Compound:
Each capsule contains: Active substance: aprepitant 80 or 125 mg
Excipients: hydroxypropylcellulose, sodium lauryl sulfate, sucrose, microcrystalline cellulose.
Capsule composition: titanium dioxide, gelatin; 125 mg capsules also contain iron oxide yellow and iron oxide red.
Description:
- 80 mg capsules
: hard gelatin capsule with white opaque cap and white opaque body with “461” and “80mg” written in black ink - 125 mg capsules
: hard gelatin capsule with pink opaque cap and white opaque body with “462” and “125mg” printed in black ink
Capsule contents
: white or almost white granules
Pharmacological properties:
Pharmacodynamics
Aprepitant is a selective, high-affinity antagonist of substance P neurokinin 1 (NK1) receptors. The binding selectivity of aprepitant at NK1 receptors is at least 3000 times greater than for other enzymes, ion channel transporters, and receptor sites, including dopamine and serotonin receptors, which are targets of current drugs used to treat chemotherapy-associated nausea and vomiting.
In preclinical studies, NK1 receptor antagonists have been shown to prevent emesis caused by chemotherapy drugs (eg, cisplatin) through a central mechanism of action. Aprepitant enters the brain and binds to brain NK1 receptors. Having a long-lasting central effect, aprepitant inhibits both the acute and delayed phases of vomiting caused by cisplatin, and also enhances the antiemetic effect of ondansetron and dexamethasone.
Pharmacokinetics
Absorption
The average absolute oral bioavailability of aprepitant is approximately 60-65%, and the average maximum plasma concentration of aprepitant (Cmax) occurs approximately 4 hours after dosing. Taking the capsule with food does not have a clinically significant effect on the bioavailability of aprepitant.
The pharmacokinetics of aprepitant over the clinical dose range is nonlinear.
Following oral administration of EMENDA at a dose of 125 mg on day 1 and then at a dose of 80 mg per day on days 2 and 3, the area under the concentration-time curve over 24 hours was approximately 19.5 mcg/hour/mL per day. day and 20.1 mcg/hour/ml on the 3rd day. Cmax was 1.5 µg/ml and 1.4 µg/ml on days 1 and 3, respectively, and was achieved approximately 4 hours (Tmax) after taking the drug.
Distribution
Aprepitant is more than 95% bound to plasma proteins. Aprepitant crosses the blood-brain barrier.
Metabolism
Aprepitant is extensively metabolized in the liver via oxidation at the morpholine ring and its side chains, primarily by CYP3A4, and only a small portion of the drug is metabolized via CYP1A2 and CYP2C19 (CYP2D6, CYP2C9, or CYP2E1 are not involved in the metabolism of aprepitant).
Removal
Aprepitant is eliminated primarily as metabolites in feces (86%) and urine (5%). The apparent plasma clearance of aprepitant is approximately 60 to 84 mL/min. The apparent terminal half-life is approximately 9 to 13 hours.
Pharmacokinetics in special groups of patients
Children
The pharmacokinetics of Emenda have not been studied in patients under the age of 18 years.
Elderly patients
No dose adjustment of Emend is required in elderly patients. After oral administration of a single dose of 125 mg Emenda on day 1 and 80 mg once daily on days 2 and 5, the area under the 24-hour concentration-time curve in older adults (>65 years) was 21 % more on day 1 and 36% more on day 5 than in persons under 65 years of age. Cmax was 10% higher on the 1st day and 24% higher on the 5th day. These differences were not clinically significant.
Patients with liver failure
No dose adjustment of EMENDA is required in patients with mild to moderate hepatic impairment. In patients with mild hepatic impairment (Child-Pugh score 5-6), after a single dose of 125 mg EMENDA on day 1 and 80 mg daily on days 2 and 3, the area under the concentration-time curve of aprepitant over 24 hours was 11% lower on day 1 and 36% lower on day 3 than in healthy people who received the same doses of the drug. In patients with moderate hepatic impairment (Child-Pugh score 7-9), the 24-hour AUC of aprepitant was 10% greater on day 1 and 18% greater on day 3 than in healthy people who received the same doses. These differences were not considered clinically significant. There is no experience with the use of Emend in patients with severe liver failure (>9 points on the Child-Pugh scale).
Patients with renal failure.
No dose adjustment is required in patients with severe renal impairment and patients with end-stage renal failure on hemodialysis. Patients with severe renal impairment (creatinine clearance <30 ml/min) and patients with end-stage renal disease requiring hemodialysis received a single dose of EMEND 240 mg. In patients with severe renal impairment, the area under the concentration-time curve for total aprepitant (both protein-bound and non-protein bound) was reduced by 21% and Cmax was reduced by 32% compared with healthy subjects. In patients with end-stage renal disease on hemodialysis, the area under the concentration-time curve for total aprepitant was reduced by 42% and Cmax by 32%. Due to the slight decrease in protein binding of aprepitant in patients with renal impairment, the area under the concentration-time curve of the pharmacologically active unbound drug in these patients was not significantly different from that in healthy subjects. Hemodialysis performed 4 and 48 hours after dosing did not have a significant effect on the pharmacokinetics of aprepitant. Less than 0.2% of the drug dose was found in the dialysate.
Floor
No dose adjustment of EMENDA is required depending on gender. After a single oral dose of EMENDA 125 mg, the Cmax of the drug in women was 16% higher than in men. The half-life (T½) of aprepitant in women was 25% less than in men, and there were no significant differences in time to maximum concentration (Tmax) between women and men. These differences in the pharmacokinetics of the drug are not considered clinically significant.
Race
No dose adjustment of EMENDA is required based on race.
Emend, 3 pcs., set of capsules
Pharmacodynamics
Antiemetic drug, selective high-affinity antagonist of neurokinin-1 (NK 1) receptors of substance P. The selectivity of aprepitant binding to NK 1 receptors is at least 3000 times higher than for other enzymes, ion channel transporters and receptor sites, including dopamine and serotonin receptors , which are the targets of current drugs used to treat chemotherapy-associated nausea and vomiting.
In preclinical studies, NK 1 receptor antagonists have been shown to prevent the development of vomiting caused by chemotherapy drugs (for example, cisplatin) due to a central mechanism of action.
Aprepitant penetrates the brain and binds to brain NK 1 receptors. Having a long-lasting central effect, aprepitant inhibits both the acute and delayed phases of vomiting caused by cisplatin, and also enhances the antiemetic effect of ondansetron and dexamethasone.
Pharmacokinetics
Suction
After oral administration, Cmax in blood plasma is reached in approximately 4 hours. Absolute bioavailability averages about 60-65%. Taking the capsule with food does not have a clinically significant effect on the bioavailability of aprepitant.
The pharmacokinetics of aprepitant over the clinical dose range is nonlinear.
After oral administration of Emend® at a dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 3, the AUC for 24 hours was approximately 19.5 mcg x h/ml on day 1. 1st day and 20.1 μg×h/ml on the 3rd day. C max was 1.5 μg/ml and 1.4 μg/ml on days 1 and 3, respectively, and was achieved approximately 4 hours after dosing.
Distribution
Plasma protein binding is more than 95%. V d at equilibrium is approximately 66 l.
Experimental studies have shown that aprepitant penetrates the placental barrier in rats and the blood-brain barrier in rats and ferrets.
In humans, aprepitant crosses the blood-brain barrier.
Metabolism
Aprepitant is extensively metabolized in the liver through oxidation at the morpholine ring and its side chains, primarily by CYP3A4, and only a small portion of the drug is metabolized by CYP1A2 and CYP2C19 (CYP2D6, CYP2C9, or CYP2E1 are not involved in the metabolism of aprepitant).
Removal
The apparent T 1/2 is approximately 9 to 13 hours.
Aprepitant is eliminated primarily as metabolites through the intestine (86%) and kidneys (5%).
The apparent plasma clearance of aprepitant is approximately 60 to 84 mL/min.
Pharmacokinetics in special clinical situations
The pharmacokinetics of Emend® in children and adolescents under 18 years of age have not been studied.
In patients aged 65 years and older, after oral administration of Emend® at a single dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 5, the AUC within 24 hours was 21% more on day 1 and 36% more on day 5 than in persons under 65 years of age. Cmax was 10% higher on the 1st day and 24% higher on the 5th day. These differences were not clinically significant.
In patients with mild hepatic impairment (Child-Pugh score 5-6), after oral administration of Emend® at a dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 3, AUC within 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 impairment (Child-Pugh score 7-9), AUC at 24 hours was 10% greater on day 1 and 18% greater on day 3 than in healthy volunteers who received those same dose. These differences were not considered clinically significant.
Patients with severe renal failure (creatinine clearance <30 ml/min) and patients in end-stage renal failure requiring hemodialysis received Emend® at a single dose of 240 mg. In patients with severe renal impairment, the AUC for total aprepitant (both protein bound and non-protein bound) was reduced by 21% and Cmax was reduced by 32% compared to healthy volunteers. In patients with end-stage renal disease on hemodialysis, the AUC for total aprepitant was 42% lower and Cmax was 32% lower. Due to the slight decrease in plasma protein binding of aprepitant in patients with renal impairment, the AUC values of the pharmacologically active unbound drug were not significantly different between these patients and healthy subjects. Hemodialysis performed 4 and 48 hours after dosing did not have a significant effect on the pharmacokinetics of aprepitant. Less than 0.2% of the aprepitant dose was detectable in the dialysate.
After a single oral dose of Emend®, the AUC 0-24 and Cmax of the drug in women were 9% and 17% higher, respectively, 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 are not clinically significant. No dose adjustment of Emend® is required depending on race. Body mass index does not affect the pharmacokinetics of aprepitant.
CONTRAINDICATIONS
-Hypersensitivity to aprepitant or any other component of the drug.
- Simultaneous use with pimozide, terfenadine, astemizole and cisapride. Severe liver failure (>9 points on the Child-Pugh scale).
CAREFULLY
EMEND should be used with caution in patients concomitantly receiving warfarin and drugs that are metabolized primarily through CYP3A4. Co-administration of EMENDA with warfarin may result in a clinically significant decrease in the international normalized ratio (INR). In patients receiving long-term warfarin therapy, MHO levels should be carefully monitored for 2 weeks with each chemotherapy cycle, and especially 7-10 days after starting the EMENDA 3-day regimen.
The effectiveness of hormonal contraceptives may decrease during the period of use and for 28 days after stopping taking EMENDA. Alternative and back-up methods of contraception should be used during treatment with EMEND and for 1 month after the last dose of EMEND.
USE IN PREGNANCY
There are no well-controlled studies in pregnant women. EMEND is not recommended for use during pregnancy.
USE DURING BREASTFEEDING
Although there is no data on the excretion of aprepitant into breast milk in nursing women, a decision should be made to stop feeding or discontinue the drug due to the possible undesirable effects of EMENDA on infants.
Emend instructions for use
Release form Capsules. Composition : 1 capsule contains: Active ingredients: aprepitant 80 mg. Excipients: hydroxypropylcellulose - 16 mg, sodium lauryl sulfate - 0.3097 mg, sucrose - 80 mg, microcrystalline cellulose (in granules) - 39.16 mg, sodium lauryl sulfate (micronized) - 0.3097 mg. Composition of hard gelatin capsule: titanium dioxide - 1.0434 mg, gelatin - up to 58 mg. Black ink SW-9008/9009. 1 capsule contains: Active substance: aprepitant 125 mg. Excipients: hydroxypropylcellulose, sodium lauryl sulfate, sucrose, microcrystalline cellulose; Capsule composition: titanium dioxide, gelatin; 125 mg capsules also contain iron oxide yellow and iron oxide red.
Packaging Blister contains 1, 3 or 5 capsules. There is 1 blister in a cardboard package.
Pharmacological action Pharmacodynamics Antiemetic drug, selective high-affinity antagonist of neurokinin-1 (NK1) receptors of substance P. The selectivity of aprepitant binding to NK1 receptors is at least 3000 times higher than for other enzymes, ion channel transporters and receptor sites, including dopamine and serotonin receptors that are the targets of current drugs used to treat nausea and vomiting associated with chemotherapy. In preclinical studies, NK1 receptor antagonists have been shown to prevent emesis caused by chemotherapy drugs (eg, cisplatin) through a central mechanism of action. Aprepitant enters the brain and binds to brain NK1 receptors. Having a long-lasting central effect, aprepitant inhibits both the acute and delayed phases of vomiting caused by cisplatin, and also enhances the antiemetic effect of ondansetron and dexamethasone.
Pharmacokinetics Absorption After oral administration, Cmax in blood plasma is achieved in approximately 4 hours. Absolute bioavailability averages about 60-65%. Taking the capsule with food does not have a clinically significant effect on the bioavailability of aprepitant. The pharmacokinetics of aprepitant over the clinical dose range is nonlinear. After oral administration of Emend® at a dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 3, the AUC for 24 hours was approximately 19.5 mcg x h/ml on day 1. 1st day and 20.1 μg×h/ml on the 3rd day. Cmax was 1.5 mcg/ml and 1.4 mcg/ml on days 1 and 3, respectively, and was achieved approximately 4 hours after dosing. Distribution Plasma protein binding is more than 95%. Vd at equilibrium is approximately 66 l. Experimental studies have shown that aprepitant penetrates the placental barrier in rats and the blood-brain barrier in rats and ferrets. In humans, aprepitant crosses the blood-brain barrier. Metabolism Aprepitant is extensively metabolized in the liver through oxidation at the morpholine ring and its side chains, primarily by CYP3A4, and only a small portion of the drug is metabolized by CYP1A2 and CYP2C19 (CYP2D6, CYP2C9 or CYP2E1 are not involved in the metabolism of aprepitant). Elimination The apparent T1/2 is approximately 9 to 13 hours. Aprepitant is excreted primarily as metabolites via the intestines (86%) and kidneys (5%). The apparent plasma clearance of aprepitant is approximately 60 to 84 mL/min. Pharmacokinetics in special clinical situations The pharmacokinetics of Emend® in children and adolescents under 18 years of age has not been studied. In patients aged 65 years and older, after oral administration of Emend® at a single dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 5, the AUC within 24 hours was 21% more on day 1 and 36% more on day 5 than in persons under 65 years of age. Cmax was 10% higher on the 1st day and 24% higher on the 5th day. These differences were not clinically significant. In patients with mild hepatic impairment (Child-Pugh score 5-6), after oral administration of Emend® at a dose of 125 mg on day 1 and then at a dose of 80 mg/day on days 2 and 3, AUC within 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 impairment (Child-Pugh score 7-9), AUC at 24 hours was 10% greater on day 1 and 18% greater on day 3 than in healthy volunteers who received those same dose. These differences were not considered clinically significant. Patients with severe renal failure (creatinine clearance <30 ml/min) and patients in end-stage renal failure requiring hemodialysis received Emend® at a single dose of 240 mg. In patients with severe renal impairment, the AUC for total aprepitant (both protein bound and non-protein bound) was reduced by 21% and Cmax was reduced by 32% compared to healthy volunteers. In patients with end-stage renal disease on hemodialysis, the AUC for total aprepitant was 42% lower and the Cmax was 32% lower. Due to the slight decrease in plasma protein binding of aprepitant in patients with renal impairment, the AUC values of the pharmacologically active unbound drug were not significantly different between these patients and healthy subjects. Hemodialysis performed 4 and 48 hours after dosing did not have a significant effect on the pharmacokinetics of aprepitant. Less than 0.2% of the aprepitant dose was detectable in the dialysate. After a single oral dose of Emend®, the AUC0-24 and Cmax of the drug in women were 9% and 17% higher, respectively, 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 are not clinically significant. No dose adjustment of Emend® is required depending on race. Body mass index does not affect the pharmacokinetics of aprepitant.
Emend, indications for use To prevent acute and delayed nausea and vomiting caused by highly or moderately emetogenic anticancer drugs (in combination with other antiemetic drugs).
Contraindications Severe liver failure (> 9 points on the Child-Pugh scale); simultaneous use with pimozide, terfenadine, astemizole and cisapride; hypersensitivity to the components of the drug. Caution: Emend should be used in patients concomitantly receiving medications that are metabolized primarily by the CYP3A4 isoenzyme. Co-administration of Emend® with warfarin can lead to a clinically significant decrease in INR. In patients receiving long-term warfarin therapy, the INR value should be carefully monitored for 2 weeks with each chemotherapy cycle and especially 7-10 days after starting the 3-day regimen of Emend. The effectiveness of hormonal contraceptives may be reduced during and for 28 days after treatment with Emend®. During treatment with Emend® and for 1 month after the last dose of Emend®, alternative and back-up methods of contraception should be used.
Method of administration and dosage 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 read the instructions for use of the serotonin 5-HT3 receptor antagonist prescribed simultaneously with Emend®. The recommended dose of Emend® for a three-day regimen is 125 mg 1 hour before taking chemotherapy drugs on the 1st day and 80 mg 1 time / day in the morning on the 2nd and 3rd days. In patients with mild or moderate hepatic impairment (Child-Pugh score 5 to 9), no dose adjustment is required. There are no clinical data on the use of the drug in patients with severe liver failure (> 9 points on the Child-Pugh scale). In patients with severe renal failure (creatinine clearance <30 ml/min), as well as in patients with end-stage renal failure on hemodialysis, no dose adjustment is required. No dose adjustment is required based on gender, age, race, or body mass index.
Use during pregnancy and breastfeeding Adequate and strictly controlled clinical studies of the safety of the drug during pregnancy have not been conducted, therefore the use of Emend® during pregnancy is not recommended. It is not known whether aprepitant is excreted into breast milk in humans. If it is necessary to use the drug during lactation, the issue of stopping breastfeeding should be decided due to the risk of undesirable effects on the infant.
Side effects The safety of aprepitant was assessed in approximately 6500 patients. Prevention of chemotherapy-induced nausea and vomiting Highly emetogenic therapy The clinical trial included 544 patients who received highly emetogenic therapy and aprepitant in the first cycle. 413 patients from this group continued therapy (the maximum number of chemotherapy courses was 6). The three-day regimen of Emend® in combination with ondansetron and dexamethasone was well tolerated by patients. The majority of adverse reactions recorded in clinical studies were defined as mild to moderate reactions. The most common adverse reactions during highly emetogenic chemotherapy in patients receiving aprepitant in combination with serotonin 5-HT3 receptor antagonists and dexamethasone (observed with a higher frequency than during therapy 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 of 1169 patients receiving different types of highly emetogenic chemotherapy and anti-nausea and vomiting regimens using aprepitant and serotonin 5-HT3 receptor antagonists and dexamethasone, or only serotonin 5-HT3 receptor antagonists and dexamethasone, the adverse reaction profile was similar. Moderately emetogenic therapy In a clinical study of 868 patients, the most common adverse reaction during moderately emetogenic chemotherapy in patients receiving aprepitant in combination with 5-HT3 receptor antagonists and dexamethasone (observed at a higher frequency than with 5-HT3 receptor antagonists and dexamethasone) , there was fatigue (1.4%). In a pooled analysis of studies of highly emetogenic and moderately emetogenic chemotherapy in patients treated with aprepitant, the following drug-related side effects were observed at a higher frequency than with standard therapy: common (≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (≥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 - loss of appetite; rarely - polydipsia. Mental disorders: infrequently - anxiety; rarely - disorientation, euphoria. From the nervous system: infrequently - dizziness, drowsiness; rarely - cognitive impairment, lethargy, taste perversion. From the senses: rarely - conjunctivitis, tinnitus. From the cardiovascular system: infrequently - rapid heartbeat, paroxysmal sensations of heat (“hot flashes”); rarely - bradycardia, cardiovascular disorders. From the respiratory system: often - hiccups; rarely - sore throat, sneezing, cough, postnasal drip, pharyngeal irritation. From the digestive system: often - dyspepsia; uncommon - belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence; rarely - hard feces, perforated duodenal ulcer, neutropenic colitis, stomatitis, bloating. From the skin and subcutaneous fat: infrequently - rash, acne; rarely - photosensitivity, increased sweating, seborrhea, increased oily skin, itchy rash. From the musculoskeletal system: rarely - muscle spasms, 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 diuresis, the presence of red blood cells in the urine, hyponatremia, decreased body weight, glucosuria, neutropenia. General disorders: often - fatigue; infrequently - asthenia, malaise; rarely - swelling, discomfort in the chest area, gait disturbance. The side effect profile in patients receiving highly emetogenic and moderately emetogenic chemotherapy during repeated courses (maximum number of courses - 6) with aprepitant was comparable to that during the 1st cycle of chemotherapy. In another study of the use of aprepitant for the prevention of chemotherapy-induced nausea and vomiting, serious side effects such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) were reported. Data from post-marketing studies Due to the fact that the reports came from volunteers from populations of unknown size, it is not possible to reliably determine the expected frequency or causal relationship with the drug. From the skin and skin appendages: itching, rash, urticaria, rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome). From the immune system: hypersensitivity reactions, including anaphylactic reactions.
Special instructions Inhibition of CYP3A4 by aprepitant may lead to increased plasma concentrations of drugs that are metabolized primarily by the CYP3A4 isoenzyme (including some chemotherapy drugs).
Use in pediatrics The safety and effectiveness of Emend® in children have not been established.
Effect on the ability to drive vehicles and other mechanisms that require increased concentration. No studies have been conducted to study the effect of Emend® on the ability to drive vehicles or operate machines. However, the side effect profile of the drug should be taken into account, which may affect patients' ability to operate machines. Patients may have different reactions to Emend®.
Drug interactions Aprepitant is a substrate, moderate inhibitor and inducer of CYP3A4, and an inducer of CYP2C9. When administered concomitantly, aprepitant may increase the plasma concentrations of drugs metabolized by the CYP3A4 isoenzyme. Emend® should not be used simultaneously with pimozide, terfenadine, astemizole, cisapride, ergot alkaloid derivatives. Inhibition of CYP3A4 by aprepitant may result in increased plasma concentrations of these drugs and potentially serious and life-threatening reactions. Aprepitant induces the metabolism of warfarin and tolbutamide. Co-administration of Emend® with these or other drugs that are metabolized by the CYP2C9 isoenzyme (for example, with phenytoin) may lead to a decrease in their plasma concentrations. There was no effect of Emend® on the AUC of R(+)- or S(-)-warfarin, however, when used together, a decrease in the minimum concentration of S(-)-warfarin was observed, which was accompanied by a decrease in INR by 14% 5 days after stopping the drug. Emend®. In patients receiving long-term warfarin therapy, INR levels should be carefully monitored for 2 weeks, and especially 7–10 days after starting the 3-day regimen of Emend, during each chemotherapy cycle. Emend® reduces the AUC of tolbutamide, a CYP2C9 substrate, 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 a 3-day treatment regimen with Emend® on days 4, 8 and 15. Interaction of the drug Emend® with drugs that are substrates of the P-glycoprotein transporter is unlikely (no interaction of the drug Emend® with digoxin). Aprepitant does not cause clinically significant changes in the pharmacokinetics of the serotonin 5HT3 receptor antagonists ondansetron, granisetron and hydrodolasetron (the active metabolite of dolasetron). With simultaneous administration of the drug Emend® and GCS, an increase in the AUC of dexamethasone (when taken orally) was noted by 2.2 times, methylprednisolone administered intravenously by 1.3 times, and methylprednisolone taken orally by 2.5 times. 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 administered intravenously is reduced by approximately 25%, when administered orally - by 50%. When using Emend® together with chemotherapeutic drugs, the metabolism of which occurs mainly or partially with the participation of the CYP3A4 isoenzyme (etoposide, vinorelbine, docetaxel and paclitaxel), the doses of these drugs do not need to be adjusted. However, caution and additional monitoring are recommended when used in patients receiving these drugs. Cases of neurotoxicity have been reported in post-marketing studies and may be considered a possible side effect of ifosfamide when used in conjunction with aprepitant. The effect of Emend® on the pharmacokinetics of docetaxel has not been identified. The effectiveness of hormonal contraceptives during use and for 28 days after stopping taking Emend® may be reduced (alternative or backup methods of contraception should be used during treatment with Emend® and for 1 month after taking the last dose of Emend®). With simultaneous oral administration of midazolam and Emend®, an increase in the AUC of midazolam was observed. A possible increase in the plasma concentration of midazolam or other benzodiazepines, the metabolism of which is carried out with the participation of the CYP3A4 isoenzyme (alprazolam, triazolam), should be taken into account when prescribing these drugs simultaneously with Emend®. Concomitant use of Emend® with drugs that inhibit the activity of the CYP3A4 isoenzyme may lead to increased plasma concentrations of aprepitant. Therefore, it is necessary to prescribe Emend® with caution in combination with strong inhibitors of the CYP3A4 isoenzyme (for example, with ketoconazole). However, co-administration of Emend with moderate inhibitors of the CYP3A4 isoenzyme (for example, diltiazem, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin and protease inhibitors) does not cause clinically significant changes in the concentration of aprepitant in the blood plasma. Concomitant use of Emend® with drugs that are strong inducers of the CYP3A4 isoenzyme (for example, rifampicin, phenytoin, carbamazepine, phenobarbital) may lead to a decrease in the plasma concentration of aprepitant and, thus, a decrease in the effectiveness of Emend®. Also, the simultaneous use of aprepitant with St. John's wort preparations is not recommended. In patients with mild to moderate hypertension, administration of an aprepitant tablet containing a dose comparable to 230 mg capsules in combination with diltiazem 120 mg three times daily for 5 days resulted in a 2-fold increase in the AUC of aprepitant and a concomitant increase in The AUC of diltiazem is 1.7 times. These pharmacokinetic effects did not result in clinically significant changes in ECG, heart rate, or blood pressure compared with changes in these parameters when taking diltiazem alone. Co-administration 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.
Overdose Symptoms: Available data on the use of aprepitant in high doses without chemotherapy (up to 600 mg once or 375 mg daily for 42 days) indicate that the drug is well tolerated. Somnolence and headache were observed in 1 patient who received 1440 mg of aprepitant. Treatment: therapy with Emend® should be discontinued and the patient's condition monitored. If necessary, carry out symptomatic therapy. Due to the antiemetic effects of aprepitant, drugs that induce vomiting are not likely to be effective. The antidote to the drug is unknown. Hemodialysis is not effective.
Storage conditions Store out of the reach of children at a temperature not exceeding 30°C.
Shelf life: 4 years.
METHOD OF APPLICATION AND DOSES
- Emend capsules are taken regardless of food intake.
- EMEND is taken for 3 days in combination with glucocorticosteroids and 5-HT3 receptor antagonists.
- The recommended dose of EMENDA is 125 mg orally 1 hour before chemotherapy on day 1 and 80 mg once daily in the morning on days 2 and 3.
The tables below show the dosage regimen depending on the degree of emetogenicity of antitumor therapy.
No dose adjustment is required depending on gender and race. In elderly patients, no dose adjustment is required.
SIDE EFFECT
Most side effects identified during clinical trials were considered mild or moderate. The most common aprepitant-related adverse events that occurred in patients receiving the drug according to the recommended regimen for highly emetogenic chemotherapy were hiccups (4.6%), weakness/fatigue (2.9%), increased ALT (2.8%), and constipation ( 2.2%), headache (2.2%) and anorexia (2.0%); in accordance with the recommended regimen for moderately emetogenic chemotherapy - increased fatigue (2.5%). The following are the side effects observed when using apripetant during antitumor therapy in accordance with the following frequency of their occurrence: often - from >1/100 to <1/10, rarely - from >1/1000 to <1/100) Hematopoietic system:
rarely - anemia, febrile neutropenia.
Central nervous system:
often - headache, dizziness;
rarely - dream disturbances, cognitive impairment, disorientation, euphoria, anxiety. Organs of vision:
rarely - conjunctivitis.
Hearing organs
: rarely - tinnitus.
Cardiovascular system
: rarely - bradycardia.
From the respiratory system
: rarely - pharyngitis, sneezing, cough, postnasal drip, pharyngeal irritation.
From the digestive system
: often - anorexia, hiccups, constipation, diarrhea, dyspepsia, belching;
rarely - nausea, acid reflux, taste disturbance, epigastric discomfort, persistent constipation, gastroesophageal reflux, perforated duodenal ulcer, abdominal pain, dry mouth, enterocolitis, bloating, stomatitis. From the skin and skin appendages
: rarely - rash, acne, increased photosensitivity, increased sweating, oily skin, itching.
From the musculoskeletal system
: rarely - muscle spasms, myalgia.
From the urinary system
: rarely - polyuria, dysuria, pollakiuria.
Changes in laboratory parameters
: often - increased levels of ALT and AST;
rarely - increased alkaline phosphatase activity, hyperglycemia, hyponatremia, microhematuria. Other
: often - weakness/fatigue; rarely - swelling, paroxysmal sensations of heat (“hot flashes”), discomfort in the chest, drowsiness, thirst, weight loss or gain, staphylococcal or fungal (candidiasis) infection.
One patient receiving aprepitant during chemotherapy had Stevens-Johnson syndrome, and in another case, angioedema and urticaria were observed when using aprepitant alone. The adverse event profile during repeated cycles of chemotherapy (up to 6) with aprepitant was comparable to that during the 1st cycle of chemotherapy.
Emend®
Highly emetogenic chemotherapy
In two well-controlled clinical studies in patients receiving highly emetogenic anticancer chemotherapy, 544 patients were treated with aprepitant during 1 cycle of chemotherapy, and 413 of these were subsequently treated with an extended chemotherapy regimen consisting of multiple cycles (up to 6 cycles). Aprepitant was administered orally in combination with ondansetron and dexamethasone and was found to be well tolerated. Most side effects noted during clinical studies were described as mild or moderate in intensity.
In cycle 1, treatment-related adverse events were reported in approximately 19% of patients treated with aprepitant and in 14% of patients treated with standard therapy. Treatment was discontinued due to treatment-related adverse reactions in 0.6% of patients treated with aprepitant and in 0.4% of patients treated with standard therapy.
The most common adverse reactions associated with aprepitant that occurred in patients receiving the drug according to the recommended regimen for highly emetogenic chemotherapy were hiccups (4.6%), increased ALT (2.8%), dyspepsia (2.6%), constipation (2.4). %), headache (2%) and decreased appetite (2%).
Moderately emetogenic chemotherapy
In two well-controlled clinical trials in patients receiving moderately emetogenic anticancer chemotherapy, 868 patients were treated with aprepitant during the first cycle of chemotherapy and 686 of them were subsequently treated with an extended chemotherapy regimen consisting of several cycles (up to 4 cycles). In both studies, aprepitant was administered orally in combination with ondansetron and dexamethasone (aprepitant regimen); it was shown to be well tolerated. Most adverse reactions observed during clinical studies were described as mild or moderate in intensity.
In a combined analysis of data from cycle 1 of these studies, treatment-related adverse reactions were reported in approximately 14% of patients treated with aprepitant, compared with 15% of patients treated with standard therapy. Treatment was discontinued due to treatment-related adverse reactions in 0.7% of patients receiving the aprepitant regimen and in 0.2% of patients receiving standard therapy.
The most common treatment-related adverse effect in patients receiving aprepitant, occurring at a higher rate than with standard therapy, was fatigue (1.4%).
Highly emetogenic and moderately emetogenic chemotherapy
In a pooled analysis of studies of highly emetogenic and moderately emetogenic chemotherapy in patients treated with aprepitant, the following drug-related side effects were observed at a higher frequency than with standard therapy: common (≥1/100 to <1/10), uncommon (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:
rarely - anemia, febrile neutropenia.
Metabolism and nutrition:
often - loss of appetite; rarely - polydipsia.
Mental disorders:
infrequently - anxiety; rarely - disorientation, euphoria.
From the nervous system:
infrequently - dizziness, drowsiness; rarely - cognitive impairment, lethargy, taste perversion.
From the senses:
rarely - conjunctivitis, tinnitus.
From the cardiovascular system:
infrequently - rapid heartbeat, paroxysmal sensations of heat (“hot flashes”); rarely - bradycardia, cardiovascular disorders.
From the respiratory system:
often - hiccups; rarely - sore throat, sneezing, cough, postnasal drip, pharyngeal irritation.
From the digestive system:
often - dyspepsia; uncommon - belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence; rarely - hard feces, perforated duodenal ulcer, neutropenic colitis, stomatitis, bloating.
From the skin and skin appendages:
infrequently - rash, acne; rarely - photosensitivity, increased sweating, seborrhea, increased oily skin, itchy rash.
From the musculoskeletal system:
rarely - muscle spasms, muscle weakness.
From the urinary system:
uncommon - dysuria; rarely - pollakiuria.
Changes in laboratory parameters:
often - increased ALT activity; infrequently - increased AST activity, increased alkaline phosphatase activity; rarely - increased diuresis, the presence of red blood cells in the urine, hyponatremia, decreased body weight, glucosuria, decreased number of neutrophils.
General disorders: often -
fatigue; infrequently - asthenia, discomfort; rarely - swelling, discomfort in the chest area, gait disturbance.
The side effect profile during extended chemotherapy (up to 6 cycles) with aprepitant was comparable to that during the 1st cycle of chemotherapy.
In another study of aprepitant for the prevention of chemotherapy-induced nausea and vomiting, a serious adverse effect, Stevens-Johnson syndrome, was reported.
Post-marketing data
Due to the fact that the reports came from volunteers from populations of unknown size, it is not possible to reliably determine the expected frequency or causal relationship with the drug.
From the skin and skin appendages:
itching, rash, urticaria, rarely - Stevens-Johnson syndrome (toxic epidermal necrolysis).
From the immune system:
hypersensitivity reactions, including anaphylactic reactions.
OVERDOSE
Available data on the use of high doses of aprepitant without chemotherapy (up to 600 mg as a single dose or 375 mg daily for 42 days) indicate that the drug is well tolerated.
Drowsiness and headache were reported in one patient who received 1440 mg of aprepitant. In case of overdose, further therapy with Emend should be discontinued and the patient should be closely monitored. There is no known antidote to the drug. If necessary, carry out symptomatic treatment. Due to the antiemetic effects of aprepitant, drugs that induce vomiting are not likely to be effective. Hemodialysis is not effective.
INTERACTION WITH OTHER MEDICINES
Aprepitant is a substrate, moderate inhibitor and inducer of CYP3A4.
Aprepitant is also a CYP2C9 inducer.
When administered concomitantly, aprepitant may increase the plasma concentrations of drugs metabolized by CYP3A4.
EMEND should not be used concomitantly with pimozide, terfenadine, astemizole and cisapride. Inhibition of CYP3A4 by aprepitant may result in increased plasma concentrations of these drugs and potentially serious and life-threatening effects.
Aprepitant induces the metabolism of warfarin and tolbutamide. Co-administration of EMENDA with these or other drugs that are metabolized by CYP2C9 (for example, phenytoin) may lead to a decrease in their plasma concentrations. There was no effect of Emend on the area under the concentration-time curve of R(+)- or S(-)-warfarin, however, when used together, a decrease in the minimum concentration of S(-)-warfarin was observed, which was accompanied by a decrease in MHO by 14% 5 days after end of taking Emend. In patients receiving long-term warfarin therapy, MHO levels should be carefully monitored for 2 weeks, and especially 7-10 days after starting the 3-day regimen of Emenda, during each chemotherapy cycle. EMEND reduced the area under the concentration-time curve of tolbutamide, a CYP2C9 substrate, 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 taken before the start of the 3-day EMENDOM treatment regimen on days 4, 8 and 15.
Interaction of EMENDA with drugs that are substrates of the P-glycoprotein transporter is unlikely (no interaction of EMENDA with digoxin). Aprepitant does not have a clinically significant effect on the pharmacokinetics of the 5HT3 receptor antagonists: ondansetron, granisetron and hydrodolasetron (the active metabolite of dolasetron).
With simultaneous administration of Emend and glucocorticosteroids, an increase in the area under the concentration-time curve for dexamethasone (taken orally) by 2.2 times, for methylprednisolone administered intravenously by 1.3 times, and methylprednisolone taken orally by 2.5 times was noted. In this regard, to achieve the desired effect, the standard dose of dexamethasone when administered orally in combination with aprepitant is reduced by 50%, methylprednisolone when administered intravenously is reduced by approximately 25%, when administered orally - by 50%.
When using Emend together with chemotherapy drugs that are metabolized primarily or in part by CYP3A4 (etoposide, vinorelbine, docetaxel and paclitaxel), the doses of these drugs do not need to be adjusted. However, caution and additional monitoring are recommended in patients receiving these drugs. No effect of Emend on the pharmacokinetics of docetaxel was detected.
The effectiveness of hormonal contraceptives during the period of use and for 28 days after stopping taking EMENDA may be reduced. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month after the last dose of EMEND.
With simultaneous oral administration of midazolam and Emend, an increase in the area under the concentration-time curve of midazolam was noted. The potential effect of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be taken into account when these drugs are coadministered with EMENDOM.
Concomitant use of EMENDA with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Therefore, caution should be exercised when EMEND is administered in combination with strong CYP3A4 inhibitors (eg, ketoconazole). However, coadministration of EMENDA with moderate CYP3A4 inhibitors (e.g., diltiazem) does not cause clinically significant changes in plasma concentrations of aprepitant.
Concomitant use of EMENDA with drugs that are strong CYP3A4 inducers (e.g., rifampin) may result in decreased plasma concentrations of aprepitant and thus a decrease in the effectiveness of EMENDA.
In patients with mild to moderate hypertension, administration of an aprepitant tablet containing a dose comparable to 230 mg capsules in combination with diltiazem 120 mg three times daily for 5 days resulted in a 2-fold increase in the area under the aprepitant concentration-time curve. times and a simultaneous increase in the area under the concentration-time curve of diltiazem by 1.7 times. These pharmacokinetic effects did not result in clinically significant changes in ECG, heart rate, or blood pressure compared with changes in these parameters when taking diltiazem alone.
Co-administration of aprepitant once daily in tablet form at a dose comparable to 85 mg or 170 mg capsules and paroxetine 20 mg once daily resulted in a decrease in the area under the concentration-time curve by approximately 25% and a decrease in Cmax by approximately 25%. 20% for both aprepitant and paroxetine.
Emend®
Highly emetogenic chemotherapy
In two well-controlled clinical studies in patients receiving highly emetogenic anticancer chemotherapy, 544 patients were treated with aprepitant during 1 cycle of chemotherapy, and 413 of these were subsequently treated with an extended chemotherapy regimen consisting of multiple cycles (up to 6 cycles). Aprepitant was administered orally in combination with ondansetron and dexamethasone and was found to be well tolerated. Most side effects noted during clinical studies were described as mild or moderate in intensity.
In cycle 1, treatment-related adverse events were reported in approximately 19% of patients treated with aprepitant and in 14% of patients treated with standard therapy. Treatment was discontinued due to treatment-related adverse reactions in 0.6% of patients treated with aprepitant and in 0.4% of patients treated with standard therapy.
The most common adverse reactions associated with aprepitant that occurred in patients receiving the drug according to the recommended regimen for highly emetogenic chemotherapy were hiccups (4.6%), increased ALT (2.8%), dyspepsia (2.6%), constipation (2.4). %), headache (2%) and decreased appetite (2%).
Moderately emetogenic chemotherapy
In two well-controlled clinical trials in patients receiving moderately emetogenic anticancer chemotherapy, 868 patients were treated with aprepitant during the first cycle of chemotherapy and 686 of them were subsequently treated with an extended chemotherapy regimen consisting of several cycles (up to 4 cycles). In both studies, aprepitant was administered orally in combination with ondansetron and dexamethasone (aprepitant regimen); it was shown to be well tolerated. Most adverse reactions observed during clinical studies were described as mild or moderate in intensity.
In a combined analysis of data from cycle 1 of these studies, treatment-related adverse reactions were reported in approximately 14% of patients treated with aprepitant, compared with 15% of patients treated with standard therapy. Treatment was discontinued due to treatment-related adverse reactions in 0.7% of patients receiving the aprepitant regimen and in 0.2% of patients receiving standard therapy.
The most common treatment-related adverse effect in patients receiving aprepitant, occurring at a higher rate than with standard therapy, was fatigue (1.4%).
Highly emetogenic and moderately emetogenic chemotherapy
In a pooled analysis of studies of highly emetogenic and moderately emetogenic chemotherapy in patients treated with aprepitant, the following drug-related side effects were observed at a higher frequency than with standard therapy: common (≥1/100 to <1/10), uncommon (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:
rarely - anemia, febrile neutropenia.
Metabolism and nutrition:
often - loss of appetite; rarely - polydipsia.
Mental disorders:
infrequently - anxiety; rarely - disorientation, euphoria.
From the nervous system:
infrequently - dizziness, drowsiness; rarely - cognitive impairment, lethargy, taste perversion.
From the senses:
rarely - conjunctivitis, tinnitus.
From the cardiovascular system:
infrequently - rapid heartbeat, paroxysmal sensations of heat (“hot flashes”); rarely - bradycardia, cardiovascular disorders.
From the respiratory system:
often - hiccups; rarely - sore throat, sneezing, cough, postnasal drip, pharyngeal irritation.
From the digestive system:
often - dyspepsia; uncommon - belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence; rarely - hard feces, perforated duodenal ulcer, neutropenic colitis, stomatitis, bloating.
From the skin and skin appendages:
infrequently - rash, acne; rarely - photosensitivity, increased sweating, seborrhea, increased oily skin, itchy rash.
From the musculoskeletal system:
rarely - muscle spasms, muscle weakness.
From the urinary system:
uncommon - dysuria; rarely - pollakiuria.
Changes in laboratory parameters:
often - increased ALT activity; infrequently - increased AST activity, increased alkaline phosphatase activity; rarely - increased diuresis, the presence of red blood cells in the urine, hyponatremia, decreased body weight, glucosuria, decreased number of neutrophils.
General disorders: often -
fatigue; infrequently - asthenia, discomfort; rarely - swelling, discomfort in the chest area, gait disturbance.
The side effect profile during extended chemotherapy (up to 6 cycles) with aprepitant was comparable to that during the 1st cycle of chemotherapy.
In another study of aprepitant for the prevention of chemotherapy-induced nausea and vomiting, a serious adverse effect, Stevens-Johnson syndrome, was reported.
Post-marketing data
Due to the fact that the reports came from volunteers from populations of unknown size, it is not possible to reliably determine the expected frequency or causal relationship with the drug.
From the skin and skin appendages:
itching, rash, urticaria, rarely - Stevens-Johnson syndrome (toxic epidermal necrolysis).
From the immune system:
hypersensitivity reactions, including anaphylactic reactions.
SPECIAL INSTRUCTIONS
EMEND should be used with caution in patients concomitantly receiving medicinal products that are metabolized primarily through CYP3A4; CYP3A4 metabolizes some chemotherapy drugs. Inhibition of CYP3A4 by aprepitant may result in increased plasma concentrations of these concomitant medications. Co-administration of EMENDA with warfarin may result in a clinically significant decrease in the International Normalized Ratio (INR) prothrombin time. In patients receiving chronic warfarin treatment, MHO should be closely monitored for 2 weeks, particularly 7 to 10 days after starting the 3-day EMENDA regimen with each chemotherapy cycle. The effectiveness of hormonal contraceptives may be reduced during and for 28 days after treatment with EMENDOM. Alternative methods of contraception should be used during treatment with EMEND and for 1 month after the last dose of EMEND.
Emend® V/V
Drug interactions following use of fosaprepitant are most likely to occur with drugs that interact with aprepitant. Further information comes from studies performed with oral aprepitant and studies of fosaprepitant combined with dexamethasone, midazolam, or diltiazem.
Aprepitant is a substrate, weak to moderate inhibitor and inducer of CYP3A4. Aprepitant is also an inducer of the CYP2C9 isoenzyme. When taken once, Emend IV 150 mg is a weak inhibitor of the CYP3A4 isoenzyme and does not induce the CYP3A4 isoenzyme. Emend IV 150 mg IV is expected to cause less or no greater induction of CYP2C9 compared to oral aprepitant.
Effect of fosaprepitant/aprepitant on the pharmacokinetics of other medicinal products
Due to the fact that aprepitant is a weak to moderate inhibitor of the CYP3A4 isoenzyme, and fosaprepitant is a weak inhibitor of the CYP3A4 isoenzyme, concomitant use of drugs that are metabolized by the CYP3A4 isoenzyme may increase their plasma concentrations. Fosaprepitant should not be used concomitantly with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant may result in increased plasma concentrations of these drugs and potentially serious or life-threatening reactions (see Contraindications).
Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized by CYP2C9. Co-administration of fosaprepitant with these or other drugs that are metabolized by CYP2C9 (eg, phenytoin) may result in decreased plasma concentrations of these drugs. An interaction between fosaprepitant and drugs that are substrates of the P-glycoprotein transporter is unlikely due to the fact that clinical studies have shown that aprepitant does not interact with digoxin when taken orally.
Antagonist 5-NT3
In clinical drug interaction studies, it was shown that aprepitant, when taken 125 mg on day 1 and 80 mg on days 2 and 3, does not cause clinically significant changes in the pharmacokinetics of serotonin 5HT3 receptor antagonists - ondansetron, granisetron and hydrodolasetron (the active metabolite of dolasetron).
Corticosteroids
Dexamethasone: When fosaprepitant 150 mg was coadministered with dexamethasone 8 mg orally on days 1, 2, and 3, administration of fosaprepitant on day 1 caused an approximately 2-fold increase in dexamethasone AUC on day 1. and 2nd days. The standard dose of oral dexamethasone plus fosaprepitant 150 mg IV on day 1 should be reduced by approximately 50% to achieve dexamethasone exposure similar to that given without fosaprepitant 150 mg IV on day 1 (see .Method of administration and dose).
Methylprednisolone: When co-administered with oral aprepitant 125 mg on day 1 and 80 mg/day on days 2 and 3, the AUC of methylprednisolone, a CYP3A4 substrate, increased by 1.3-fold. 1st day and 2.5 times on the 3rd day, with intravenous administration of methylprednisolone at a dose of 125 mg on the 1st day and with oral administration at a dose of 40 mg on the 2nd and 3rd days.
Chemotherapy drugs
In clinical studies, chemotherapy drugs metabolized primarily or partially by CYP3A4 were administered following oral administration of aprepitant: etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan and paclitaxel. Doses of these drugs were not adjusted to account for potential drug interactions. Caution should be exercised and the patient's condition should be carefully monitored when using chemotherapy drugs, the metabolism of which occurs mainly or partially with the participation of the CYP3A4 isoenzyme. Cases of neurotoxicity have been reported in post-marketing studies.
Warfarin
Aprepitant was administered to healthy subjects receiving long-term warfarin therapy as a single dose of 125 mg PO 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 R(+) or S(-) of warfarin on day 3 with oral aprepitant, there was a decrease in the trough concentration of S(-) warfarin (a substrate of the CYP2C9 isoenzyme) by 34%, which was accompanied by a decrease prothrombin time by 14% (INR) 5 days after stopping oral aprepitant. In patients receiving long-term warfarin therapy, the prothrombin time (INR) should be closely monitored for 2 weeks with each chemotherapy cycle and especially 7 to 10 days after starting fosaprepitant.
Tolbutamide
Aprepitant, when administered orally at a dose of 125 mg on day 1 and 80 mg on days 2 and 3, decreased the AUC of tolbutamide (CYP2C9 substrate) by 23% on day 4 and by 28% on day 8. day and by 15% on day 15, while tolbutamide in a single dose of 500 mg was prescribed before the start of a three-day oral aprepitant regimen on days 4, 8, and 15.
Oral contraceptives When co-administered with aprepitant capsules 100 mg once daily for 14 days and an oral contraceptive containing 35 mcg ethinyl estradiol and 1 mg norethindrone, there was a 43% decrease in ethinyl estradiol AUC and an 8% decrease in norethindrone AUC.
In another study, a single dose of an oral contraceptive containing ethinyl estradiol and norethindrone given on days 1 to 21 was combined with concomitant oral aprepitant at 125 mg on days 8 and 80 mg/day on days 9 and 21. Day 10, ondansetron 32 mg IV on day 8 and dexamethasone given orally at 12 mg on day 8 and 8 mg/day on days 9, 10, 11. In the study, the AUC of ethinyl estradiol decreased by 19% on day 10, and there was a 64% decrease in ethinyl estradiol trough concentrations from days 9 to 21. Although oral aprepitant had no effect on norethindrone AUC on day 10, norethindrone trough concentrations decreased by up to 60% from days 9 to 21.
The effectiveness of hormonal contraceptives may be reduced while you are taking fosaprepitant and for 28 days after you stop taking fosaprepitant. An alternative or additional method of contraception should be used during treatment with fosaprepitant and for 1 month after taking fosaprepitant.
Midazolam
When fosaprepitant 150 mg IV was coadministered with midazolam 2 mg orally as a single dose on day 1, an approximately 1.8-fold increase in the AUC of midazolam was observed. With a similar dosing regimen on day 4, there was no effect on AUC. Fosaprepitant 150 mg intravenously is a weak inhibitor of CYP3A4, as a single dose on day 1 did not result in either inhibition or induction of CYP3A4, in contrast to the results obtained on day 4.
Effect of other medicinal products on the pharmacokinetics of aprepitant
Aprepitant is a CYP3A4 substrate, and concomitant use of fosaprepitant with drugs that inhibit CYP3A4 may result in increased plasma concentrations of aprepitant. Therefore, caution should be exercised when fosaprepitant is used in combination with strong CYP3A4 inhibitors (e.g., ketoconazole), but coadministration of aprepitant with moderate CYP3A4 inhibitors (e.g., diltiazem) does not result in clinically significant changes in aprepitant plasma concentrations.
Aprepitant is a substrate of the CYP3A4 isoenzyme, as a result of which concomitant use of fosaprepitant with drugs that are strong inducers of the CYP3A4 isoenzyme (for example, rifampicin) may lead to a decrease in its plasma concentration and a decrease in effectiveness.
Ketoconazole When a single 125 mg oral dose of aprepitant was administered on day 5 of a 10-day treatment regimen with ketoconazole (400 mg/day), a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the terminal half-life of aprepitant increased approximately 5-fold. 3 times. Fosaprepitant should be used with caution in combination with strong CYP3A4 inhibitors.
Rifampicin
When aprepitant was administered as a single 375 mg oral dose on day 9 of a 14-day treatment regimen with rifampicin, a strong CYP3A4 inducer, the AUC of aprepitant decreased by approximately 11-fold and the terminal half-life of aprepitant decreased by approximately 3-fold. Concomitant use of fosaprepitant with drugs that are strong inducers of the CYP3A4 isoenzyme may result in decreased plasma concentrations and decreased efficacy.
interaction data
Diltiazem
In patients with mild to moderate hypertension, an infusion of fosaprepitant 100 mg over 15 minutes in combination with diltiazem 120 mg three times daily resulted in a 1.5-fold increase in the AUC of aprepitant and a 1.4-fold increase in the AUC of diltiazem.
Pharmacokinetic effects resulted in a small but clinically significant decrease in diastolic pressure (16.8 mmHg decrease with fosaprepitant and 10.5 mmHg without fosaprepitant) and a small but clinically significant decrease in systolic pressure ( a decrease of 24.4 mm Hg when prescribing fosaprepitant and by 18.8 mm Hg without fosaprepitant), but did not cause clinically significant changes in heart rate and PR interval compared to changes in these indicators when taking only diltiazem.
In the same study, aprepitant was administered once daily as a tablet at a dose comparable to 230 mg capsules and diltiazem at a dose of 120 mg three times daily for 5 days, which resulted in a 2-fold increase in aprepitant AUC and simultaneous increase in AUC of diltiazem by 1.7 times. These pharmacokinetic effects did not result in clinically significant changes in ECG, heart rate, or blood pressure compared with changes in these parameters when taking diltiazem alone.
Paroxetine Co-administration of aprepitant once daily in tablet form at a dose comparable to 85 mg or 170 mg capsules and paroxetine at a dose of 20 mg once daily resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% as for aprepitant and paroxetine.
