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.
Compound
1 capsule contains:
Active substances: 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.
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. 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).
Removal
Apparent T1/2 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 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.
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, 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.
special instructions
Inhibition of CYP3A4 by aprepitant may result in increased plasma concentrations of drugs that are primarily metabolized by CYP3A4 (including some chemotherapy drugs).
Use in pediatrics
The safety and effectiveness of Emend® in children have not been established.
Impact 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 machinery. 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®.
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.
Directions for use and doses
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.
The tables show the dosage regimen depending on the degree of emetogenicity of antitumor therapy.
Highly emetogenic chemotherapy
| A drug | Day 1 | Day 2 | Day 3 | Day 4 |
| Emend® | 125 mg orally 1 hour before chemotherapy | 80 mg (morning) | 80 mg (morning) | — |
| Dexamethasone | 12 mg orally 30 minutes before the start of chemotherapy | 8 mg orally (morning) | 8 mg orally (morning) | 8 mg orally (morning) |
| Serotonin 5-HT3 receptor antagonists | see relevant prescribing information | — | — | — |
Moderately emetogenic chemotherapy
| A drug | Day 1 | Day 2 | Day 3 |
| Emend® | 125 mg orally 1 hour before chemotherapy | 80 mg (morning) | 80 mg (morning) |
| Dexamethasone | 12 mg orally 30 minutes before the start of chemotherapy | — | — |
| Serotonin 5-HT3 receptor antagonists | see relevant prescribing information | — | — |
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.
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.
