Aprepitant capsules

Pharmacological action Aprepitant is a selective high-affinity antagonist of the human substance P neurokinin 1 (NK1) receptor. It has low or no affinity for the 5-hydroxytryptamine receptor 3 (5-HT3), dopamine receptor and glucocorticoid receptor, the targets of other existing drugs for the treatment of chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). Preclinical studies have shown that NK1 receptor antagonists can inhibit vomiting caused by cytotoxic chemotherapy drugs such as cisplatin. Preclinical and human positron emission tomography (PET) studies of aprepitant have shown that aprepitant can penetrate the blood-brain barrier and occupy NK1 receptors in the brain. Aprepitant can inhibit vomiting in the acute and delayed phases caused by cisplatin, and enhance the antiemetic activity of the 5-HT3 receptor antagonist ondansetron and the glucocorticoid dexamethasone on vomiting caused by cisplatin. Toxicological action In a repeated dose toxicity study of rats given oral administration of aprepitant for 6 consecutive months, the dose reached the maximum feasible dose of 1000 mg/kg twice a day. (Systemic exposure levels in female and male rats were similar or lower than those in adults, respectively), resulting in increased liver weights with hepatocellular hypertrophy, increased thyroid weights with thyroid follicular cell hypertrophy and/or hyperplasia, and pituitary cell vacuolation. This result is a species-specific consequence of hepatic CYP enzyme induction in rats, and these pathological changes were also observed in rats given other hepatic CYP enzyme inducers that differ in structure and pharmacology from aprepitant. In a repeat-dose toxicity study of dogs given oral aprepitant for 9 months, toxicity was manifested by a slight increase in serum alkaline phosphatase activity and a decrease in the albumin/globulin ratio at a dose of 5 mg/kg twice daily (systemic exposure level greater than or equal to 13 times the systemic exposure level at the adult dose); a significant decrease in body weight gain, testicular degeneration, and prostate atrophy were observed at a dose of ≥25 mg/kg twice daily (systemic exposure level is 31 times the systemic exposure level at the adult dose); and a slight increase in liver weight was observed at a dose of 500 mg/kg twice daily (systemic exposure level is 70 times the systemic exposure level at the adult dose), but there was no histological correlation. No toxicity was observed in dogs given aprepitant 32 mg/kg daily for 1 year (systemic exposure level is 6 times the systemic exposure level at the adult dose). Genotoxicity: Aprepitant was negative in the Ames test, human lymphoblastoid (TK6) gene mutation test, rat hepatocyte DNA fragmentation test, Chinese hamster ovary (CHO) cell chromosome aberration test, and mouse micronucleus test. Reproductive toxicity: Aprepitant has no effect on fertility or reproductive behavior in male and female rats at a maximum feasible dose of 1000 mg/kg, twice daily. The exposure of male rats at this dose is lower than that of humans at the recommended dose, and the exposure of female rats is equivalent to 1.6 times that of humans. Pregnant rats and rabbits were given aprepitant orally at doses of up to 1000 mg/kg twice daily and 25 mg/kg daily (exposures are equivalent to 1.6 times and 1.4 times the exposure at the recommended dose of humans, respectively), and no damage to the fetus was observed; at these doses, aprepitant can be transported to the placenta of rats and rabbits. In rats and rabbits, the concentration of aprepitant in fetal plasma is approximately 27% and 56% of the maternal plasma concentration of aprepitant. Higher concentrations of aprepitant can be observed in milk of lactating rats given aprepitant at 1000 mg/kg twice daily. At this dose, the average concentration of the drug in milk is 90% of the average concentration of the drug in plasma. Carcinogenicity: A 2-year carcinogenicity study was conducted in SD rats and CD-1 mice. The dose of rats was 0.05-1000 mg/kg, twice daily, and the exposure at the highest dose was about 0.7-1.6 times the exposure at the recommended human dose of 125 mg/day. The incidence of thyroid follicular cell adenoma and thyroid follicular cell carcinoma increased in male rats at doses of 5-1000 mg/kg, twice daily. The incidence of hepatocellular adenoma increased in female rats at doses of 5-1000 mg/kg, twice daily, and hepatocellular carcinoma and thyroid follicular cell adenoma increased at doses of 125-1000 mg/kg, twice daily. The dose of mice was 2.5-2000 mg/kg/day, and the exposure at the highest dose was about 2.8-3.6 times the exposure at the recommended human dose. Skin fibrosarcoma was seen in male mice at doses of 125-500 mg/kg.

The main ingredient of this product is aprepitant. Chemical name: 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one. Molecular formula: C23H21F7N4O3. Molecular weight: 534.43

The contents of this product are white or off-white pellets.

Aprepitant capsules are administered in combination with other antiemetic drugs to prevent acute and delayed nausea and vomiting during initial and repeated treatment with highly emetogenic anti-cancer chemotherapy (see "Dosage and Administration").

This product is available in the form of oral capsules. In the combination therapy of aprepitant capsules with a glucocorticoid and a 5-HT3 antagonist, this product is administered for 3 days. Read the instructions of the 5-HT3 antagonist carefully before starting treatment. The recommended dose of this product is 125 mg orally 1 hour before chemotherapy (day 1) and 80 mg orally once a day in the morning of days 2 and 3. In a clinical study conducted in China, the following treatment regimen was used to prevent nausea and vomiting caused by highly emetogenic anti-cancer chemotherapy: oral aprepitant 1 hour before chemotherapy on day 1 and in the morning of days 2 and 3. Dexamethasone was taken 30 minutes before chemotherapy on day 1 and in the morning of days 2-4, and the dosage was determined based on drug interactions. Granisetron was used 30 minutes before chemotherapy on day 1. General Information For additional information on the use of this product in combination with glucocorticoids, see "Drug Interactions". For antiemetics used in combination, see their instructions. This product can be taken with or without food. Patients of different ages, genders, races and body mass index (BMI) do not need to adjust the dosage of the drug. Clinical research data on the use of this product in patients with severe renal insufficiency (creatinine clearance 9 points).

The overall safety of aprepitant was evaluated in approximately 6,500 patients. Highly emetogenic chemotherapy (HEC) domestic clinical trial A randomized controlled clinical study was conducted in Chinese patients receiving highly emetogenic anti-cancer chemotherapy (HEC), in which 412 patients received aprepitant in the first cycle of chemotherapy, of which 240 patients continued to enter the second stage of chemotherapy. The overall tolerability of the aprepitant combined with granisetron and dexamethasone (aprepitant treatment group) was good. The main adverse events in the clinic were mild to moderate. In the first cycle, approximately 11.7% of patients in the aprepitant treatment group reported drug-related adverse events, compared with approximately 13.3% of patients receiving standard therapy. The most common drug-related clinical adverse events in the aprepitant treatment group and slightly higher than the standard treatment group were constipation (7.8% and 7.6%, respectively) and decreased appetite (2.9% and 1.9%, respectively). There were similar drug-related laboratory changes in the aprepitant group and the standard treatment group, with an incidence of 5.4% and 6.7%, respectively. The drug-related laboratory changes in the aprepitant treatment group that were higher than the standard treatment group included increased blood glucose levels, increased blood creatinine, increased blood potassium, increased blood urea, neutropenia, and proteinuria. The incidence rates were 0.5% and 0%, respectively. The adverse event characteristics of the second cycle were generally similar to the first cycle. Global clinical studies In 2 randomized controlled clinical trials conducted in patients receiving highly emetogenic anti-cancer chemotherapy (HEC), 544 patients received aprepitant treatment in the first cycle of chemotherapy, and 413 of them continued to enter multiple cycles to 6 cycles of chemotherapy. Patients who received aprepitant capsules in combination with ondansetron and dexamethasone (aprepitant regimen) were generally well tolerated. In these clinical studies, most adverse reactions were mild to moderate. In the first cycle of chemotherapy, the incidence of drug-related adverse reactions in the aprepitant treatment group was approximately 19%, while that in the standard treatment group was approximately 14%. The rate of discontinuation of aprepitant treatment due to drug-related adverse reactions was 0.6% in the aprepitant group and 0.4% in the standard-therapy group. The most common drug-related adverse reactions in the aprepitant group and higher than in the standard-therapy group included hiccups (4.6%), ALT (alanine aminotransferase) elevation (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2.0%), and decreased appetite (2.0%). In another active-controlled clinical study of aprepitant in highly emetogenic chemotherapy in 1,169 patients, the adverse event profile was generally similar to that of other studies of aprepitant in highly emetogenic chemotherapy. Moderately emetogenic chemotherapy (MEC) global clinical trials In 2 randomized controlled clinical trials in patients receiving moderately emetogenic antineoplastic chemotherapy (MEC), 868 patients received aprepitant in the first cycle of chemotherapy, and 686 of these patients continued to enter multiple cycles of chemotherapy up to 4 cycles. In both studies, aprepitant capsules were generally well tolerated by patients taking them in combination with ondansetron and dexamethasone (aprepitant regimen). In these clinical studies, most adverse reactions were mild to moderate in severity. In a combined analysis of the first cycle data from the two studies, drug-related adverse reactions were reported at an incidence of approximately 14% in the aprepitant group and approximately 15% in the standard-therapy group. The number of patients who discontinued aprepitant treatment due to drug-related adverse reactions was 0.7% in the aprepitant group and 0.2% in the standard-therapy group. The most common drug-related adverse reaction in the aprepitant group and significantly higher than in the standard-therapy group was fatigue (1.4%). Highly and Moderately Emetogenic Chemotherapy Global Clinical Trials A combined analysis of studies of highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) revealed that drug-related adverse reactions with a higher incidence in the aprepitant group than in the standard-therapy group included the following: [Common (≥1/100,

It is contraindicated for patients who are allergic to any of the ingredients in this product. This product should not be used simultaneously with pimozide, terfenadine, astemizole, and cisapride. Aprepitant can produce a dose-dependent inhibition of the cytochrome P450 isoenzyme 3A4 (CYP3A4), thereby increasing the blood concentrations of these drugs, which may cause serious or life-threatening adverse reactions (see "Drug Interactions").

Precautions for children: The safety and effectiveness of this product in children have not been established. Precautions for pregnancy and lactation: Adequate and well-controlled studies have not been conducted in pregnant women. Aprepitant should be used during pregnancy only if the potential benefits to the mother and fetus outweigh the potential risks. This product can be secreted into the milk of rats. It is not known whether this product can be secreted into human milk. Because many drugs are secreted into human milk and because of the possible adverse effects of this product on breastfed infants, a decision must be made whether to discontinue breastfeeding or discontinue drug treatment based on the importance of the drug to the mother. Precautions for the elderly: The safety and effectiveness of this product in the elderly (age ≥65 years) is different from that in younger patients (

Aprepitant is a substrate, mild to moderate (dose-dependent) inhibitor and inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Drug interaction data are all from foreign studies. In a domestic clinical study, higher exposure levels of aprepitant were observed in Chinese patients. Clinically relevant drug interactions must be carefully monitored. Effect of aprepitant on the pharmacokinetics of other drugs: As a moderate (125mg/80mg) inhibitor of CYP3A4, aprepitant can increase the plasma concentrations of oral drugs metabolized by CYP3A4. Aprepitant (125mg/80mg) can also increase the plasma concentrations of intravenous drugs metabolized by CYP3A4, but to a lesser extent than oral drugs. This product should not be used in combination with pimozide, terfenadine, astemizole, or cisapride. Aprepitant's dose-dependent inhibition of CYP3A4 can lead to increased plasma concentrations of these drugs, which may lead to serious or life-threatening reactions (see [Contraindications]). Studies have shown that aprepitant can induce the metabolism of S(-)warfarin and tolbutamide, which are metabolized by CYP2C9. Co-administration of aprepitant with these drugs and other drugs known to be metabolized by CYP2C9, such as phenytoin, may result in decreased plasma concentrations of these drugs. There is no interaction between aprepitant and drugs that are substrates of the P-glycoprotein transporter because no interaction was shown between aprepitant and digoxin in clinical drug interaction studies. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant had no clinically significant effect on the pharmacokinetics of ondansetron, granisetron, or hydroxydolasetron (the active metabolite of dolasetron). Glucocorticoids: Dexamethasone: Co-treatment with aprepitant 125 mg and oral dexamethasone 20 mg on day 1 and with aprepitant 80 mg daily and oral dexamethasone 8 mg on days 2 to 5 resulted in a 2.2-fold increase in the AUC of the CYP3A4 substrate dexamethasone on days 1 and 5. Therefore, if used in combination with aprepitant (125 mg/80 mg therapy), the usual oral dose of dexamethasone should be reduced by approximately 50% to achieve exposure levels similar to those without aprepitant. In clinical studies of aprepitant for the prevention of chemotherapy-induced nausea and vomiting, the daily dose of dexamethasone was reduced by approximately 50% (see [Dosage and Administration]). Methylprednisolone: Oral administration of aprepitant 125 mg on day 1 and 80 mg daily on days 2 to 3 increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold and 2.5-fold on days 1 and 3, respectively. The dosing regimen of methylprednisolone was 125 mg on day 1, intravenous infusion, and 40 mg orally on days 2 and 3. Therefore, when used in combination with aprepitant (125 mg/80 mg regimen), the conventional intravenous dose of methylprednisolone must be reduced by approximately 25%, while the conventional oral dose of methylprednisolone should be reduced by approximately 50% to achieve methylprednisolone exposure levels similar to those without aprepitant. Chemotherapeutic drugs: In clinical studies, aprepitant (125 mg/80 mg regimen) was co-administered with the following chemotherapeutic drugs that are primarily or partially metabolized by CYP3A4: etoposide, vinorelbine, docetaxel, and paclitaxel, and no dose adjustment of these drugs was required based on potential drug interactions. In domestic clinical studies, the number of patients receiving CYP3A4 substrates vinblastine and vincristine was small, so the information on interactions with these drugs was limited. Given the high exposure levels of aprepitant observed in Chinese patients in domestic clinical studies, special attention must be paid to monitoring the safety of patients receiving vinblastine and vincristine or other chemotherapeutic drugs metabolized by CYP3A4. Docetaxel: In a separate pharmacokinetic study, aprepitant (125 mg/80 mg therapy) did not affect the pharmacokinetics of docetaxel. Vinorelbine: In a separate pharmacokinetic study, aprepitant (125 mg/80 mg therapy) did not affect the pharmacokinetics of vinorelbine. Warfarin: In healthy subjects who were stable on long-term warfarin therapy, aprepitant 125 mg was administered orally as a single dose on day 1 and 80 mg was administered orally daily on days 2 and 3. Although aprepitant had no effect on the plasma AUC of R(+) or S(-) warfarin measured on day 3, trough concentrations of S(-) warfarin (CYP2C9 substrate) decreased by 34% and prothrombin time (reported as international normalized ratio or INR) decreased by 14% within 5 days after the end of aprepitant treatment. Therefore, in patients receiving long-term warfarin therapy, the prothrombin time (INR) must be closely monitored for 2 weeks, especially within 7 to 10 days, after each chemotherapy cycle of 3-day aprepitant. Tolbutamide: After a single oral dose of tolbutamide 500 mg before 3-day aprepitant treatment and on days 4, 8, and 15, the AUC of tolbutamide (CYP2C9 substrate) was reduced by 23%, 28%, and 15% on days 4, 8, and 15, respectively. Oral contraceptives: Coadministration of aprepitant 100 mg capsules once daily for 14 days with an oral contraceptive containing 35 ug ethinyl estradiol and 1 mg norethindrone reduced the AUC of ethinyl estradiol by 43% and the AUC of norethindrone by 8%. In another study, an oral contraceptive containing ethinyl estradiol and norethindrone was taken once daily on days 1 to 21, aprepitant 125 mg was taken orally on day 8, aprepitant 80 mg was taken orally on days 9 and 10, ondansetron 32 mg was given intravenously on day 8, and dexamethasone 12 mg was given orally as a single dose, and dexamethasone 8 mg was given orally on days 9, 10, and 11. In this study, the AUC of ethinyl estradiol decreased by 19% on day 10, and trough concentrations of ethinyl estradiol decreased by 64% on days 9 to 21. Although aprepitant had no effect on the AUC of norethindrone on day 10, trough concentrations of norethindrone decreased by 60% on days 9 to 21. The effectiveness of hormonal contraceptives is reduced during treatment with aprepitant and for 28 days after treatment. An alternative or back-up method of contraception should be used during treatment with aprepitant and for 1 month after the last dose of aprepitant. Midazolam: Following oral administration of aprepitant 125 mg on day 1 and 80 mg daily on days 2 to 5, and a single oral dose of midazolam 2 mg on days 1 and 5, aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on day 1 and 3.3-fold on day 5. The potential for increased plasma concentrations of midazolam or other benzodiazepines metabolized by CYP3A4 (alprazolam, triazolam) must be considered when coadministering aprepitant (125 mg/80 mg) with these drugs. In another study of midazolam, IV, aprepitant 125 mg was administered orally on day 1 and 80 mg daily on days 2 and 3, and midazolam 2 mg was administered IV prior to the 3-day aprepitant treatment and on days 4, 8, and 15 of aprepitant treatment. Compared to the aprepitant treatment period on days 1 to 3, aprepitant increased the AUC of midazolam by 25% on day 4 and decreased the AUC of midazolam by 19% on day 8. These effects are not clinically important. The AUC of midazolam on day 15 was similar to that observed during the baseline period. A study of intravenous midazolam and aprepitant has also been completed. Midazolam 2 mg was given as an intravenous infusion 1 hour after a single oral dose of aprepitant 125 mg. The plasma AUC of midazolam increased 1.5-fold. This effect is not clinically important. Effects of Other Drugs on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate of CYP3A4; therefore, coadministration of aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Therefore, caution is warranted when coadministering aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole); however, coadministration of aprepitant with moderate CYP3A4 inhibitors (e.g., diltiazem) did not result in clinically significant changes in aprepitant plasma concentrations. Aprepitant is a CYP3A4 substrate; therefore, coadministration of aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin) may result in decreased aprepitant plasma concentrations, potentially leading to reduced efficacy of aprepitant. Ketoconazole: When a single oral dose of 125 mg aprepitant was administered on day 5 of a 10-day course of ketoconazole 400 mg daily, the AUC of aprepitant increased approximately 5-fold, and the mean terminal half-life of aprepitant was prolonged approximately 3-fold. Caution is warranted when coadministering aprepitant with strong CYP3A4 inhibitors. Rifampin: When a single oral dose of 375 mg of aprepitant was administered on day 9 of a 14-day course of treatment with the strong CYP3A4 inducer rifampin, 600 mg daily, the AUC of aprepitant decreased approximately 11-fold, and the mean terminal half-life decreased approximately 3-fold. Coadministration of aprepitant with drugs that induce CYP3A4 activity may result in decreased plasma concentrations of aprepitant and reduced efficacy. Interactions: Diltiazem: In patients with mild to moderate hypertension, oral administration of aprepitant tablets similar to the 230 mg capsule formulation once daily with diltiazem 120 mg three times daily for 5 days resulted in a 2-fold increase in the AUC of aprepitant and a 1.7-fold increase in the AUC of diltiazem. These pharmacokinetic effects did not result in clinically significant changes in the electrocardiogram, heart rate, or blood pressure beyond those caused by diltiazem alone. Paroxetine: Coadministration of aprepitant tablets similar to 85 mg or 170 mg capsules once daily with paroxetine 20 mg once daily resulted in an approximately 25% decrease in the AUC of aprepitant and paroxetine and an approximately 20% decrease in Cmax.

Seal tightly and store below 30°C.

125mg*1 tablet 80mg*2 tablets

24 months

Qilu Pharmaceutical Co., Ltd.

• Founded in:

  1992-08-21

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  No. 317, Xinluo Street, High-tech Zone, Jinan City, Shandong Province

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  91370000614073351Q

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  600 million yuan

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