The generic name is Arepitan Capsule.
English name Aprepitant Capsules
Chinese Pinyin Arepitan Capsule
The main ingredient is aripipitan.
Specification (1) 80mg; (2)125mg
Dose oral capsule
Packaging aluminum-plastic plate packaging.
Store in the original packaging below 30℃. .
Valid for 48 months.
Registration number of imported drugs
80 mg: H20 130543
125mg: 20 130544
80mg and 125mg: H20 130545.
Production enterprise
Company name: Merck Sharp &; Dome Australia ltd
Address: 54-68 Findel Street, South glanville, New South Wales, Australia, 2 142.
Name of manufacturer: Merck Sharp &; Duomei company
Address: No.770 Sumney Town Pike, West Point Military Academy, Pennsylvania, USA 19486.
Name of packaging factory: Merck Sharp &; Dome Australia ltd
Address: 54-68 Findel Street, South glanville, New South Wales, Australia, 2 142.
raw material
The main ingredient of this product is aripipitan.
Chemical name: 5-[(2r, 3s)-2-[(1r)-1-[3,5- bis (trifluoromethyl) phenyl] ethoxy ]-3-(4- fluorophenyl) -4- morpholinyl] methyl]-66.
Chemical structural formula:
Molecular formula: C23H2 1F7N4O3.
Molecular weight: 534.43
Character; Role; letter
This product is a hard capsule with white granules.
80mg: white opaque hard capsule with the words' 461'and' 80mg' printed on it.
125mg: opaque hard capsule, white capsule body, pink capsule cap, printed with the words' 462' and' 125mg'. The dosage form of the product is an oral capsule.
Take this product for 3 days in the combined treatment scheme of Arepitan capsule, glucocorticoid and 5-HT3 antagonist. Please read the instructions of 5-HT3 antagonist carefully before starting treatment. The recommended dosage of this product is 1 hour before chemotherapy (the first 1 day) 125mg, and 80mg in the morning of the second and third days, once a day.
In a clinical study conducted in China, the following treatment schemes were used to prevent nausea and vomiting caused by anti-tumor chemotherapy for high vomiting: day 1 day, day 2, day 3 and day 4. Aripitam * oral 125 mg, oral 80 mg, oral 80 mg, dexamethasone-free oral 6 mg, oral 3.75 mg, oral 3.75 mg, oral granisetron? Before chemotherapy 1 hour, on 1 day, and on the morning of the second and third days, 3 mg, none, none * Aripitam was given orally.
* * Dexamethasone is taken 30 minutes before chemotherapy on 1 day and in the morning of the second to fourth day, and the dosage is determined according to drug interaction.
Granisetron was used 30 minutes before chemotherapy on 1 day.
general specification
For other information about the combination of this product and glucocorticoid, please refer to "Drug Interaction".
Compound antiemetic drugs can be found in the instructions.
This product can be taken with or without food.
Patients of different age, sex, race and body mass index (BMI) do not need to adjust the drug dosage.
Patients with severe renal insufficiency (creatinine clearance rate
Patients with mild or moderate hepatic insufficiency (Child-Pugh grade 5-9) do not need to adjust the dosage of this product. At present, there is no clinical research data on the use of this product in patients with severe liver dysfunction (Child-Pugh grading score >: 9). Those who are allergic to any component of this product are prohibited.
This product should not be used together with pimozide, terfenadine, astemizole and cisapride. Aripitam can inhibit cytochrome P450 isoenzyme 3A4(CYP3A4) in a dose-dependent manner, which may lead to serious or life-threatening adverse reactions (see "Drug Interaction"). This product is a dose-dependent CYP3A4 inhibitor, so patients who are mainly metabolized by CYP3A4 must use it with caution. Some chemotherapeutic drugs are metabolized by CYP3A4 (see Drug Interaction). The moderate inhibitory effect of aripipitan 125mg/80mg on CYP3A4 can increase the plasma concentration of these drugs (see "Drug Interaction").
When this product is combined with warfarin, the international normalized ratio (INR) of prothrombin time can be significantly reduced. For patients who need to take warfarin for a long time, INR should be closely monitored within two weeks after the start of warfarin three-day regimen in each chemotherapy cycle, especially on day 7- 10 (see "Drug Interaction").
During taking this product and within 28 days after taking it, the curative effect of sex hormone contraceptives can be reduced. Therefore, during the treatment with this product and within 1 month after the last use of this product, other contraceptive measures or remedial methods should be selected for contraception (see "Drug Interaction").
Medication for pregnant and lactating women
Adequate and well-controlled studies have not been conducted in pregnant women. Arepitan should only be used during pregnancy when its potential benefits to the mother and fetus outweigh its potential risks.
Arepitan can be secreted into the milk of mice. It is not clear whether this product can be secreted into human milk. Because many drugs can be secreted into human milk, and this product may have adverse reactions to breast-fed babies, it is necessary to decide whether to stop breast-feeding or drug treatment according to the importance of drugs to mothers.
Children's medication
The safety and effectiveness of this product for children have not been determined.
Medication for the elderly
In clinical research, the elderly (age? 65 years old) than young patients (
The data of drug interaction are all from foreign studies. A domestic clinical study found that the exposure level of China patients was high. Clinically relevant drug interactions must be carefully monitored.
Effects of Aripitam on Pharmacokinetics of Other Drugs
Aripipitan, as a moderate (125mg/80mg) inhibitor of CYP3A4, can increase the plasma concentration of oral drugs metabolized by CYP3A4. Arepitan (125mg/80mg) can also increase the plasma concentration of intravenous drugs metabolized by CYP3A4, but to a lesser extent than oral drugs.
This product should not be used with pimozide, terfenadine, astemizole or cisapride. The dose-dependent inhibitory effect of ARIPITAN on CYP3A4 can lead to the increase of plasma concentration of these drugs, which may lead to serious or life-threatening reactions (see "Contraindications").
Studies have shown that aripiptan can induce the metabolism of S(-) warfarin and tolbutamide metabolized by CYP2C9. When this product is combined with these drugs and other drugs known to be metabolized by CYP2C9 (such as phenytoin), the blood concentration of these drugs can be reduced.
This product has no interaction with the substrate drug of P- glycoprotein transporter, because it has no interaction with digoxin in clinical drug interaction research.
5-HT3 Antagonist: In the study of clinical drug interaction, the effect of aripipitan on the pharmacokinetics of ondansetron, granisetron or hydroxydorasetron (the active metabolite of dorasetron) has no clinical significance.
Glucocorticoid:
Dexamethasone: the combined treatment of aripipitan 1 25mg and dexamethasone 20mg on day 1 day, and the combined treatment of this product 80mg and dexamethasone 8mg on day 2-5 can lead to the AUC of dexamethasone increased by 2.2 times on day1day and day 5. Therefore, if it is combined with aripiptan (125mg/80mg therapy), the routine oral dose of dexamethasone should be reduced by about 50%, so that the exposure level of dexamethasone is similar to that when it is not used. In the clinical study of aripiptan in preventing nausea and vomiting caused by chemotherapy, the daily dose of dexamethasone was reduced by about 50% (see "Usage and Dosage").
Methylprednisolone: taking aripipitan 1 25mg orally on 1 day and 40mg orally on the 2nd to 3rd day can increase the AUC of methylprednisolone on 1 day and the 3rd day by 1.3 times and 2.5 times respectively. The dosage regimen of methylprednisolone is1day. Therefore, when combined with aripipitan (125mg/80mg therapy), the routine intravenous infusion dose of methylprednisolone must be reduced by about 25%, while the routine oral dose of methylprednisolone should be reduced by about 50%, so that the exposure level of methylprednisolone is similar to that without aripipitan.
Chemotherapeutic drugs: In clinical research, aripipitan (125mg/80mg therapy) is used in combination with the following chemotherapeutic drugs mainly or partially metabolized by CYP3A4: etoposide, vinorelbine, docetaxel and paclitaxel, and the dosage of these drugs does not need to be adjusted according to the potential drug interaction.
In domestic clinical research, the number of patients receiving vinblastine and vincristine as substrates of CYP3A4 is small, so the information about the interaction of these drugs is limited. In view of the high exposure level of aripipitan in China patients observed in domestic clinical studies, special attention must be paid to monitoring the safety of patients receiving vinblastine and vincristine or other chemotherapy drugs metabolized by CYP3A4.
Docetaxel: In an independent pharmacokinetic study, aripipitan (125mg/80mg therapy) did not affect the pharmacokinetics of docetaxel.
Vinorelbine: In an independent pharmacokinetic study, aripipitan (125mg/80mg therapy) did not affect the pharmacokinetics of vinorelbine.
Warfarin: In healthy subjects who have been receiving warfarin for a long time, aripipitan 1 25mg was taken orally once a day, and 80mg was taken orally on the 2nd and 3rd days. Although Arepitan had no effect on the plasma AUC of R(+) or S(-) warfarin measured on the 3rd day, the trough concentration of S(-) warfarin (CYP2C9 substrate) decreased by 34% and the prothrombin time (reported as international standardized ratio or INR) shortened by 65,438 04% within 5 days after treatment with Arepitan. Therefore, in patients receiving long-term warfarin treatment, prothrombin time (INR) must be closely monitored within 2 weeks, especially within 7 to 10 days, after receiving aripiptam for 3 days in each chemotherapy cycle.
Toluene sulfonylureas: Aripiptam 125mg was taken orally on the 65th and 438+0 days, and 500mg was taken orally on the 2nd and 3rd days. Toluene sulfonylurea (CYP2C9 substrate) was taken orally on the 4th, 8th and 65th, 438+05th day before the three-day treatment with aripipitan.
Oral contraceptives: the combined use of aripipitan 100mg capsules 1 time a day for 14 days, combined with oral contraceptives containing 35ug ethinylestradiol and 1mg norethindrone, can reduce the AUC of ethinylestradiol by 43% and norethindrone by 8%.
In another study, oral contraceptives containing ethinylestradiol and norethindrone were administered once a day from 1 to 2 1, with aripipitan 125mg on the 8th day, aripipitan 80mg on the 9th and 10 days, and ondansetron 32mg and dexamethasone intravenously on the 8th day. In this study, the AUC of ethinylestradiol decreased by 19% on day 10, while the valley concentration of ethinylestradiol decreased by 64% from day 9 to day 2 1 0. Although aripiptan had no effect on AUC of norethindrone on day 10, the trough concentration of norethindrone decreased by 60% from day 9 to day 2 10.
The effectiveness of hormonal contraceptives decreased during and within 28 days after aripipitan treatment. During the treatment of aripipitan and within 1 month after the last treatment of aripipitan, alternative or backup contraceptive methods should be used.
Midazolam: After taking aripipitan 1 25mg orally on 1 day, 80mg orally on the 2nd-5th day, and 1 midazolam 2mg orally on the 5th day, aripipitan can make the AUC of midazolam, a sensitive substrate of CYP3A4, at/kloc-. When aripiptan (125mg/80mg) is used in combination with these drugs, it is necessary to consider the potential impact of the increased plasma concentration of midazolam or other benzodiazepines (alprazolam and triazolam) metabolized by CYP3A4.
In another study on intravenous infusion of midazolam, aripipitan 1 25mg was given orally on day/kloc-0, and 80mg was given orally on days 2 and 3. Midazolam 2mg was injected intravenously 3 days before aripipitan treatment and 4,8 and 15 days after aripipitan treatment. Compared with the treatment period of aripiptan 1 ~ 3 days, this product can increase the AUC of midazolam by 25% on the 4th day and decrease the AUC of midazolam by 19% on the 8th day. These effects have no important clinical significance. The AUC of midazolam at day 15 was similar to that at baseline.
The study on intravenous administration of midazolam and aripiptan was also completed. After a single oral administration of aripipitan, midazolam 2mg was injected intravenously at 65438±025mg. The plasma AUC of midazolam increased by 65438 0.5 times. This effect has no important clinical significance. Specific information about the overdose of this product has not been obtained. A single oral dose of 600mg of aripiptan is usually well tolerated by healthy subjects. Aripipitan 375mg once a day for 42 days was basically well tolerated among patients who participated in the non-CINV study. Among the 33 cancer patients, aripiptan was taken orally once a day at/kloc-0, and once at 250 375mg every second to fifth day, which was basically well tolerated.
1 patients who received 1440mg aripiptan had symptoms of drowsiness and headache.
In case of overdose, the treatment of this product must be stopped and general support treatment and monitoring should be taken. Because Aripitam has antiemetic activity, it may be ineffective to induce vomiting with drugs.
Aripitam cannot be removed by hemodialysis. pharmacological action
Aripitam is a selective high affinity antagonist of human substance P neurokinin 1(NK 1) receptor. It has low affinity or no affinity with other existing drugs used to treat chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV), such as 5- hydroxytryptamine receptor 3(5-HT3), dopamine receptor and glucocorticoid receptor.
Preclinical studies have shown that NK 1 receptor antagonists can inhibit vomiting caused by cytotoxic chemotherapy drugs such as cisplatin. The preclinical and human positron emission tomography (PET) studies of aripipitan show that aripipitan can penetrate the blood-brain barrier and occupy NK 1 receptor in the brain. Arepitan can inhibit acute and delayed vomiting induced by cisplatin, and enhance the antiemetic activity of 5-HT3 receptor antagonist ondansetron and glucocorticoid dexamethasone on cisplatin-induced vomiting.
Toxicological study
In the toxicity test of repeated use of aripipitan in rats for six consecutive menstrual periods, the maximum feasible dose is 1000mg/kg, twice a day (the total body exposure level of female rats and male rats is similar to or lower than that of adult rats, respectively), which can lead to the increase of liver weight with hypertrophy of hepatocytes, the increase of thyroid weight with hypertrophy and/or proliferation of thyroid follicular cells, and the formation of pituitary vacuoles. This result is a species-specific result induced by hepatic CYP enzyme in rats, and these pathological changes can also be observed in rats given other hepatic CYP enzyme inducers with different structures and pharmacological effects from ARIPITAN.
In the toxicity test of repeated administration of aripipitan to dogs for 9 consecutive menstrual periods, in? At the dose of 5mg/kg twice a day (the whole body exposure level is greater than or equal to 13 times of the adult dose), the toxicity shows that the serum alkaline phosphatase activity is slightly increased and the albumin/globulin ratio is decreased; Are you online? At the dose of 25mg/kg, twice a day (the total body exposure level is 365,438+0 times that of adults), significant weight gain and loss, testicular degeneration and prostate atrophy can be observed. At the dose of 500 mg/kg twice a day (the total body exposure level is 70 times that of adults), a slight increase in liver weight can be observed, but there is no histological correlation. During the period of 1 year, dogs were given 32 mg/kg of aripipitan every day (the whole body exposure level was 6 times that of adults), and no toxicity was observed.
Genetic toxicity: Ames test of aripipitan, gene mutation test of human lymphoblastoid cell (TK6), DNA breakage test of rat hepatocytes, chromosome aberration test of China hamster ovary (CHO) cells and micronucleus test of mice were all negative.
Reproductive toxicity: The maximum feasible dose of aripipitan is 65,438+000 mg/kg, twice a day, which has no effect on the fertility or reproductive behavior of male and female rats. At this dose, the exposure of male rats is lower than that recommended by human, and the exposure of female rats is 1.6 times that of human.
The pregnant rats and rabbits were given aripipitan orally, with the dosage as high as 65,438+000 mg/kg, twice a day, and the dosage was 25mg/kg (the exposure was 65,438+0.6 times and 65,438+0.4 times of the recommended dosage, respectively), and no damage was found to the fetus. At these doses, aripipitan can be transported to the placenta of rats and rabbits. In rats and rabbits, the fetal plasma concentration of aripiptan is about 27% and 56% of the maternal plasma concentration.
Lactating rats were given aripipitan 1000mg/kg twice a day, and a higher concentration of aripipitan was observed in their milk. At this dose, the average concentration of milk drug is 90% of the average concentration of plasma drug.
Carcinogenicity: SD rats and CD- 1 mice were tested for carcinogenicity for 2 years. Rats were given 0.05- 1000mg/kg twice a day, and the exposure of the highest dose was about 0.7- 1.6 times of the recommended dose 125mg/ day. At the dose of 5- 1000mg/kg twice a day, the incidence of thyroid follicular adenoma and thyroid follicular carcinoma in male rats increased. At the dose of 5- 1000mg/kg twice daily, the incidence of hepatocellular carcinoma and thyroid follicular adenoma increased in female rats. At the dose of 125- 1000mg/kg twice daily,
The dose given to mice is 2.5-2000 mg/kg/day, and the exposure of the highest dose is about 2.8-3.6 times of the recommended dose. Dermatofibrosarcoma was found in male mice at the dose of 125-500 mg/kg. absorb
The average absolute oral bioavailability of aripiptan is about 60% to 65%, and the average peak plasma concentration (Cmax) of aripiptan can be achieved within about 4 hours (Tmax). Taking aripiptam capsules in standard breakfast has no clinical effect on the bioavailability of aripiptam.
In the clinical dose range, the pharmacokinetics of aripiptan is nonlinear. In healthy young adults, after a single oral dose of 80mg to 125mg after meals, AUC0-? The increase is 26% greater than the dose.
After single oral administration of 1 25mg and 80mg of aripipitan on day 1 and day 2 and day 3 respectively, the AUC of 0-24h on day/kloc-0 and day 3 was about 19.5 μ g/ml and 20. 1 μ g/hr, respectively. Cmax of 1 and 3 days were 1.5μg/mL and 1.4mcg/mL, respectively, and reached (Tmax) in about 4 hours.
Healthy young subjects in China received a single oral dose of 125mg (day 1 day) or a 3-day regimen of aripiptan (including a single oral dose of 1 25mg/day and a single oral dose of 80mg/day 2-3), and the median Tmax of aripiptan was after administration. On day 1 and day 3, the Cmax values (Tmax) reached in about 4 hours were 3.3μg/mL and 4.3μg/mL respectively.
Be distributed
The binding rate of aripipitan to plasma protein is more than 95%. The geometric average of the steady-state apparent distribution volume (Vdss) of human body is about 66L.
Aripitan can penetrate the rat placenta and the blood-brain barrier of rats and ferrets. Studies on human PET show that aripipitan can penetrate the blood-brain barrier (see "Pharmacology and Toxicology", mechanism of action).
To metabolize.
Aripitam can perform a wide range of metabolism. In healthy young adults, within 72 hours after a single oral dose of 300mg[ 14C]-, aripiptan accounts for about 24% of the radioactive markers in plasma, indicating that there are a large number of metabolites in plasma. Seven metabolites of aripipitan were found in human plasma, and they have only weak activity. The metabolism of aripipitan mainly occurs through the oxidation of morpholine ring and side chain. In vitro studies using human liver microsomes showed that aripipitan was mainly metabolized by CYP3A4, and a few were metabolized by CYP 1A2 and CYP2C 19, but CYP2D6, CYP2C9 or CYP2E 1 had no metabolic effects on it.
Clear the table
Arepitam is mainly eliminated by metabolism; Arepitan cannot be excreted through the kidneys. After a single oral administration of 300mg[ 14C]- aripipitan to healthy subjects, 5% and 86% of radioactive markers were recovered in urine and feces, respectively.
The apparent plasma clearance rate of aripiptan is about 60 to 84 ml/min. The apparent terminal half-life is about 9 to 13 hours.
Characteristics of patients
gender
After a single oral administration of aripiptan, the AUC 0-24 hours and Cmax of aripiptan in women were 9% and 65438 07% higher than those in men, respectively. The half-life of aripiptan in women is about 25% shorter than that in men, while the Tmax of men and women is similar. These differences have no clinical significance. There is no need to adjust the dosage of this product according to gender.
the aged
Old man (? 65-year-old) was given 1 25 mg aripiptan 1 time on 1 day, and after taking 80mg aripiptan daily on the 2nd to 5th day, the AUC0-24hr of aripiptan on1day and the 5th day increased by 2 1% and 36 respectively. Cmax of 1 and 5-day-old is higher than that of young adults 10% and 24% respectively. These differences have no clinical significance. Elderly patients do not need to adjust the dose of this product.
children
Pharmacokinetics of this product has not been evaluated in patients younger than 18 years old.
race
After a single oral administration of this product, the AUC of Spaniards is about 27% and 365,438+0% higher than that of whites and blacks from 0 to 24 hours, respectively. The Cmax of Spaniards is 19%, which is 29% higher than that of Caucasians and blacks. After a single oral administration of this product, the AUC 0-24 hours and Cmax of Asians are 74% and 47% higher than those of whites, respectively. The drug exposure levels AUC0-24hr and Cmax in China are higher than those in non-China subjects, and these differences have no important clinical significance. Further research on drug price comparison is under way. At present, it is not recommended to adjust the dose of this product according to race.
Body mass index (BMI)
Body mass index has no significant clinical effect on the pharmacokinetics of aripiptan.
hepatic insufficiency
Patients with mild to moderate liver dysfunction are well tolerated. In patients with mild liver dysfunction (Child-Pugh score of 5-6), after taking 1 25mg aripipitan once a day on/kloc-0, and taking 80mg once a day on the 2nd and 3rd days, the AUC of aripipitan on 1 day and 3rd day was lower than that of healthy subjects receiving the same treatment. In patients with moderate liver dysfunction (Child-Pugh score 7-9), the AUC of aripipitan at 1 and the 3rd day was 0-24 hours higher than that of healthy subjects receiving the same treatment 10% and 18% respectively. These differences between AUC 0-24 hours have no clinical significance; Therefore, patients with mild to moderate liver dysfunction do not need to adjust the dose of this product.
Clinical or pharmacokinetic data of patients with severe liver dysfunction (Child-Pugh score greater than 9) have not been obtained.
Renal insufficiency
Patients with severe renal insufficiency (CrCl < 30ml/min) and patients with end-stage renal disease (ESRD) who need hemodialysis were given 240mg aripiptan orally once.
In patients with severe renal insufficiency, AUC0-? Compared with healthy subjects, Cmax decreased by 265438 0% and 32% respectively. In hemodialysis patients with end-stage renal disease, AUC0? And Cmax decreased by 42% and 32% respectively. Because the protein binding rate of aripipitan is only moderately decreased in patients with renal disease, the AUC of pharmacologically active non-protein binding drugs is not significantly affected compared with healthy subjects in patients with renal insufficiency. Hemodialysis at 4 or 48 hours after administration had no significant effect on the pharmacokinetics of aripiptan. The recovered dose in dialysate is less than 0.2%.
Patients with severe renal insufficiency or patients with end-stage renal disease undergoing hemodialysis do not need to adjust the dosage of this product.