Date of approval.
Date of revision.
Arepitant Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Aprepitant Capsules
English Name: Aprepitant Capsules
Hanyu Pinyin: Aruipitan Jiaonang
Ingredients
The main ingredient of this product is Aripitant
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
Chemical structure formula.
Molecular formula: C23H21F7N4O3
Molecular weight: 534.43
Properties
The content of this product is white or off-white small pills.
Indications
Arepitant capsules are used in combination with other antiemetic drugs for the prevention of acute and delayed nausea and vomiting during initial and repeated treatment with highly emetogenic antineoplastic chemotherapy (see “Dosage and Administration”).
Specification
(1) 80mg; (2) 125mg
Dosage]
The dosage form of this product is oral capsule.
It is administered for 3 days in combination with a glucocorticoid and a 5-HT3 antagonist. The instructions for the 5-HT3 antagonist need to be read carefully before starting treatment. The recommended dose of this product is 125 mg orally 1 hour prior to chemotherapy (day 1) and 80 mg orally once daily in the morning on days 2 and 3.
In a clinical study conducted in China, the following regimen was used to prevent nausea and vomiting due to highly emetogenic antineoplastic chemotherapy.
Day 1 Day 2 Day 3 Day 4 Arepitant* oral 125 mg oral 80 mg oral 80 mg no dexamethasone** oral 6 mg oral 3.75 mg oral 3.75 mg oral 3.75 mg granisetron† intravenous infusion 3 mg no no no * oral arepitant 1 hour before chemotherapy on day 1 and in the morning on days 2 and 3.
**Dexamethasone 30 minutes prior to Day 1 chemotherapy and in the morning of Days 2-4 at a dose determined by drug interactions.
†Glastron 30 minutes prior to chemotherapy on Day 1.
General Information
See Drug Interactions for additional information on the use of this product in combination with glucocorticoids.
For antiemetic agents used in combination, please refer to their instructions.
This product may or may not be taken with or without food.
Dose adjustment is not required for patients of different ages, genders, races, and body mass indexes (BMI).
Dose adjustment of this product is not required in patients with severe renal insufficiency (creatinine clearance <30 ml/min) and in patients with end-stage renal disease undergoing hemodialysis.
Patients with mild to moderate hepatic insufficiency (Child-Pugh score of 5-9) do not require dose adjustment. There are no clinical studies on the use of this product in patients with severe hepatic insufficiency (Child-Pugh classification score > 9).
[Adverse Reactions].
The overall safety of aripitant was evaluated in approximately 6500 patients.
Highly emetogenic chemotherapy (HEC)
Domestic clinical trials
A randomized controlled clinical study was conducted in Chinese patients receiving highly emetogenic antineoplastic chemotherapy (HEC) in which 412 patients received aripitant in cycle 1 of chemotherapy and 240 of them went on to phase 2 chemotherapy. The dosing regimen of aripitant combined with granisetron and dexamethasone (aripitant treatment arm) was generally well tolerated. The major adverse events seen in the clinic were mild to moderate.
In the first cycle, drug-related adverse events were reported in approximately 11.7% of patients in the aripitant treatment group, compared with approximately 13.3% of patients on standard therapy.
The most common and slightly higher drug-related clinical adverse events in the aripitant-treated group than in the standard therapy group were constipation (7.8% and 7.6%, respectively) and loss of appetite (2.9% and 1.9%, respectively).
There were similar drug-related laboratory changes in the aripitant and standard treatment groups, with incidences of 5.4% and 6.7%, respectively. Drug-related laboratory changes that were higher in the aripitant group than in the standard treatment group included elevated blood glucose levels, elevated blood creatinine, elevated blood potassium, elevated blood urea, neutropenia, and proteinuria. The incidence rates were 0.5% and 0%, respectively.
The adverse event profile in the second cycle was generally similar to that of the first cycle.
Global Clinical Studies
In 2 randomized, controlled clinical trials in patients receiving highly emetogenic antineoplastic chemotherapy (HEC), 544 patients received aripitant during the first cycle of chemotherapy, and 413 of these patients went on to multiple to 6 cycles of chemotherapy. Patients treated with aricitabine capsules in combination with ondansetron and dexamethasone (aricitabine regimen) were generally well tolerated. In these clinical studies, most adverse reactions were mild to moderate in severity.
In the first cycle of chemotherapy, the incidence of drug-related adverse reactions was approximately 19% in the aripitant treatment group compared to approximately 14% in the standard treatment group. Discontinuation of aripitant therapy due to drug-related adverse reactions was 0.6% in the aripitant-treated group compared with 0.4% in the standard-treatment group.
The most common drug-related adverse reactions in the aripitant treatment group and higher than in the standard treatment group included: eructation (4.6%), elevated ALT (alanine aminotransferase) (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2.0%), and loss of appetite (2.0%).
In another positive drug-controlled clinical study of 1169 patients receiving aripitant for highly emetogenic chemotherapy, the adverse event profile was generally similar to that of other studies of aripitant for 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 aripitant during the first cycle of chemotherapy, and 686 of these patients went on to multiple to 4 cycles of chemotherapy. In these 2 studies, the combination of aripitant capsules with ondansetron and dexamethasone (aripitant regimen) was largely well tolerated by patients. The majority of adverse reactions in these clinical studies were mild to moderate in severity.
In a combined analysis of the first cycle data from these 2 studies, the incidence of drug-related adverse reactions was reported to be approximately 14% in the aripitant treatment group and approximately 15% in the standard treatment group. Discontinuation of aripitant treatment due to drug-related adverse reactions was 0.7% in the aripitant treatment group and 0.2% in the standard treatment group.
The most common and significantly higher drug-related adverse reaction in the aripitant group than in the standard treatment group was fatigue (1.4%).
Highly and moderately emetogenic chemotherapy
Global Clinical Trials
In a combined analysis of highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) studies, the drug-related adverse reactions that occurred at a higher rate in the aripitant treatment group than in the standard treatment group included the following.
[common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000)]
Infections and infectious diseases.
Rare: Candidiasis, staphylococcal infections
Blood and lymphatic system disorders.
Unusual: anemia, neutropenic fever
Metabolic and nutritional disorders.
Common: decreased appetite
Rare: excessive drinking
Psychiatric disorders.
Uncommon: anxiety
Rare: disorientation, euphoria
Neurological disorders.
Uncommon: vertigo, somnolence
Rare: cognitive impairment, somnolence, taste abnormalities
Ocular disorders.
Rare: conjunctivitis
Ear and vagus disorders.
Rare: Tinnitus
Cardiac disorders.
Unusual: bradycardia, palpitations
Vascular disease.
Uncommon: flushing of the face
Respiratory, thoracic and mediastinal disorders.
Common: eruption
Rare: oropharyngeal pain, sneezing, coughing, postnasal drip, throat irritation
Gastrointestinal disorders.
Common: indigestion
Uncommon: belching, nausea, gastroesophageal reflux disease, vomiting, abdominal pain, dry mouth, flatulence
Rare: hard stools, perforated duodenal ulcer, neutropenic colitis, stomatitis, abdominal distention
Skin and subcutaneous tissue disorders.
Unusual: rash, acne
Rare: photosensitivity reactions, hyperhidrosis, seborrhea, skin lesions, rash, pruritus
Musculoskeletal and connective tissue disorders.
Rare: muscle spasms, muscle weakness
Renal and urinary disorders.
Uncommon: difficulty urinating
Rare: urinary frequency
Systemic and administration site disorders.
Common: fatigue and weakness
Uncommon: weakness, discomfort
Rare: edema, chest discomfort, pace disorder
Study findings.
Common: elevated ALT levels
Uncommon: elevated AST levels, elevated blood alkaline phosphatase levels
Rare: increased urine output, positive urine red blood cells, decreased blood sodium, decreased body weight, glycosuria, decreased neutrophils
The overall profile of adverse reactions during multiple cycles to a maximum of 6 cycles of chemotherapy was generally similar to that observed during the first cycle of chemotherapy.
In another study on chemotherapy-induced nausea and vomiting (CINV) there was 1 patient treated with both aripitant and other antineoplastic chemotherapeutic agents and Stevens-Johnson syndrome was reported.
Other clinical studies
Studies of a single dose of 40 mg of aripitant for the prevention of postoperative nausea and vomiting (PONV) in patients receiving general balanced anesthesia but not chemotherapy, where adverse reactions identified at a higher rate than the positive control drug (ondansetron) included: decreased ALT, epigastric pain, abdominal bowel sounds, dysphonia, dyspnea, hyperalgesia, insomnia, pupillary constriction, nausea Intuition disturbance, gastric discomfort, decreased visual acuity, and shortness of breath.
In addition, there were two serious adverse events: constipation and fractional bowel obstruction in a study of high-dose aripitant for the prevention of postoperative nausea and vomiting.
In a non-CINV/non-PONV clinical study, angioedema and urticaria were reported in a patient taking arapitant.
Postmarketing Experience:
The following adverse reactions were reported in the post-marketing use of aripitant. These adverse reactions were from patients who reported them spontaneously and in a population with an unknown sample size, and it is usually not possible to reliably estimate the incidence of these adverse reactions or to determine their causal relationship with the drug.
Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rare Stevens-Johnson syndrome, and toxic epidermal necrolysis
Immune system disorders: hypersensitivity reactions, including anaphylactic reactions
Contraindications】It is contraindicated in people who are hypersensitive to any of the ingredients in this product.
This product should not be used simultaneously with pimozide, terfenadine, astemizole, cisapride. Arepitant may cause dose-dependent inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4), resulting in increased blood levels of these drugs, which may cause serious or life-threatening adverse reactions (see “Drug Interactions”).
Precautions]
This product is a dose-dependent CYP3A4 inhibitor and must be used with caution in combination with drugs that are primarily metabolized by CYP3A4; certain chemotherapeutic agents are metabolized by CYP3A4 (see Drug Interactions). Moderate inhibition of CYP3A4 by aripitant 125 mg/80 mg therapy may increase the blood levels of these concomitant drugs (see Drug Interactions).
Concomitant use of this product with warfarin may result in a significant decrease in the International Normalized Ratio (INR) of prothrombin time. Patients requiring long-term warfarin therapy should be monitored closely for two weeks after the start of each chemotherapy cycle with a 3-day dosing regimen of this drug, especially on days 7-10 (see Drug Interactions).
The efficacy of sex hormonal contraceptives may be reduced during and up to 28 days after administration of this drug. Therefore, other contraceptive measures or remedies should be used during treatment with this product and for 1 month after the last dose of this product (see Drug Interactions).
Use in Pregnant and Lactating Women
Adequate and well-controlled studies have not been conducted in pregnant women. Arepitant should be used during pregnancy only if the potential benefits to the mother and fetus outweigh the potential risks.
Arepitant can be secreted into the milk of rats. It is not known whether this product can be secreted into human breast milk. Because many drugs can be secreted into human milk and because of the potential for adverse reactions in nursing infants, the decision to discontinue nursing or to discontinue drug therapy must be based on the importance of the drug to the mother.
Pediatric Use]
The safety and efficacy of using this product in children have not been established.
Geriatric use]
In clinical studies, the safety and efficacy of this product in the elderly (age ≥65 years) were comparable to those in younger patients (<65 years). Therefore, no dose adjustment is required for elderly patients. Drug Interactions]
Arepitant is a substrate, mild to moderate (dose-dependent) inhibitor and inducer of CYP3A4. Arepitant is also a CYP2C9 inducer.
Data on drug interactions were obtained from foreign studies. High levels of aripitant exposure were observed in Chinese patients in a domestic clinical study. Careful monitoring of clinically relevant drug interactions is necessary.
Effect of aripitant on the pharmacokinetics of other drugs
As a moderate (125 mg/80 mg) inhibitor of CYP3A4, arilpitant increases the plasma concentration of oral drugs metabolized by CYP3A4. Arepitant (125 mg/80 mg) may also increase plasma concentrations of intravenous drugs metabolized by CYP3A4, but to a lesser extent relative to oral drugs.
It should not be used in combination with pimozide, terfenadine, astemizole, or cisapride. Dose-dependent inhibition of CYP3A4 by aripitant may lead to increased plasma concentrations of these drugs and may result in serious or life-threatening reactions (see Contraindications).
Studies have shown that aripitant induces the metabolism of S(-) warfarin and toluenosulfonylurea via CYP2C9. Combination of this drug with these and other drugs known to be metabolized by CYP2C9, such as phenytoin, may result in lower blood levels of these drugs.
There is no interaction between this product and the substrate class of P-glycoprotein transporter proteins because no interaction was shown between this product and digoxin in clinical drug interaction studies.
5-HT3 antagonists: In clinical drug interaction studies, there was no clinically significant effect of aripitant on the pharmacokinetics of ondansetron, granisetron, or hydroxydolasetron (the active metabolite of dolasetron).
Glucocorticoids.
Dexamethasone: Combination therapy with aripitant 125 mg with oral dexamethasone 20 mg on day 1 and this product 80 mg daily with oral dexamethasone 8 mg on days 2 through 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 aripitant (125 mg/80 mg therapy), the routine oral dose of dexamethasone should be reduced by approximately 50% so that exposure levels to dexamethasone are similar to those that would have occurred in the absence of this product. In clinical studies of aripitant for the prevention of chemotherapy-induced nausea and vomiting, the daily dose of dexamethasone was reduced by approximately 50% (see “Dosage and Administration”).
Methylprednisolone: 125 mg orally on day 1 and 80 mg orally on days 2 to 3 increased the AUC of the CYP3A4 substrate methylprednisolone by 1.3-fold on day 1 and 2.5-fold on day 3, where methylprednisolone was administered as 125 mg intravenously on day 1 and 40 mg orally on days 2 and 3. Thus, compared with When used in combination with arrepitant (125 mg/80 mg therapy), the routine intravenous infusion dose of methylprednisolone must be reduced by approximately 25% and the routine oral dose of methylprednisolone should be reduced by approximately 50% so that the exposure level of methylprednisolone is similar to the exposure level without arrepitant.
Chemotherapeutic agents: Chemotherapeutic agents known to be metabolized via CYP3A4 include polyenol, paclitaxel, etoposide, irinotecan, isocyclophosphamide, cyclophosphamide, imatinib, vincristine, vincristine, and vincristine. In clinical studies, aripitant capsules (125 mg/80 mg regimen) were commonly combined with etoposide, vincristine, polygalactin, isocyclophosphamide, cyclophosphamide, irinotecan, and paclitaxel. Doses of drugs with potential drug interactions were not adjusted in the study. There are insufficient data on the interaction of aripitant capsules with other chemotherapeutic agents that are metabolized by CYP3A4. Caution and careful monitoring are recommended for patients using these or other chemotherapeutic agents that are primarily metabolized by CYP3A4. Neurotoxicity, a potential adverse effect of isocyclophosphamide, has been reported in post-marketing safety events when aripitant was combined with isocyclophosphamide (see “Precautions” for details).
In domestic clinical studies, the number of patients receiving the CYP3A4 substrates vincristine and vincristine is small, so information on interactions with these drugs is limited. Special care must be taken to monitor the safety of patients receiving vincristine and vincristine or other chemotherapeutic agents that are metabolized by CYP3A4.
Docetaxel: In a separate pharmacokinetic study, aripitant (125 mg/80 mg therapy) did not affect the pharmacokinetics of docetaxel.
Vincristine: In a separate pharmacokinetic study, aripitant (125 mg/80 mg therapy) did not have an effect on the pharmacokinetics of vincristine.
Warfarin: In healthy subjects stably treated with long-term warfarin, a single oral dose of aricitabine 125 mg on day 1 and 80 mg daily on days 2 and 3 was administered orally. although aricitabine had no effect on the plasma AUC of R(+) or S(-) warfarin measured on day 3, the trough of S(-) warfarin (a CYP2C9 substrate) decreased by 34% within 5 days after the end of aricitabine treatment. concentrations decreased by 34% and prothrombin time (reported as international normalized ratio or INR) was shortened by 14%. Therefore, in patients receiving long-term warfarin therapy, prothrombin time (INR) must be closely monitored over a 2-week period, especially over 7 to 10 days, after a 3-day aripitant treatment in each chemotherapy cycle.
Toluenosulfonylurea: oral aripitant 125 mg on day 1 and 80 mg daily on days 2 and 3, while the AUC of toluenosulfonylurea (CYP2C9 substrate) was reduced by 23%, 28%, and 15% on days 4, 8, and 15, respectively, before the 3-day aripitant treatment and after a single oral dose of toluenosulfonylurea 500 mg on days 4, 8, and 15.
Oral contraceptives: The combination of aripitant 100 mg capsules once daily for 14 days with oral contraceptives containing 35 μg ethinyl estradiol and 1 mg norethindrone resulted in a 43% reduction in the AUC of ethinyl estradiol and an 8% reduction in the AUC of norethindrone.
In another study, oral contraceptives containing ethinylestradiol and norethindrone were administered orally once daily on days 1 to 21, 125 mg of oral aripitant on day 8, 80 mg of oral aripitant daily on days 9 and 10, ondansetron 32 mg IV infusion and a single oral dose of dexamethasone 12 mg on day 8, and 8 mg of oral dexamethasone daily on days 9, 10, and 11. In this In this study, the AUC of ethinylestradiol decreased by 19% on day 10, and the trough concentration of ethinylestradiol decreased by 64% on days 9 to 21. Although aripitant had no effect on the AUC of norethindrone on day 10, the trough concentration of norethindrone decreased by 60% on days 9 to 21.
The effectiveness of hormonal contraceptives decreased during and up to 28 days after aripitant treatment. Alternative or backup contraceptive methods should be used during aripitant treatment and for 1 month after the last aripitant treatment.
Midazolam: After oral aripitant 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, aripitant increased the AUC of the sensitive CYP3A4 substrate midazolam by 2.3-fold and 3.3-fold on days 1 and 5, respectively. The potential effect of elevated blood levels of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) must be taken into account when combining aripitant (125 mg/80 mg) with these drugs.
In another study of midazolam, administered by intravenous infusion, midazolam 125 mg orally on day 1, 80 mg orally daily on days 2 and 3, and 2 mg intravenously before a 3-day aripitant treatment and on days 4, 8, and 15 of aripitant treatment were given. This product increased the AUC of midazolam on day 4 by 25% and decreased the AUC of midazolam on day 8 by 19% compared with the aripitant treatment period of days 1 to 3. These effects were not clinically significant. The AUC of midazolam at day 15 was similar to that observed during the baseline period.
A study of intravenously administered midazolam and aripitant was also completed. Midazolam 2 mg was given 1 hour after a single oral dose of 125 mg of aripitant by intravenous infusion. The plasma AUC of midazolam was increased 1.5-fold. This effect was not clinically significant.
Effect of other drugs on the pharmacokinetics of aripitant
Arepitant is a substrate for CYP3A4; therefore, co-administration of arepitant with drugs that can inhibit CYP3A4 activity can result in increased blood concentrations of arepitant. Therefore, caution must be exercised when combining aripitant with a potent CYP3A4 inhibitor (e.g., ketoconazole); however, the combination of this product and a moderate CYP3A4 inhibitor (e.g., diltiazem) does not result in clinically meaningful changes in plasma concentrations of aripitant.
Arepitant is a substrate for CYP3A4; therefore, the combination of arepitant with a drug that potently induces CYP3A4 activity (e.g., rifampin) can result in a decrease in plasma concentrations of arepitant and may lead to a reduction in the efficacy of arepitant.
Ketoconazole: At a single oral dose of 125 mg of aricitabine on day 5 of a 10-day treatment with the potent CYP3A4 inhibitor ketoconazole, 400 mg daily, the AUC of aricitabine was increased approximately 5-fold, and the mean terminal half-life of aricitabine was prolonged approximately 3-fold. Caution must be exercised when combining aricitabine with a potent CYP3A4 inhibitor.
Rifampin: On a single oral dose of 375 mg of aricitabine on day 9 of a 14-day course of the potent CYP3A4 inducer rifampin, 600 mg daily, the AUC of aricitabine decreased approximately 11-fold and the mean terminal half-life was approximately 3-fold shorter. Combining aricitabine with drugs that induce CYP3A4 activity can result in decreased blood levels and reduced efficacy of aricitabine.
Other interactions
Diltiazem: In patients with mild to moderate hypertension, oral administration of aripitant 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 aripitant and a 1.7-fold increase in the AUC of diltiazem. These pharmacokinetic effects did not result in clinically meaningful changes in electrocardiogram, heart rate, or blood pressure, except for changes caused by diltiazem alone.
Paroxetine: Combining aricitabine tablets similar to 85 mg or 170 mg capsules – once daily with paroxetine 20 mg once daily resulted in an approximate 25% decrease in AUC and an approximate 20% decrease in Cmax for both aricitabine and paroxetine.
[Drug Overdose].
Specific information on overdose of this product is not available. A single oral dose of aripitant at a maximum of 600 mg was generally well tolerated in healthy subjects. In patients enrolled in the non-CINV study, aripitant 375 mg once daily for up to 42 days was generally well tolerated. In 33 cancer patients, a single oral dose of 375 mg aripitant on day 1 and 250 mg orally once daily on days 2 to 5 was generally well tolerated.
One patient treated with 1440 mg of arilpitant developed symptoms of sleepiness and headache.
If an overdose occurs, treatment with this product must be discontinued and general supportive therapy and monitoring must be instituted. Because of the antiemetic activity of aripitant, measures to induce vomiting with medication may not be effective with aripitant.
Arepitant cannot be cleared by hemodialysis.
Pharmacology and Toxicology
Pharmacological effects
Arepitant is a selective high-affinity antagonist of the human substance P neurokinin 1 (NK1) receptor. It has low or no affinity for 5-hydroxytryptamine receptor 3 (5-HT3), dopamine receptors and glucocorticoid receptors, the targets of action of other available drugs for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV).
Preclinical studies have shown that NK1 receptor antagonists can inhibit vomiting induced by cytotoxic chemotherapeutic agents such as cisplatin. Preclinical and human positron emission tomography (PET) studies of aripitant have shown that aripitant crosses the blood-brain barrier and occupies NK1 receptors in the brain. Arepitant inhibits acute and delayed vomiting induced by cisplatin and enhances the antiemetic activity of the 5-HT3 receptor antagonist ondansetron and the glucocorticoid dexamethasone.
Toxicological studies
Repeated oral administration of aripitant in rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (systemic exposure levels approximating or lower than adult dose systemic exposure levels in female and male rats, respectively) for 6 months resulted in increased liver weight with hepatocellular hypertrophy, increased thyroid weight with thyroid follicular cell hypertrophy and/or hyperplasia, and pituitary cell vacuole formation. This result is species-specific for hepatic CYPase induction in rats, and these pathological changes were also observed in rats given other hepatic CYPase inducers with different structural and pharmacological effects than aripitant.
In a repeated administration toxicity test in dogs given orally for 9 months, toxicity was characterized by a slight increase in serum alkaline phosphatase activity and a decrease in the albumin/globulin ratio at doses of ≥5 mg/kg twice daily (systemic exposure levels greater than or equal to 13 times the systemic exposure levels of the adult dose); at doses of ≥25 mg/kg twice daily (systemic exposure levels 31 times the systemic exposure levels of the adult dose). At a dose of ≥25 mg/kg twice daily (31 times the systemic exposure level of the adult dose), a significant reduction in body weight gain, testicular degeneration and prostate atrophy was observed; at a dose of 500 mg/kg twice daily (70 times the systemic exposure level of the adult dose), a slight increase in liver weight was observed, but there was no histological correlation. No toxicity was observed in dogs given aripitant 32 mg/kg daily for 1 year (systemic exposure level 6 times the systemic exposure level of the adult dose).
Genotoxicity: The results of the aripitant Ames test, human lymphoblastoid (TK6) gene mutation test, rat hepatocyte DNA breakage test, Chinese hamster ovary (CHO) cell chromosome aberration test and mouse micronucleus test were all negative.
Reproductive toxicity: The maximum feasible dose of aripitant, 1000 mg/kg, administered twice daily, did not affect fertility or reproductive behavior in male and female rats, and the exposure of male rats at this dose was lower than that at the recommended human dose, and the exposure of female rats was 1.6 times that of humans.
No damage to fetuses was observed in pregnant rats and rabbits given aripitant orally at doses up to 1000 mg/kg twice daily and 25 mg/kg daily (1.6 and 1.4 times the exposure at the recommended human dose, respectively); at these doses, aripitant was transported to the rat and rabbit placentas. In rats and rabbits, fetal plasma aripitant concentrations were approximately 27% and 56% of maternal plasma aripitant concentrations.
In lactating rats given aripitant at 1000 mg/kg twice daily, higher concentrations of aripitant were observed in the milk. At this dose, the mean milk drug concentration was 90% of the mean plasma drug concentration.
Carcinogenicity: A 2-year carcinogenicity test was conducted in SD rats and CD-1 mice. Rats were administered at doses of 0.05-1000 mg/kg twice daily, and exposure at the highest dose was approximately 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 was increased in male rats at doses of 5-1000 mg/kg twice daily. The incidence of hepatocellular adenoma, hepatocellular carcinoma and thyroid follicular cell adenoma were increased in female rats at 5-1000 mg/kg twice daily and 125-1000 mg/kg twice daily.
In mice administered at doses of 2.5-2000 mg/kg/day, the exposure at the highest dose was approximately 2.8-3.6 times the exposure at the recommended human dose. Dermal fibrosarcoma was seen in male mice at doses of 125-500mg/kg.
Pharmacokinetics]
Absorption
The mean absolute oral bioavailability of aripitant is approximately 60% to 65%, and aripitant reaches its mean peak plasma concentration (Cmax) at approximately 4 hours (Tmax). There is no clinically meaningful effect on the bioavailability of aripitant when aripitant capsules are taken with a standard breakfast.
In the clinical dose range, the pharmacokinetics of aripitant are nonlinear. In healthy young adults, the increase in AUC0-∞ was 26% greater than the increase in dose following a single oral dose of 80 mg to 125 mg after a meal. After a single oral dose of 125 mg aripitant on day 1 and 80 mg orally once daily on days 2 and 3, the AUC0-24hr on days 1 and 3 were approximately 19.5 μg-hr/mL and 20.1 μg-hr/mL, respectively. the Cmax on days 1 and 3 were 1.5 μg/ mL and 1.4 mcg/mL, respectively, and were reached within approximately 4 hours (Tmax).
The geometric mean AUC0-24hr on days 1 and 3 were 19.4 μg-hr/mL and 27.8 μg-hr/mL, respectively, for healthy young Chinese subjects receiving a 3-day regimen of aripitant (including 125 mg single oral dose on day 1 and 80 mg single oral dose on days 2-3). day 1 The geometric mean Cmax was 1.4 μg/mL and 1.8 μg/mL on day 1 and day 3, respectively. the median Tmax was the same on day 1 and day 3, both at 4 hr.
Distribution
The binding of aripitant to plasma proteins was >95%. In humans, the geometric mean of the steady-state apparent volume of distribution (Vdss) is approximately 66 L.
Arepitant penetrates the rat placenta and penetrates the blood-brain barrier in rats and ferrets. PET studies in humans suggest that aripitant penetrates the blood-brain barrier (see “Pharmacology and Toxicology”, Pharmacological Effects).
Metabolism
Arepitant undergoes extensive metabolism. In healthy young adults, within 72 hours after a single oral dose of 300 mg of [14C]-aripitant, aripitant accounted for approximately 24% of the plasma radiolabel, indicating the presence of a large number of metabolites in plasma. Seven aripitant metabolites were identified in human plasma, and they were only weakly active. The metabolic effects of arrepitant occur mainly through oxidation on the morpholine ring and side chains. In vitro studies using human liver microsomes suggest that aripitant is metabolized mainly by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19, while it is not metabolized by CYP2D6, CYP2C9 or CYP2E1.
Clearance
Arepitant is primarily cleared by metabolism; arepitant is not excreted by the kidneys. After a single oral dose of 300 mg of [14C]-aripitant in healthy subjects, 5% and 86% of the radiolabel was recovered in urine and feces, respectively.
The apparent plasma clearance of aripitant was approximately 60 to 84 mL/min. The apparent terminal half-life was approximately 9 to 13 hours.
Characteristics in patients
Gender
The AUC0-24hr and Cmax of areapitant after a single oral dose were 9% and 17% higher in women than in men. The half-life of aripitant was approximately 25% shorter in women than in men, and the Tmax was similar in men and women. These differences were not clinically significant. No dose adjustment for this product based on gender is required.
Older Adults
In older adults (≥65 years of age), after a single oral dose of 125 mg aripitant on day 1 and 80 mg aripitant once daily on days 2 through 5, the AUC0-24hr was 21% and 36% higher on days 1 and 5, respectively, and the Cmax was 10% and 24% higher on days 1 and 5, respectively, than in younger adults. These differences were not clinically significant. In elderly patients, no dose adjustment of this product is required.
Children
The pharmacokinetics of this product have not been evaluated in patients younger than 18 years of age.
Ethnicity
After a single oral dose of this product, the AUC0-24hr was approximately 27% and 31% higher in Hispanics than in Caucasians and Blacks. Cmax was 19% and 29% higher in Hispanics than in Caucasians and blacks. After a single oral dose of this product, AUC0-24hr and Cmax were 74% and 47% higher in Asians than in Caucasians, respectively. Drug exposure levels AUC0-24hr and Cmax were higher in Chinese than in non-Chinese subjects; these differences were not clinically significant and further pharmacokinetic studies are underway. Dose adjustment of this product based on ethnicity is not recommended at this time.
Body Mass Index (BMI)
Body mass index has no clinically significant effect on the pharmacokinetics of aripitant.
Hepatic insufficiency
This product is well tolerated in patients with mild to moderate hepatic insufficiency. In patients with mild hepatic insufficiency (Child-Pugh score of 5 to 6), after a single oral dose of 125 mg aripitant on day 1 and 80 mg once daily on days 2 and 3, the AUC0-24hr of aripitant was 11% and 36% lower on days 1 and 3, respectively, than in healthy subjects receiving the same therapy. In patients with moderate hepatic insufficiency (Child-Pugh score of 7 to 9), the AUC0-24hr on days 1 and 3 were 10% and 18% higher, respectively, for aripitant than for healthy subjects receiving the same therapy. these differences in AUC0-24hr were not clinically significant; therefore, no dose adjustment of this product is required in patients with mild to moderate hepatic insufficiency.
Clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9) have not been obtained.
Renal Insufficiency
A single oral dose of 240 mg aripitant was administered in patients with severe renal insufficiency (CrCl less than 30 mL/min) and in patients with end-stage renal disease (ESRD) requiring hemodialysis.
In patients with severe renal insufficiency, the AUC0-∞ and Cmax of all aripitant (protein-bound and protein-unbound) in vivo decreased by 21% and 32%, respectively, compared with healthy subjects. In patients with end-stage renal disease receiving hemodialysis, the AUC0-∞ and Cmax of all aripitant in vivo decreased by 42% and 32%, respectively. Because protein binding of aripitant was only moderately decreased in patients with renal disease, the AUC of pharmacologically active nonprotein-bound drugs was not significantly affected in patients with renal insufficiency compared with healthy subjects. Hemodialysis performed 4 or 48 hours after dosing did not have a significant effect on the pharmacokinetics of aripitant; less than 0.2% of the dose was recovered in the dialysate.
No dose adjustment is required in patients with severe renal insufficiency or in patients with end-stage renal disease receiving hemodialysis.
Storage]
Seal and store below 30℃.
Package】
Aluminum-aluminum packaging. Composition: polyamide/aluminum/polyvinyl chloride cold pressed solid pharmaceutical compound hard tablets and pharmaceutical aluminum foil.
125mg, 80mg combination package: 125mg 1 capsule and 80mg 2 capsules/board/box.
125mg: 1 capsule/plate, 5 capsules/plate, 10 capsules/plate.
80mg: 2 capsules/plate, 5 capsules/plate, 10 capsules/plate.
Package in each box.
(1) 3 capsules: 1 capsule of 125mg and 2 capsules of 80mg.
(2) 15 capsules: 5 capsules 125mg/plate and 5 capsules 80mg/plate x 2 plates.
(3) 30 capsules: 10 capsules 125mg/plate and 10 capsules 80mg/plate x 2 plates.
Expiration date
24 months
Execution Standard
Approval number
[Drug Marketing Licensee
Name: Qilu Pharmaceutical Co.
Registered address: No. 317 Xinluo Street, Jinan High-tech Zone
Manufacturer
Company Name: Qilu Pharmaceutical Co.
Production Address: No. 317 Xinluo Street, Jinan High-tech Zone
Postal Code: 250100
Telephone number: 400-127-7799
Fax number: 0531-83126288 83126545
Website: www.qilu-pharma.com