Emend intravenous lyophilizate 150mg vials, 1pc

Composition

Active ingredient:  257.6 mg of fosaprepitant dimeglumin, which is equivalent to 157.5 mg of fosaprepitant in 1 vial.

Auxiliary substances:  disodium edetate-19.7 mg, polysorbate 80-78.8 mg, lactose anhydrous-393.8 mg, sodium hydroxide or hydrochloric acid-up to pH 9.2 mg

Pharmacological action

An antiemetic drug. The active metabolite of fosaprepitant is aprepitant, a selective high – affinity neurokinin 1 (NK1) receptor antagonist of substance P. Isotope studies have shown that the selectivity of binding of aprepitant to NK1 receptors is at least 3000 times higher than with other enzymes, transport proteins, ion channels and receptors, including dopamine and serotonin receptors, which are targets of existing drugs to prevent nausea and vomiting in the presence of chemotherapy.

In preclinical studies, NK1 receptor antagonists have been shown to prevent vomiting caused by chemotherapeutic drugs such as cisplatin due to a central mechanism of action. According to positron emission tomography (PET) studies, aprepitant penetrates the brain and binds to the brain’s NK1 receptors. The central action 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 corticosteroids (dexamethasone).

In a randomized, double-blind, placebo-controlled QTc interval study, a single 200 mg dose of fosaprepitant did not affect the QTc interval value.

With a single intravenous use of fosaprepitant at a dose of 150 mg in healthy volunteers, the binding of NK1 receptors in the brain was 100% after 24 hours, at least 97% after 48 hours, and 75% after 120 hours. The proportion of bound NK1 receptors correlated with the plasma concentration of aprepitant.

Indications

To prevent acute and delayed nausea and vomiting caused by highly or moderately emetogenic anticancer drugs (in combination with other antiemetic drugs).

Use during pregnancy and lactation

Adequate and strictly controlled clinical studies on the use of the drug in pregnant women and women during lactation have not been conducted. The use of the drug during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

There are no data on the excretion of the drug in breast milk. Due to the fact that many medications are excreted in breast milk and due to the risk of undesirable effects on the infant, the question of stopping breastfeeding or stopping the use of the drug should be decided taking into account the need for the drug for the mother.

Contraindications

• severe hepatic insufficiency (more than 9 points on the Child-Pugh scale);
• concomitant use with pimozide, terfenadine, astemizole and cisapride;
• pregnancy;
• childhood;
• hypersensitivity to fosaprepitant, aprepitant, polysorbate-80 or any other component of the drug.

With caution. Due to the fact that fosaprepitant is rapidly metabolized to aprepitant (it is a weak or moderate inhibitor of the CYP3A4 isoenzyme), it should be used with caution in patients receiving concomitant medications that are mainly metabolized with the participation of the CYP3A4 isoenzyme; some chemotherapeutic drugs are metabolized with the participation of the CYP3A4 isoenzyme. The weak inhibitory effect of fosaprepitant at a dose of 150 mg on the CYP3A4 isoenzyme may lead to an increase in the concentrations of these concomitantly ingested drugs.

There are isolated reports of immediate allergic reactions, such as redness, erythema and dyspnoea, that occurred during the infusion of fosaprepitant and usually disappeared after the infusion was stopped and appropriate therapy was performed. It is not recommended to resume the infusion of the drug in patients who have experienced similar allergic reactions.

Concomitant oral use of fosaprepitant with warfarin may result in a clinically significant reduction in prothrombin time (INR). In patients receiving long-term warfarin therapy, MHO should be carefully monitored for 2 weeks, especially 7-10 days after starting fosaprepitant with each cycle of chemotherapy.

The effectiveness of hormonal contraceptives may decrease during and within 28 days after taking fosaprepitant. During treatment with fosaprepitant and for 1 month after taking fosaprepitant, alternative or additional methods of contraception should be used.

Side effects

Due to the fact that fosaprepitant is metabolized to aprepitant, the same adverse reactions as for aprepitant are possible when using the drug.

Aprepitant for oral use

The most common adverse events associated with high-emeteogenic chemotherapy in patients receiving aprepitant on a three-day regimen and observed with a higher frequency than with standard therapy were: hiccups (4.6%), increased ALT activity (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2%) and decreased appetite (2%). The most common adverse event associated with moderate-emeteogenic chemotherapy in patients treated with aprepitant, and observed with a higher frequency than with standard therapy, was fatigue (1.4%).

In a combined analysis of studies of high-emetogenic and moderate-emetogenic chemotherapy, the following drug-related adverse events were observed in patients treated with aprepitant on a three-day regimen, and with a higher frequency than with standard therapy.

The frequency was determined as follows: often (>1/100, ><1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10 000,

Infectious and parasitic diseases: rarely-candidiasis, staphylococcal infection.

From the hematopoietic system: infrequently-anemia, febrile neutropenia.

Mental disorders: infrequently-anxiety; rarely-euphoria, disorientation.

Nervous system disorders: infrequently – dizziness, drowsiness; rarely-cognitive impairment, lethargy, perversion of taste.

From the side of the visual organ: rarely-conjunctivitis.

Hearing disorders and labyrinth disorders: rarely-tinnitus.

From the cardiovascular system: infrequently-rapid heartbeat, paroxysmal sensations of heat (hot flashes); rarely – bradycardia, cardiovascular disorders.

Respiratory system disorders: often – hiccups; rarely-sore throat, sneezing, coughing, postnasal congestion syndrome, pharyngeal irritation.

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

Skin and subcutaneous tissue disorders: infrequently-rash, acne; rarely-photosensitivity, increased sweating, seborrhea, increased skin oiliness, itchy rash.

Musculoskeletal disorders: rarely-muscle spasms, muscle weakness.

From the urinary system: infrequently-dysuria; rarely-pollakiuria.

General disorders and disorders at the injection site: often-fatigue, decreased appetite; infrequently-weakness, discomfort; rarely-polydipsia, edema, chest discomfort, gait disorder.

Laboratory and instrumental data: often-increased ALT activity; infrequently-increased ACT activity, alkaline phosphatase; rarely-increased diuresis, presence of red blood cells in the urine, hyponatremia, weight loss, glucosuria, decrease in the number of neutrophils.

The adverse event profile during 6 cycles of chemotherapy in studies of high-emetogenic and moderate-emetogenic chemotherapy with aprepitant was comparable to that during the first cycle of chemotherapy.

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

Fosaprepitant for intravenous use

In a controlled clinical trial in patients receiving highly emetogenic chemotherapy, the safety profiles of Emend® IV (fosaprepitant) administered on day 1 were comparable to those in studies of oral use of aprepitant on a three-day regimen.

The following are additional clinically significant side effects associated with the use of fosaprepitant at a dose of 150 mg, and not noted in the clinical studies described above with the use of aprepitant inside (three-day regimen).

General disorders and disorders of combined use: infrequently-erythema, pruritus, pain at the injection site; rarely-compaction at the injection site.

Skin and subcutaneous tissue disorders: infrequently-erythema.

From the cardiovascular system: infrequently-increased blood pressure, paroxysmal sensations of heat (hot flashes), thrombophlebitis (mainly thrombophlebitis at the injection site).

Other studies

A single 40 mg dose of Emend® (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 higher than with the use of the reference drug (ondansetron): increased ALT activity, upper abdominal pain, atypical intestinal murmur, dysarthria, dyspnoea, hypesthesia, insomnia, miosis, nausea, sensitivity disorders, intestinal discomfort, decreased visual acuity, wheezing (wheezing).

Two serious adverse events were reported when studying the use of aprepitant in higher doses to prevent postoperative nausea and vomiting — 1 case of constipation and 1 case of partial intestinal obstruction.

One report of angioedema and urticaria was received as a serious adverse event in a study using aprepitant not to prevent postoperative or chemotherapy-induced nausea and vomiting.

Data from post-marketing studies

In the post-marketing period, the following side effects were reported. Due to the fact that reports were received from volunteers from population groups with an undetermined number, it is impossible to reliably determine the expected frequency or causal relationship with the use of the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely-Stevens-Johnson syndrome.

From the immune system: hypersensitivity reactions, including anaphylactic reactions.

Immediate allergic reactions, such as redness, erythema, and dyspnoea, have been reported during fosaprepitant infusion.

Interaction

Drug interactions after the use of fosaprepitant are most likely to occur with drugs that interact with aprepitant. Further information is obtained from studies performed with aprepitant for oral use and studies of the combined use of fosaprepitant together with dexamethasone, midazolam or diltiazem.

Aprepitant is a substrate, weak or moderate inhibitor and inducer of CYP3A4. Aprepitant is also a CYP2C9 inducer. With a single dose, Emend® IV 150 mg is a weak inhibitor of CYP3A4 and does not cause induction of CYP3A4. It is expected that the drug Emend® IV 150 mg when administered intravenously will cause less or similar induction of CYP2C9 compared to aprepitant for oral use.

Effect of fosaprepitant/aprepitant on the pharmacokinetics of other medicinal products

Due to the fact that aprepitant is a weak or moderate inhibitor of CYP3A4, and fosaprepitant is a weak inhibitor of CYP3A4, with the simultaneous use of drugs that are metabolized with the participation of CYP3A4, their plasma concentrations may increase.

Fosaprepitant should not be used concomitantly with pimozide, terfenadine, astemizole or cisapride. Inhibition of CYP3A4 under the influence of aprepitant can lead to an increase in the concentration of these drugs in plasma and to potentially serious or life-threatening reactions.

Aprepitant was found to induce the metabolism of S ( -) warfarin and tolbutamide, which are metabolized by CYP2C9. Concomitant use of fosaprepitant with these or other drugs that are also metabolized with the participation of CYP2C9 (for example, with phenytoin) may lead to a decrease in the plasma concentration of these drugs.

The interaction of fosaprepitant with drugs that are substrates of the P-glycoprotein transporter is unlikely due to the fact that in clinical studies there was no interaction of aprepitant with digoxin when taken orally.

Serotonin 5-HT3 receptor antagonists

In clinical drug interaction studies, it was found that aprepitant administered at a dose of 125 mg on day 1 and 80 mg on days 2 and 3 does not cause clinically significant changes in the pharmacokinetics of serotonin 5-HT3 receptor antagonists-ondansetron, granisetron and hydrodolasetron (the active metabolite of dolasetron).

Corticosteroids

Dexamethasone: concomitant use of fosaprepitant 150 mg and oral dexamethasone 8 mg on days 1,2, and 3 resulted in an approximately 2-fold increase in dexamethasone AUC on days 1 and 2. The standard dose of dexamethasone (when administered orally) in combination with fosaprepitant 150 mg (iv on day 1) should be reduced by approximately 50% to achieve a dexamethasone exposure similar to that given without fosaprepitant 150 mg iv on day 1.

Methylprednisolone: with simultaneous use of aprepitant for oral use at a dose of 125 mg on day 1 and at a dose of 80 mg/day on days 2 and 3, an increase in the AUC of methylprednisolone, a CYP3A4 substrate, was observed by 1.3 times on day 1 and 2.5 times on day 3, with intravenous use of methylprednisolone at a dose of 125 mg on day 1 and with oral use at a dose of 40 mg on days 2 and 3-y days.

Chemotherapeutic drugs

In clinical studies following oral use of aprepitant, chemotherapeutic agents primarily or partially metabolized by CYP3A4 were prescribed: etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan, and paclitaxel. The doses of these drugs were not adjusted for potential drug interactions. Caution should be exercised and the patient’s condition carefully monitored when using chemotherapeutic drugs, the metabolism of which mainly or partially occurs with the participation of CYP3A4. In post-marketing studies, cases of neurotoxicity were reported as a possible side effect of ifosfamide used simultaneously with aprepitant.

Docetaxel: in a separate study of the pharmacokinetics of oral aprepitant (to prevent chemotherapy-induced nausea and vomiting) no effect on the pharmacokinetics of docetaxel was observed.

Vinorelbine: in a separate study of the pharmacokinetics of oral aprepitant (to prevent chemotherapy-induced nausea and vomiting) no effect on the pharmacokinetics of vinorelbine was observed.

Warfarin

Aprepitant was administered to healthy volunteers receiving long-term warfarin therapy, once at a dose of 125 mg orally on day 1 and at a dose of 80 mg / day on days 2 and 3. Despite the absence of any effect on the AUC of R(+) or S(-) warfarin on day 3 with oral use of aprepitant, there was a 34% decrease in the minimum concentration of S (-) warfarin (a CYP2C9 substrate), which was accompanied by a 14% decrease in prothrombin time (MHO) 5 days after the end of oral use of aprepitant. In patients receiving long-term warfarin therapy, prothrombin time (MHO) should be carefully monitored for 2 weeks with each cycle of chemotherapy, and especially 7-10 days after the start of fosaprepitant use.

Tolbutamide

Aprepitant, when administered orally at a dose of 125 mg on day 1 and 80 mg on days 2 and 3, causes a decrease in the AUC of tolbutamide (a CYP2C9 substrate) by 23% on day 4,28% on day 8, and 15% on day 15, while tolbutamide in a single dose of 500 mg was prescribed before the start of the three-day oral regimen of aprepitant on days 4,8, and 15.

Oral contraceptives

With the simultaneous use of aprepitant in capsules of 100 mg 1 time/day for 14 days and an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, a decrease in the AUC of ethinyl estradiol by 43% and a decrease in the AUC of norethindrone by 8% was noted. In another study, the use of an oral contraceptive containing ethinyl estradiol and norethindrone, prescribed from days 1 to 21, was combined with the use of aprepitant for oral use 125 mg on day 8 and 80 mg/day on days 9 and 10, ondansetron-iv at a dose of 32 mg on day 8 and dexamethasone for oral use 12 mg on day 8 and 8 mg/day on day 9,10th,11th days. In the study, the AUC of ethinyl estradiol decreased by 19% on day 10, and there was a 64% decrease in the minimum concentration of ethinyl estradiol from days 9 to 21. Despite the absence of the effect of aprepitant for oral use on the AUC of norethindrone on day 10, there was a decrease in the minimum concentration of norethindrone to 60% from days 9 to 21. The effectiveness of hormonal contraceptives during the period of use and within 28 days after the end of taking fosaprepitant may be reduced. During treatment with fosaprepitant and for 1 month after the end of fosaprepitant use, alternative or additional methods of contraception should be used.

Midazolam

When fosaprepitant was co-administered intravenously at a dose of 150 mg and midazolam once orally at a dose of 2 mg on day 1, an increase in AUC0-∞of midazolam by approximately 1.8 times was observed. With a similar dosage regimen on day 4, there was no effect on AUC. Fosaprepitant for intravenous use at a dose of 150 mg is a weak inhibitor of CYP3A4, since its use once in a single dose on day 1 did not lead to either inhibition or induction of CYP3A4, in contrast to the results obtained on day 4.

Effect of other drugs on the pharmacokinetics of aprepitant

Aprepitant is a substrate of CYP3A4, so the simultaneous use of fosaprepitant with drugs that inhibit the activity of CYP3A4 may lead to an increase in the concentration of aprepitant in blood plasma.Therefore, fosaprepitant should be used with caution in combination with strong CYP3A4 inhibitors (for example, ketoconazole), but concomitant use of aprepitant with moderate CYP3A4 inhibitors (for example, diltiazem) does not cause clinically significant changes in the concentration of aprepitant in blood plasma. Aprepitant is a CYP3A4 substrate, so concomitant use of fosaprepitant with drugs that are strong inducers of CYP3A4 (for example, rifampicin) may lead to a decrease in its plasma concentration and to a decrease in effectiveness.

Ketoconazole

When aprepitant was administered orally once at a dose of 125 mg on day 5 of a 10-day treatment regimen with ketoconazole (400 mg / day), which is a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold, and the final T 1/2 of aprepitant increased approximately 3-fold. Caution should be exercised when using fosaprepitant in combination with strong CYP3A4 inhibitors.

Rifampicin

When aprepitant was administered orally once at a dose of 375 mg on day 9 of a 14-day treatment regimen with rifampicin, which is a strong inducer of CYP3A4, the AUC of aprepitant decreased approximately 11-fold, and the final T 1/2 of aprepitant decreased approximately 3-fold. Concomitant use of fosaprepitant with drugs that are strong inducers of CYP3A4 may lead to a decrease in plasma concentrations and a decrease in efficacy.

Additional data on the interaction of

Diltiazem

In patients with mild to moderate arterial hypertension, infusion of fosaprepitant at a dose of 100 mg for 15 minutes in combination with diltiazem at a dose of 120 mg 3 times/day led to an increase in the AUC of aprepitant by 1.5 times and an increase in the AUC of diltiazem by 1.4 times. Pharmacokinetic effects resulted in a small but clinically significant decrease in diastolic blood 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 blood pressure (a decrease of 24.4 mm Hg with fosaprepitant and 18.8 mm Hg without fosaprepitant), but did not cause clinically significant changes in changes in heart rate, PR interval compared to changes in these indicators when using diltiazem alone. In the same study, aprepitant was administered 1 time/day as tablets at a dose comparable to 230 mg of the drug in capsules, and diltiazem at a dose of 120 mg 3 times / day for 5 days, which led to a 2-fold increase in aprepitant AUC and a simultaneous 1.7-fold increase in diltiazem AUC. These pharmacokinetic effects did not result in clinically significant changes in ECG, heart rate, or blood pressure compared to changes in these parameters when using diltiazem alone.

Paroxetine

Concomitant use of aprepitant 1 time/day in tablet form at a dose comparable to 85 mg or 170 mg of the drug in capsules, and paroxetine at a dose of 20 mg 1 time/day resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% for both aprepitant and paroxetine.

How to take, course of use and dosage

The drug Emend ® IV (fosaprepitant) is used on the 1st day of chemotherapy in the form of an intravenous infusion lasting from 20 to 30 minutes approximately 30 minutes before chemotherapy. Emend ® IV should be used in combination with corticosteroids and 5-HT3 antagonists.

Preparation of the solution for infusion of the drug Emend® In/In 150 mg:

1. The contents of the bottle should be dissolved in 5 ml of 0.9% sodium chloride solution (to avoid foaming, the solution should be directed along the wall of the bottle). You should carefully rotate the bottle (do not shake it!).

2. The resulting solution must be added to an infusion bag or vial containing 145 ml of 0.9% sodium chloride solution to obtain a total volume of 150 ml. Carefully mix the contents of the bag or bottle. Before use, the infusion solution should be examined for sediment or discoloration. The prepared solution should be stored at a temperature of up to 25°C and used for 24 hours.

All medicinal products for parenteral use should be carefully examined before use for mechanical inclusions and discoloration in all cases where the properties of the solution and the material of the container allow it.

Incompatibility. Fosaprepitant is incompatible with solutions containing divalent cations (for example, Ca, Mg), including Hartmann’s solution and Ringer’s solution with lactate. Emend ® IV should not be diluted or mixed with solutions whose physical and chemical compatibility has not been proven.

Overdose

A single dose of fosaprepitant up to 200 mg intravenously or oral use of aprepitant up to 600 mg was well tolerated. 3 out of 33 volunteers who received fosaprepitant at a dose of 200 mg had mild thrombosis at the injection site.

In studies not related to chemotherapy-induced nausea and vomiting, aprepitant was well tolerated when administered at a dose of 375 mg 1 time/day for 42 days. In 33 cancer patients, aprepitant was well tolerated with a single dose of 375 mg on day 1 and 250 mg 1 time/day from days 2 to 5.

Drowsiness and headache were reported in 1 patient treated with 1440 mg of aprepitant.

Treatment: There is no specific information available to address the symptoms of overdose with Emend® IV; the drug should be discontinued and general maintenance therapy and monitoring of the patient’s condition should be provided. Due to the antiemetic effect of aprepitant, medications that cause vomiting may not be effective. In case of an overdose of aprepitant, hemodialysis is ineffective.

Special instructions

When using Emend® IV in combination with other antiemetic drugs, follow the instructions for use of these drugs.

According to data obtained in clinical trials, the efficacy and safety of aprepitant in elderly patients (≥65 years) were comparable to those in younger patients ( No dose adjustment is required in elderly patients.

Use in pediatrics

The safety and efficacy of the drug in children have not been studied.

Influence on the ability to drive motor vehicles and manage mechanisms

Studies on the effect of Emend® IV on the ability to drive a car and work with mechanisms have not been conducted. However, some side effects associated with the use of Emend® IV may affect the ability to drive vehicles and perform other activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Lyophilizate for preparation of solution for infusions.

Active ingredient

Fosaprepitant

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Cancer