"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. W hen fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. W hen aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see DRUG INTERACTIONS].
Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, the oral aprepitant 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 the oral aprepitant regimen was coadministered.
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].
Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use.
Coadministration With Warfarin (a CYP2C9 substrate)
Coadministration of fosaprepitant or aprepitant 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 fosaprepitant with each chemotherapy cycle [see DRUG INTERACTIONS].
Coadministration With Hormonal Contraceptives
Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or back-up methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see DRUG INTERACTIONS].
Chronic Continuous Use
Chronic continuous use of EMEND for Injection 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.
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 for Injection and to reread it each time the prescription is renewed.
Patients should follow the physician's instructions for the EMEND for Injection regimen.
Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely.
Patients who develop an infusion site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation.
EMEND for Injection 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 fosaprepitant with each chemotherapy cycle.
Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0-24hr) of 0.7 to 1.6 times the human exposure (AUC0-24hr = 19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant.
Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test.
Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).
Use In Specific Populations
Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant 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) 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.
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.
Safety and effectiveness of EMEND for Injection in pediatric patients have not been established.
In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% 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 [see CLINICAL PHARMACOLOGY].
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 fosaprepitant or aprepitant is administered in these patients [see CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 8/27/2014
This monograph has been modified to include the generic and brand name in many instances.
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