Description
Release form
Capsules.
Packaging
In a blister pack of 3 capsules. In a cardboard box 1 blister.
Pharmacological action of
Pharmacodynamics of
Antiemetic drug, selective high affinity neurokinin-1 (NK1) receptor antagonist of substance P. The selectivity of aprepitant binding to NK1 receptors is at least 3,000 times higher than for other channel and carrier enzymes, ion carriers including dopamine and serotonin receptors, which are targets of currently existing drugs used to treat nausea and vomiting associated with chemotherapy.
Preclinical studies have shown that NK1 receptor antagonists prevent the development of vomiting caused by chemotherapeutic drugs (e.g. cisplatin) due to the central mechanism of action.
Aprepitant penetrates the brain and binds to brain NK1 receptors. Possessing a long central action, aprepitant inhibits both acute and delayed phases of vomiting caused by cisplatin, and also enhances the antiemetic effect of ondansetron and dexamethasone.
Pharmacokinetics
Absorption
After oral administration of Cmax in plasma is achieved after about 4 hours. Absolute bioavailability averages about 60-65%. Taking the capsule at the same time as eating does not have a clinically significant effect on the bioavailability of aprepitant.
The pharmacokinetics of aprepitant in the clinical dose range is non-linear.
After ingestion of the drug Emend ® at a dose of 125 mg on the 1st day and then at a dose of 80 mg / day on the 2nd and 3rd days, the AUC for 24 hours was approximately 19.5 μg h / ml in 1 day and 20.1 mcg h / ml on the 3rd day. Cmax was 1.5 μg / ml and 1.4 μg / ml on the 1st and 3rd days, respectively, and was achieved approximately 4 hours after taking the drug.
Distribution of
Plasma protein binding is more than 95%. Vd in equilibrium is approximately 66 liters.
Experimental studies have shown that aprepitant crosses the placental barrier in rats and through the BBB in rats and ferrets.
In humans, the aprepitant penetrates the BBB.
Metabolism
Aprepitant undergoes intensive metabolism in the liver through oxidation in the morpholine ring and its side chains mainly under the influence of CYP3A4 and only a small part of the drug is metabolized with the participation of CYP1A2 and CYP2C19 (CYP2D6, CYP2C9 or CYP2E1 are not involved in the metabolism.
Excretion of
Apparent T1 / 2 is approximately 9 to 13 hours.
Aprepitant is excreted mainly in the form of metabolites through the intestines (86%) and the kidneys (5%).
The apparent plasma clearance of aprepitant is approximately 60 to 84 ml / min.
Pharmacokinetics in special clinical cases
Pharmacokinetics of the drug Emend ® in children and adolescents under the age of 18 has not been studied.
In patients aged 65 years and older after ingestion of the drug Emend ® in a single dose of 125 mg on the 1st day and then at a dose of 80 mg / day on the 2nd and 5th days, AUC for 24 hours was 21 % more on the 1st day and 36% more on the 5th day than those under 65 years of age. Cmax was 10% higher on day 1 and 24% higher on day 5. These differences were not clinically significant.
In patients with mild liver failure (5-6 points on the Child-Pugh scale) after ingestion of the drug Emend ® at a dose of 125 mg on the 1st day and then at a dose of 80 mg / day on the 2nd and 3rd days AUC for 24 hours was 11% less on day 1 and 36% less on day 3 than in healthy volunteers who received the same doses of the drug. In patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), AUC for 24 hours was 10% more on day 1 and 18% more on day 3 than in healthy volunteers who received same dose. These differences are not recognized as clinically significant.
Patients with severe renal insufficiency (CC <30 ml / min) and patients with end-stage renal failure requiring hemodialysis received Emend ® once in a dose of 240 mg. In patients with severe renal insufficiency, AUC for total aprepitant (both bound and non-protein bound) was reduced by 21%, and Cmax was reduced by 32% compared with healthy volunteers. In patients with end-stage renal failure undergoing hemodialysis, the AUC for total aprepitant was lower by 42%, and Cmax by 32%. Due to a slight decrease in the binding of aprepitant to plasma proteins in patients with renal insufficiency, the AUC values of the pharmacologically active unbound drug in these patients and in healthy individuals did not differ significantly. Hemodialysis performed 4 and 48 hours after taking the drug did not have a significant effect on the pharmacokinetics of aprepitant. In the dialysate, less than 0.2% of the aprepitant dose was detected. After a single oral administration of the drug Emend ® AUC0-24 and Cmax in women were 9% and 17% respectively higher than in men. T1 / 2 of aprepitant in women was 25% less than in men, and there were no significant differences in the time to reach Cmax between women and men. These differences in pharmacokinetic parameters do not have clinical significance. Dose adjustment of the drug Emend ® depending on race is not required. Body mass index does not affect the pharmacokinetics of aprepitant. Indications For the prevention of acute and delayed nausea and vomiting caused by highly or moderately emetogenic antitumor drugs (in combination with other antiemetic drugs). Contraindications Severe hepatic insufficiency (> 9 points on the Child-Pugh scale)
concurrent use with pimozide, terfenadine, astemizole and cisapride
hypersensitivity to the drug.
Caution: Emend ® should be used in patients simultaneously receiving drugs that are metabolized primarily with the participation of the CYP3A4 isoenzyme. The simultaneous administration of the drug Emend ® with warfarin can lead to a clinically significant decrease in INR. In patients receiving long-term therapy with warfarin, the INR value should be carefully monitored for 2 weeks with each chemotherapy cycle, and especially 7-10 days after the start of taking Emend ® according to a 3-day regimen. The effectiveness of hormonal contraceptives may decrease during and within 28 days after treatment with Emend ®. During treatment with Emend ® and within 1 month after taking the last dose of Emend ®, alternative and backup methods of contraception should be used.
Pregnancy and lactation
There were no adequate and strictly controlled clinical trials of pregnancy safety during pregnancy, therefore the use of the drug Emend ® during pregnancy is not recommended.
It is not known whether aprepitant with breast milk is excreted in humans. If you need to use the drug during lactation, you should decide on the termination of breastfeeding due to the risk of an undesirable effect on the baby.
Composition
1 capsule contains:
Active ingredient: aprepitant 80 and 125 mg.
Excipients: hydroxypropyl cellulose, sodium lauryl sulfate, sucrose, microcrystalline cellulose
Capsule composition: titanium dioxide, gelatin capsules 125 mg also contain iron oxide yellow and iron oxide red.
Dosage and administration of
The drug is taken orally, regardless of food intake.
Emend ® is prescribed for 3 days in combination with GCS and serotonin 5-HT3 receptor antagonists.
Before starting treatment, you should familiarize yourself with the instructions for use of the serotonin 5-HT3 receptor antagonist, which is prescribed simultaneously with the drug Emend ®. The recommended dose of the drug Emend ® with a three-day regimen is 125 mg 1 hour before taking chemotherapeutic drugs on the 1st day and 80 mg 1 time / day in the morning on the 2nd and 3rd days.
The tables show the regimen of drugs depending on the degree of emetogenicity of antitumor therapy. relevant medical instructions
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Moderate emetogenic chemotherapy
Day 1
Day 2
Day 3
Emend ®
125 mg orally 1 hour before the start of chemotherapy 80 mg srdl 80 mg srdlpm 80 mg
Dexamethasone
12 mg orally 30 minutes before the start of chemotherapy
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Antagonists of serotonin 5-HT3
receptors see the relevant medical instructions for
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In patients with mild to moderate (9 to 5) on Child-Pugh scale) correction no dose required. Clinical data on the use of the drug in patients with severe hepatic insufficiency (> 9 points on the Child-Pugh scale) are not available.
In patients with severe renal failure (CC <30 ml / min), as well as in patients with end-stage renal failure undergoing hemodialysis, dose adjustment is not required. Dose adjustment based on gender, age, race or body mass index is not required. Side effects Aprepitant safety was evaluated in approximately 6500 patients. Prevention of nausea and vomiting caused by chemotherapy High-emetogenic therapy 544 patients who received high-emetogenic therapy and aprepitant in the first cycle participated in the clinical study. 413 patients from this group continued therapy (the maximum number of chemotherapy courses was 6). The three-day regimen of taking Emend ® in combination with ondansetron and dexamethasone was well tolerated by patients. Most adverse reactions recorded in clinical studies have been identified as mild to moderate reactions. The most common adverse reactions associated with highly emetogenic chemotherapy in patients receiving aprepitant in combination with serotonin 5-HT3 receptor antagonists and dexamethasone (were observed more frequently than with serotonin 5-HT3 receptor antagonists and dexamethasone): hiccups (4, 6%), increased ALT activity (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2%) and decreased appetite (2%). In an additional clinical study in 1169 patients, treated with various types of highly emetogenic chemotherapy and nausea and vomiting prophylaxis regimens using aprepitant and antagonists of serotonin 5-HT3 receptors and dexamethasone or only antagonists of serotonin 5-HT3 receptors and dexamethasone, the profile of adverse reactions was the same. Moderate emetogenic therapy In a clinical trial involving 868 patients, the most frequent adverse reaction associated with moderate emetogenic chemotherapy in patients receiving aprepitant in combination with 5-HT3 receptor antagonists and dexamethasone was observed with a greater frequency than with 5-HT3 receptor antagonists and dexamethasone), was fatigue (1.4%). In a combined analysis of studies of high-emetogenic and moderate-emetogenic chemotherapy in patients receiving aprepitant treatment, the following were observed: side effects associated with taking the drug, and with a greater frequency than with standard therapy: often (from 1/100 to <1/10) infrequently (from 1/1000 to <1/100) rarely (from 1 / 10,000 to <1/1000). Infectious and parasitic diseases: rarely – candidiasis, staphylococcal infection. From the hematopoietic system: infrequently – anemia, febrile neutropenia. From the side of metabolism and nutrition: often – decreased appetite rarely – polydipsia. Mental disorders: infrequently – anxiety rarely – disorientation, euphoria. From the nervous system: infrequently – dizziness, drowsiness rarely – cognitive impairment, lethargy, perversion of taste. From the sensory organs: rarely – conjunctivitis, tinnitus. From the cardiovascular system: infrequently – heart palpitations, paroxysmal sensation of heat (hot flashes) rarely – bradycardia, cardiovascular disorders. From the respiratory system: often – hiccups rarely – sore throat, sneezing, cough, postnasal syndrome, pharyngeal irritation. From the digestive system: often – dyspepsia infrequently – belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence rarely – hard feces, perforated duodenal ulcer, neutropenic colitis, stomatitis, stomatitis, stenosis. On the part of the skin and subcutaneous fat: rarely – rash, acne rarely – photosensitivity, excessive sweating, seborrhea, increased oily skin, itchy rash. From the musculoskeletal system: rarely – muscle cramps, muscle weakness. From the urinary system: infrequently – dysuria rarely – pollakiuria. Changes in laboratory parameters: often – increased ALT activity infrequently – increased AST activity, increased alkaline phosphatase activity rarely – increased urine output, red blood cells in the urine, hyponatremia, weight loss, glucosuria, neutropenia. General disorders: often – fatigue infrequently – asthenia, malaise rarely – swelling, discomfort in the chest area, impaired gait. The profile of side effects in patients receiving highly emetogenic and moderately emetogenic chemotherapy during repeated courses (the maximum number of courses is 6) with the use of aprepitant was comparable to that during the 1st chemotherapy cycle. In another study on the use of aprepitant to prevent chemotherapy-induced nausea and vomiting, serious side effects were reported – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome). Data from post-registration studies Due to the fact that reports came from volunteers from undetermined populations, it is not possible to reliably determine the expected frequency or causal relationship with taking the drug. From the side of the skin and skin appendages: itching, rash, urticaria, rarely Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome). On the part of the immune system: hypersensitivity reactions, including anaphylactic reactions. Drug Interaction Aprepitant is a substrate, a moderate CYP3A4 isoenzyme inhibitor and inducer, as well as a CYP2C9 isoenzyme inducer. When administered concurrently, aprepitant may increase plasma concentrations of drugs whose metabolism occurs with the participation of the CYP3A4 isoenzyme. Emend ® should not be used concurrently with pimozide, terfenadine, astemizole, cisapride, and ergot alkaloid derivatives. Inhibition of CYP3A4 isoenzyme under the influence of aprepitant can lead to increased plasma concentrations of these drugs and potentially serious and life-threatening reactions. Aprepitant induces the metabolism of warfarin and tolbutamide. Concomitant administration of Emend ® with these or other drugs that are metabolized by the CYP2C9 isoenzyme (eg, phenytoin) may lead to a decrease in Aprepitant induces the metabolism of warfarin and tolbutamide. Concomitant administration of Emend ® with these or other drugs that are metabolized by the CYP2C9 isoenzyme (eg, phenytoin) may lead to a decrease in Aprepitant induces the metabolism of warfarin and tolbutamide. Concomitant administration of Emend ® with these or other drugs that are metabolized by the CYP2C9 isoenzyme (eg, phenytoin) may lead to a decrease intheir plasma concentrations. The effect of Emend ® on AUC of R (+) – or S (-) – warfarin was not noted, however, when co-administered, a decrease in the minimum concentration of S (-) – warfarin was observed, which was accompanied by a 14% decrease in INR 5 days after the end of administration. Emend ®. Patients receiving warfarin therapy for a long time should carefully monitor the level of INR for 2 weeks, and especially for 7-10 days after starting Emend ® 3-day regimen, during each cycle of chemotherapy. Emend ® reduces the AUC of tolbutamide, a substrate of the CYP2C9 isoenzyme, by 23% on day 4, by 28% on day 8, and by 15% on day 15. In this case, tolbutamide in a single dose of 500 mg was prescribed before the start of the 3-day regimen of Emend ® in the 4th, 8th and 15th days. It is unlikely to interact with Emend ® with drugs that are substrates of the P-glycoprotein transporter (no interaction of Emend ® with digoxin). Aprepitant does not cause clinically relevant changes in the pharmacokinetics of serotonin 5HT3 receptor antagonists – ondansetron, granisetron, and hydrodoletetron (the active metabolite of dolasetron). Increased AUC of dexamethasone (when taken orally) by 2.2 times, methylprednisolone injected into / into – by 1.3 times, and methylprednisolone taken by inward – by 2.5 times with the administration of Emend ® and GKS. In this regard, to achieve the desired effect, the standard dose of dexamethasone when taken orally in combination with aprepitant is reduced by 50%, methylprednisolone when injected / reduced by about 25%, when administered orally – by 50%. When using the drug Emend ® together with chemotherapeutic drugs, the metabolism of which mainly or partially occurs with the participation of the CYP3A4 isoenzyme (etoposide, vinorelbine, docetaxel and paclitaxel), the doses of these drugs can not be adjusted. However, caution is advised when administered to patients receiving these drugs and additional follow-up should be provided. In post-registration studies, cases of neurotoxicity have been reported, which can be considered as a possible side effect of ifosfamide used with aprepitant. The effect of Emend ® on the pharmacokinetics of docetaxel has not been established. The efficacy of hormonal contraceptives during and up to 28 days after the end of Emend ® may be reduced (alternative or back-up contraceptive methods should be used during treatment with Emend ® and within 1 month after receiving the last dose of Emend ®). An increase in the midazolam AUC was observed with oral administration of midazolam and Emend ®. The possible increase in plasma concentrations of midazolam or other benzodiazepines metabolised by the CYP3A4 isoenzyme (alprazolam, triazolam) should be taken into consideration when co-administered with Emend ®. Concomitant administration of Emend ® with drugs that inhibit CYP3A4 isoenzyme activity, may increase the concentration of aprepitant in blood plasma. Therefore, Emend ® should be used with caution in combination with potent CYP3A4 isoenzyme inhibitors (eg, ketoconazole). However, concomitant administration of Emend ® with moderate CYP3A4 isoenzyme inhibitors (eg, diltiazem, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, and protease inhibitors) does not cause clinically relevant changes in apeptive plasma concentrations. Concomitant administration of Emend ® with drugs that are potent inducers of the CYP3A4 isoenzyme (eg, rifampicin, phenytoin, carbamazepine, phenobarbital) may lead to a decrease in the concentration of aprepitant in the plasma and, thus, to a decrease in efficacy. Also, the simultaneous use of aprepitant with the products of St. John’s wort is not recommended. In patients with mild to moderate hypertension, taking aprepitant tablet containing a dose comparable to 230 mg capsule, in combination with diltiazem at a dose of 120 mg 3 times / day for 5 days resulted in an increase in the AUC of aprepitant twice and simultaneously a 1.7-fold increase in diltiazem AUC. These pharmacokinetic effects did not lead to clinically significant changes in ECG, heart rate, or blood pressure compared to changes in these parameters when taking diltiazem alone. Concomitant administration of aprepitant 1 time / day in tablet form at a dose comparable to 85 mg or 170 mg capsule, and paroxetine at a dose of 20 mg 1 time / day resulted in an AUC decrease of approximately 25% and a Cmax of approximately 20% for both aprepitant and paroxetine. overdose Symptoms: available data on the use of aprepitant in high doses without chemotherapy (once up to 600 mg or 375 mg daily for 42 days) indicate good tolerability of the drug. In 1 patient, taking 1440 mg of aprepitant, drowsiness and headache were observed. Treatment: Emend ® should be discontinued and patient should be monitored. If necessary, conduct symptomatic therapy. Due to the antiemetic action of aprepitant, vomiting drugs are unlikely to be effective. The antidote to the drug is unknown. Hemodialysis is not effective. Storage conditions Keep out of the reach of children at a temperature not exceeding 30 ° C. The Expiration of is 4 years. Deystvuyuschee substances Aprepytant Holiday conditions out pharmacies Prescription Dosage form Dosage form capsules
