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英文药名：EMEND(aprepitant capsules) 中文药名：阿瑞吡坦胶囊 生产厂家：美国默克
The recommended oral dosage of EMEND is 40 mg within 3 hours prior to induction of anesthesia. EMEND may be taken with or without food. 2.3 Geriatric Patients No dosage adjustment is necessary for the elderly. 2.4 Patients with Renal Impairment No dosage adjustment is necessary for patients with renal impairment or for patients with end stage renal disease (ESRD) undergoing hemodialysis. 2.5 Patients with Hepatic Impairment No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic impairment (Child-Pugh score >9). 2.6 Coadministration with Other Drugs For additional information on dose adjustment for corticosteroids when coadministered with EMEND, see Drug Interactions (7.1). Refer to the full prescribing information for coadministered antiemetic agents. 3 DOSAGE FORMS AND STRENGTHS Capsules EMEND 40 mg are opaque, hard, gelatin capsules, with white body and mustard yellow cap with "464" and "40 mg" printed radially in black ink on the body. Capsules EMEND 80 mg are white, opaque, hard, gelatin capsules, with "461" and "80 mg" printed radially in black ink on the body. Capsules EMEND 125 mg are opaque, hard, gelatin capsules, with white body and pink cap with "462" and "125 mg" printed radially in black ink on the body. 4 CONTRAINDICATIONS EMEND is contraindicated in patients who are hypersensitive to any component of the product. EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions (7.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 CYP3A4 Interactions EMEND (aprepitant), a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125-mg/80-mg regimen, could result in elevated plasma concentrations of these concomitant medications. Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions (7.1)]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, EMEND (125-mg/80-mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125-mg/80-mg regimen) was co-administered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions (7.1)]. 5.2 Coadministration with Warfarin (a CYP2C9 substrate) Coadministration of EMEND with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for the prevention of postoperative nausea and vomiting [see Drug Interactions (7.1)]. 5.3 Coadministration with Hormonal Contraceptives Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions (7.1)]. 5.4 Patients with Severe Hepatic Impairment There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients [see Clinical Pharmacology (12.3) and Dosage and Administration (2.5)]. 5.5 Chronic Continuous Use Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use. 6 ADVERSE REACTIONS The overall safety of aprepitant was evaluated in approximately 5300 individuals. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 6.1 Clinical Trials Experience Chemotherapy Induced Nausea and Vomiting Highly Emetogenic Chemotherapy In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone. In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Table 1 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3%. Table 1: Percent of Patients Receiving Highly Emetogenic Chemotherapy with Clinical Adverse Experiences (Incidence ≥3%) — Cycle 1
Moderately Emetogenic Chemotherapy During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy. In the combined analysis of Cycle 1 data for these 2 studies, the adverse experience profile in both moderately emetogenic chemotherapy studies was generally comparable to the highly emetogenic chemotherapy studies. Table 2 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3%. Table 2: Percent of Patients Receiving Moderately Emetogenic Chemotherapy with Clinical Adverse Experiences (Incidence ≥3%) — Cycle 1
Highly and Moderately Emetogenic Chemotherapy The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen in either HEC or MEC studies: Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection. Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant neoplasm, non-small cell lung carcinoma. Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia. Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia. Psychiatric disorders: anxiety disorder, confusion, depression. Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor. Eye disorders: conjunctivitis. Cardiac disorders: myocardial infarction, palpitations, tachycardia. Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension. Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance. Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased. Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash. Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia. Renal and urinary disorders: dysuria, renal insufficiency. Reproductive system and breast disorders: pelvic pain. General disorders and administrative site conditions: edema, malaise, pain, rigors. Investigations: weight loss. Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study. Laboratory Adverse Experiences Table 3 shows the percent of patients with laboratory adverse experiences reported at an incidence ≥3% in patients receiving highly emetogenic chemotherapy. Table 3: Percent of Patients Receiving Highly Emetogenic Chemotherapy with Laboratory Adverse Experiences (Incidence ≥3%) — Cycle 1
The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1. Postoperative Nausea and Vomiting In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40-mg aprepitant orally and 538 patients were administered 4-mg ondansetron IV. Clinical adverse experiences were reported in approximately 60% of patients treated with 40-mg aprepitant compared with approximately 64% of patients treated with 4-mg ondansetron IV. Table 4 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3% of the combined studies. Table 4: Percent of Patients Receiving General Anesthesia with Clinical Adverse Experiences (Incidence ≥3%)
Infections and infestations: postoperative infection Metabolism and nutrition disorders: hypokalemia, hypovolemia. Nervous system disorders: dizziness, hypoesthesia, syncope. Vascular disorders: hematoma Respiratory, thoracic and mediastinal disorders: dyspnea, hypoxia, respiratory depression. Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia. Skin and subcutaneous tissue disorders: urticaria General disorders and administrative site conditions: hypothermia, pain. Investigations: blood pressure decreased Injury, poisoning and procedural complications: operative hemorrhage, wound dehiscence. Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: Nervous system disorders: dysarthria, sensory disturbance. Eye disorders: miosis, visual acuity reduced. Respiratory, thoracic and mediastinal disorders: wheezing Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort. There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40-mg aprepitant. Laboratory Adverse Experiences One laboratory adverse experience, hemoglobin decreased (40-mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia. The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present. The adverse experience of ALT increased occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%). Other Studies In addition, two serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus. Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis. Immune system disorders: hypersensitivity reactions including anaphylactic reactions. Nervous system disorders: Events of ifosfamide-induced neurotoxicity have been reported after aprepitant and ifosfamide coadministration. 7 DRUG INTERACTIONS Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. 7.1 Effect of Aprepitant on the Pharmacokinetics of Other Agents CYP3A4 substrates: Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect. As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see Contraindications (4)]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg). 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone [see Dosage and Administration (2.1)]. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended. Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40-mg dose of aprepitant has not been studied, a single 40-mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended. Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel. Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree. Other Chemotherapeutic Agents: EMEND should be used with caution in patients receiving other chemotherapeutic agents that are primarily metabolized through CYP3A4 [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. CYP2C9 substrates (Warfarin, Tolbutamide): Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs. Warfarin: A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with EMEND. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for the prevention of postoperative nausea and vomiting. Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important. Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%. In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone. The coadministration of EMEND may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND. Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important. In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline. An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (e.g., elderly patients) and degree of monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with EMEND for the chemotherapy induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3). 7.2 Effect of Other Agents on the Pharmacokinetics of Aprepitant Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND. Ketoconazole: When a single 125-mg dose of EMEND was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of EMEND was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND. 7.3 Additional Interactions EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study. Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic effects Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0‑24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0‑24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of EMEND in pediatric patients have not been established. 8.5 Geriatric Use In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with EMEND, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. 10 OVERDOSAGE No specific information is available on the treatment of overdosage. Drowsiness and headache were reported in one patient who ingested 1440 mg of aprepitant. In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. 11 DESCRIPTION EMEND (aprepitant) is a substance P/neurokinin 1 (NK1) receptor antagonist, chemically described as 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. Its empirical formula is C23H21F7N4O3, and its structural formula is:
Aprepitant is a white to off-white crystalline solid, with a molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.
Ondansetron 32 mg I.V. was used in the clinical trials of EMEND. Although this dose was used in clinical trials, this is no longer the currently recommended dose. Refer to the ondansetron package insert for the current dosing. During these studies, 95% of the patients in the aprepitant group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of aprepitant patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11). The antiemetic activity of EMEND was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints: Primary endpoint: complete response (defined as no emetic episodes and no use of rescue therapy) Other prespecified endpoints: complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale) no emesis (defined as no emetic episodes regardless of use of rescue therapy) no nausea (maximum VAS <5 mm on a 0 to 100 mm scale) no significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale) A summary of the key study results from each individual study analysis is shown in Table 6 and in Table 7. Table 6: Percent of Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase for Study 1 — Cycle 1
Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm = nausea as bad as it could be. N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation Overall: 0 to 120 hours post-cisplatin treatment Acute phase: 0 to 24 hours post-cisplatin treatment Delayed phase: 25 to 120 hours post-cisplatin treatment Not statistically significant when adjusted for multiple comparisons. Not statistically significant. In both studies, a statistically significantly higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately. In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen, and the incidence of first emesis was reduced in the aprepitant regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1.
Figure 1: Percent of Patients Receiving Highly Emetogenic Chemotherapy Who Remain Emesis Free Over Time — Cycle 1
1 hour prior to chemotherapy 30 minutes prior to chemotherapy 30 to 60 minutes prior to chemotherapy and 8 hours after first ondansetron dose. The antiemetic activity of EMEND was evaluated based on the following endpoints: Primary endpoint: complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy) Other prespecified endpoints: no emesis (defined as no emetic episodes regardless of use of rescue therapy) no nausea (maximum VAS <5 mm on a 0 to 100 mm scale) no significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale) complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale) complete response during the acute and delayed phases. A summary of the key results from this study is shown in Table 9. Table 9: Percent of Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment Group and Phase — Cycle 1
Patient-Reported Outcomes: In a phase III study in patients receiving moderately emetogenic chemotherapy, the impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the aprepitant regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the "No Vomiting Domain" of this composite endpoint. Multiple-Cycle Extension: Patients receiving moderately emetogenic chemotherapy were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. Antiemetic effect for patients receiving the aprepitant regimen is maintained during all cycles. Postmarketing Trial: In a postmarketing, multicenter, randomized, double-blind, parallel-group, clinical study in 848 cancer patients, the aprepitant regimen (N=430) was compared with a standard of care therapy (N=418) in patients receiving a moderately emetogenic chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV (<1500 mg/m2); or cytarabine IV (>1 g/m2). Of the 430 patients who were randomized to receive the aprepitant regimen, 76% were women and 24% were men. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. The aprepitant-treated patients in this clinical study ranged from 22 to 85 years of age, with a mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years. Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers. The antiemetic activity of EMEND was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period. A summary of the key results from this study is shown in Table 10. Table 10: Percent of Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment Group for Study 2 — Cycle 1
In this study, a statistically significantly higher proportion of patients receiving the aprepitant regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the aprepitant regimen (69%) in Cycle 1 had a complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively). In a subgroup analysis by tumor type, a numerically higher proportion of patients receiving aprepitant were observed to have no vomiting and complete response compared to patients receiving standard therapy. For gender, the difference in complete response rates between the aprepitant and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. A similar difference for gender was observed for the no vomiting endpoint. 14.2 Prevention of Postoperative Nausea and Vomiting (PONV) In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (PONV Studies 1 and 2), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. Patients were randomized to receive 40-mg aprepitant, 125-mg aprepitant, or 4-mg ondansetron. Aprepitant was given orally with 50 mL of water 1 to 3 hours before anesthesia. Ondansetron was given intravenously immediately before induction of anesthesia. A comparison between the 125-mg dose and the 40-mg dose did not demonstrate any additional clinical benefit. The remainder of this section will focus on the results in the 40-mg aprepitant dose recommended for PONV. Of the 564 patients who received 40-mg aprepitant, 92% were women and 8% were men; of these, 58% were White, 13% Hispanic American, 7% Multi-Racial, 14% Black, 6% Asian, and 2% Other. The age of patients treated with 40-mg aprepitant ranged from 19 to 84 years, with a mean age of 46.1 years. 46 patients were 65 years or older, with 13 patients being 75 years or older. The antiemetic activity of EMEND was evaluated during the 0 to 48 hour period following the end of surgery. The two pivotal studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. PONV Study 1 was a multinational study including the U.S., whereas, PONV Study 2 was conducted entirely in the U.S. Efficacy measures in PONV Study 1 included: no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary) time to first use of rescue medication in the 0 to 24 hours following the end of surgery (exploratory) time to first emesis in the 0 to 48 hours following the end of surgery (exploratory). A closed testing procedure was applied to control the type I error for the primary endpoints. The results of the primary and secondary endpoints for 40-mg aprepitant and 4-mg ondansetron are described in Table 11: Table 11: PONV Study 1 – Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population)
Δ Difference (%): Aprepitant 40 mg minus Ondansetron. Estimated odds ratio for Aprepitant versus Ondansetron. A value of >1 favors Aprepitant over Ondansetron P-value of two-sided test <0.05. LB= lower bound of 1-sided 97.5% confidence interval for the odds ratio. Based on the prespecified fixed sequence multiplicity strategy, Aprepitant 40 mg was not superior to Ondansetron. The use of aprepitant did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of aprepitant delayed the time to first vomiting, as depicted in Figure 3.
Δ Difference (%): Aprepitant 40 mg minus Ondansetron. Estimated odds ratio: Aprepitant 40 mg versus Ondansetron. Not statistically significant after pre-specified multiplicity adjustment. 16 HOW SUPPLIED/STORAGE AND HANDLING No. 3854 — 80-mg capsules: White, opaque, hard gelatin capsule with "461" and "80 mg" printed radially in black ink on the body. They are supplied as follows: NDC 0006-0461-02 unit-of-use BiPack of 2 NDC 0006-0461-06 unit-dose package of 6. No. 3855 — 125-mg capsules: Opaque, hard gelatin capsule with white body and pink cap with "462" and "125 mg" printed radially in black ink on the body. They are supplied as follows: NDC 0006-0462-06 unit-dose package of 6. No. 3862 — Unit-of-use TriPack containing one 125-mg capsule and two 80-mg capsules. NDC 0006-3862-03. No. 6741 — 40-mg capsules: Opaque, hard gelatin capsule with white body and mustard yellow cap with "464" and "40 mg" printed radially in black ink on the body. They are supplied as follows: NDC 0006-0464-10 unit-of-use package of 1 NDC 0006-0464-05 unit-dose package of 5. Storage Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION "See FDA-Approved Patient Labeling (Patient Information)" Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed. Patients should be instructed to take EMEND only as prescribed. For the prevention of chemotherapy induced nausea and vomiting (CINV), patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For the prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40-mg capsule of EMEND) within 3 hours prior to induction of anesthesia. Allergic reactions, which may be serious, and may include hives, rash and itching and cause difficulty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely. EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for the prevention of postoperative nausea and vomiting. Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND. ------------------------------------------------ 注：以下产品不同规格和不同价格，购买以咨询为准！ ------------------------------------------------ 产地国家: 美国 原产地英文商品名: Emend 40mg/cap 1Caps/box 原产地英文药品名: Aprepitant 中文参考商品译名: Emend 40毫克/胶囊 1胶囊/盒 中文参考药品译名: 阿瑞吡坦 生产厂家中文参考译名: 美国默克 生产厂家英文名: Merck -------------------------------------------------------- 产地国家: 美国 原产地英文商品名: Emend 40mg/cap 5Caps/box 原产地英文药品名: Aprepitant 中文参考商品译名: Emend 40毫克/胶囊 5胶囊/盒 中文参考药品译名: 阿瑞吡坦 生产厂家中文参考译名: 美国默克 生产厂家英文名: Merck -------------------------------------------------------- 产地国家: 美国 原产地英文商品名: Emend 80mg/cap 2Caps/box 原产地英文药品名: Aprepitant 中文参考商品译名: Emend 80毫克/胶囊 2胶囊/盒 中文参考药品译名: 阿瑞吡坦 生产厂家中文参考译名: 美国默克 生产厂家英文名: Merck -------------------------------------------------------- 产地国家: 美国 原产地英文商品名: Emend 80mg/cap 6Caps/box 原产地英文药品名: Aprepitant 中文参考商品译名: Emend 80毫克/胶囊 6胶囊/盒 中文参考药品译名: 阿瑞吡坦 生产厂家中文参考译名: 美国默克 生产厂家英文名: Merck -------------------------------------------------------- 产地国家: 美国 原产地英文商品名: Emend 125mg/cap 6Caps/box 原产地英文药品名: Aprepitant 中文参考商品译名: Emend 125毫克/胶囊 6胶囊/盒 中文参考药品译名: 阿瑞吡坦 生产厂家中文参考译名: 美国默克 生产厂家英文名: Merck -------------------------------------------------------- 产地国家: 美国 原产地英文商品名: Emend Trifold Pack 3Cap/DS PK(1*125mg+2*80mg) 原产地英文药品名: Aprepitant 中文参考商品译名: Emend 3胶囊/板装(1*125毫克+2*80毫克) 中文参考药品译名: 阿瑞吡坦 生产厂家中文参考译名: 美国默克 生产厂家英文名: Merck | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
