or additional methods of contraception.

Midazolam. At simultaneous use of a fosaprepitant in/in in a dose of 150 mg and midazolam once orally in a dose of 2 mg in the 1st day increase in AUC0-∞ midazolam approximately by 1.8 times was observed. At the similar mode of dosing in the 4th day there was no influence on AUC. The Fosaprepitant for in/in uses in a dose of 150 mg is weak CYP3A4 inhibitor since use once in a single dose in the 1st day did not lead it neither to inhibition, nor to induction of CYP3A4, unlike the results received in the 4th day.

Influence of other medicines on pharmacokinetics of an aprepitant. The Aprepitant is CYP3A4 substrate owing to what simultaneous use of a fosaprepitant with drugs which inhibit activity of CYP3A4 can lead to increase in concentration of an aprepitant in a blood plasma. Therefore, it is necessary to appoint with care a fosaprepitant in a combination with strong CYP3A4 inhibitors (for example, with ketokonazoly), but simultaneous use of an aprepitant with moderate CYP3A4 inhibitors (for example, with diltiazem) does not cause clinically significant changes of concentration of an aprepitant in a blood plasma. The Aprepitant is CYP3A4 substrate owing to what simultaneous use of a fosaprepitant with drugs which are the strong inductors CYP3A4 (for example, with rifampicin) can lead to reduction of its concentration in plasma and to decrease in efficiency.

Ketokonazol. At use of an aprepitant inside once in a dose of 125 mg in the 5th day of the 10-day scheme of treatment ketokonazoly (400 mg/days), the being strong CYP3A4, AUC inhibitor of an aprepitant increased approximately by 5 times, and final T1/2 of an aprepitant increased approximately by 3 times. It is necessary to appoint with care a fosaprepitant in a combination with strong CYP3A4 inhibitors.

Rifampicin. At purpose of an aprepitant inside once in a dose of 375 mg in the 9th day of the 14-day scheme of treatment by the rifampicin which is the strong inductor CYP3A4, AUC of an aprepitant decreased approximately by 11 times, and final T1/2 of an aprepitant decreased approximately by 3 times. Simultaneous use of a fosaprepitant with drugs which are the strong inductors CYP3A4 can lead to reduction of concentration in plasma and to decrease in efficiency.

Additional data on interaction. Diltiazem. At patients with slight and moderate arterial hypertension infusion of a fosaprepitant in a dose of 100 mg within 15 min. in a combination with diltiazem in a dose of 120 mg of 3 times/days led to increase in AUC of an aprepitant by 1.5 times and to increase in AUC diltiazem by 1.4 times. Pharmacokinetic effects led to small, but clinically significant decrease in the diastolic ABP (decrease by 16.8 mm hg at use of a fosaprepitant and on 10.5 mm hg without fosaprepitant) and to small, but clinically significant decrease in the systolic ABP (decrease by 24.4 mm hg at purpose of a fosaprepitant and to 18.8 mm hg without fosaprepitant), but did not cause clinically significant changes of ChSS, PR interval in comparison with change of these indicators at use only of diltiazem. In the same research the aprepitant was appointed 1 times/days in the form of tablets in the dose comparable from 230 mg of drug in capsules, and diltiazem in a dose of 120 mg of 3 times/days within 5 days that 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 use only diltiazem.

Paroksetin. Simultaneous 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 liver failure of heavy degree (more than 9 points on a scale of Chayld-Pyyu);

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

— pregnancy;

— children's age;

— hypersensitivity to a fosaprepitant, an aprepitant, polysorbate-80 or any other component of drug.

With care. In view of the fact that the fosaprepitant is quickly metabolized in an aprepitant (is weak or moderate inhibitor of an isoenzyme CYP3A4), it should be applied with care at the patients who are at the same time receiving medicines which metaboliziruyetsya mainly with the participation of CYP3A4 isoenzyme; some chemotherapeutic drugs are metabolized with the participation of CYP3A4 isoenzyme. The weak inhibiting effect of a fosaprepitant in a dose of 150 mg on an isoenzyme of CYP3A4 can lead to increase in concentration of these medicines which are at the same time accepted inside.

There are single data on allergic reactions of immediate type, such as reddening, an erythema and диспноэ which arose during infusion of a fosaprepitant and disappeared usually after the termination of infusion and performing the corresponding therapy. It is not recommended to resume drug infusion to patients at whom similar allergic reactions were noted.

Co-administration of a fosaprepitant orally with warfarin can lead to clinically significant decrease in a prothrombin time (MNO). At the patients receiving long therapy by warfarin it is necessary to control carefully MHO within 2 weeks, especially in 7-10 days after the beginning of reception of a fosaprepitant at each cycle of chemotherapy.

Efficiency of hormonal contraceptives can decrease in time and within 28 days after reception of a fosaprepitant. During treatment by a fosaprepitant and within 1 month after reception of a fosaprepitant it is necessary to use alternative or additional methods of contraception.

Overdose:

At single introduction to volunteers of a fosaprepitant in a dose to 200 mg in/in or reception of an aprepitant inside in a dose to 600 mg good tolerance was noted. At 3 of 33 volunteers receiving a fosaprepitant in a dose of 200 mg fibrinferments in the place of an injection of weak degree of manifestation were noted.

During the researches which are not connected with studying induced by chemotherapy of nausea and vomiting, good tolerance of an aprepitant at appointment in a dose of 375 mg of 1 times/days within 42 days was noted. At 33 oncological patients good tolerance of an aprepitant at single use in a dose of 375 mg in the 1st day and 250 mg of 1 times/days was noted with 2nd for the 5th days.

It was reported about emergence of drowsiness and a headache at 1 patient who accepted 1440 mg of an aprepitant.

Treatment: special information on elimination of symptoms of overdose by the drug Emend® In/in is absent; drug should be cancelled and provided the general maintenance therapy and control of a condition of the patient. Due to the antiemetic action of an aprepitant the medicines causing vomiting can be inefficient. At overdose of an aprepitant the hemodialysis is inefficient.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature from 2 °C to 8 °C. A period of validity - 2 years. The prepared solution should be stored at a temperature up to 25 °C and to use during 24 h.

Issue conditions:

According to the recipe

Packaging:

Bottles from glass like I volume of 10 ml (1) - packs cardboard.