Pharmacy & Therapeutics - September 2008 - (Page 528)

DRUG FORECAST fied form of Cremophor EL. It is believed that this purity might be one reason that hypersensitivity reactions are less pronounced than with paclitaxel (Taxol).18 Of 1,323 patients mentioned in the prescribing information (PI) for ixabepilone, 1% (n = 9) experienced severe hypersensitivity reactions.18 Three of these nine patients were able to receive re-treatment. Ixabepilone should not be given to patients who have a history of severe hypersensitivity (grade 3/4) to Cremophor EL or its derivatives. Premedication with H1 and H2 antihistamines is advocated for all patients to reduce the risk of their experiencing any such reactions.18,39 In contrast to clinical practice with the taxanes,62,63 corticosteroid premedication is not necessary unless the patient has experienced a hypersensitivity reaction to ixabepilone. Because patients are likely to have been heavily pretreated, antiemetic therapy should be used as part of the premedication protocol before treatment with ixabepilone. The use of ixabepilone is contra indicated in patients with neutropenia or thrombocytopenia (neutrophil count below 1,500/mm3 or platelet counts of less than 100,000/mm3). Grade 4 neutropenia (below 500 cells/mm3) occurred in 36% of patients treated with ixabepilone plus capecitabine and in 23% of those receiving ixabepilone alone.18,44 The neutropenia-related death rate was higher in patients with significant liver impairment. Because of this adverse event, ixabepilone/capecitabine is contraindicated in patients with AST or ALT levels above 2.5 times the ULN or with bilirubin above 1 times the ULN, as stated in the boxed warning.18 events, alopecia occurred at a notably high rate.36,37,39 In the pivotal phase 3 study, adverse events related to ixabepilone plus capecitabine were usually mild to moderate and generally manageable (see Table 2), although a higher rate of treatmentrelated mortality was reported in patients with liver dysfunction.44 The addition of ixabepilone to capecitabine significantly increased grade 3/4 hematological toxicity, predominantly neutropenia, even though the rates of febrile neutropenia and infection were low. Grade 3/4 nonhematological events also occurred more frequently with the combination (including neuropathy, fatigue, and myalgia), but the addition of ixabepilone to capecitabine did not increase the incidence of grade 3/4 hand–foot syndrome or diarrhea, the predominant toxicities associated with capecitabine. Caution is advised when ixabepilone is administered to patients with pre-existing neuropathy. The presence of grade 1 neuropathy and prior treatment with neurotoxic chemotherapy do not predict the development or worsening of neuropathy.18 Patients with grade 2 neuropathy were excluded from clinical trials. Neuropathy is perhaps the most clinically relevant adverse event associated with ixabepilone; on average, 23% of patients experience grade 3/4 neuropathy. Ixabepilone-associated neuropathy is cumulative and mainly sensory, although in most cases it is reversible and can be managed by dose reductions and delays in treatment. Therapy should be interrupted at the first signs of neuropathy and should be restarted when neuropathy has returned to the baseline level or when severity has diminished to grade 1. Dose modification of ixabepilone, capecitabine, or both, is the most effective approach to managing the hematological and other nonhematological toxicities associated with this combination.18,44 Several doses and schedules for ixabepilone have been investigated, and alternative daily and weekly schedules continue to be studied in ongoing efforts to optimize the agent’s therapeutic ratio. increase plasma concentrations of ixabepilone. Ixabepilone doses should be reduced if the drug is being admin istered concomitantly with a strong inhibitor of CYP 3A4, such as ketoconazole (Nizoral, Janssen), itraconazole (Sporanox, Janssen), ritonavir (Norvir, Abbott), amprenavir (Agenerase, GlaxoSmithKline), indinavir (Crixivan, Merck), nelfinavir (Viracept, Agouron), delavirdine (Rescriptor, Pfizer) or voriconazole (Vfend, Pfizer). In vitro data are consistent with available clinical data (e.g., with ketoconazole). 64 Caution should be used when mild or moderate CYP 3A4 inhibitors such as er ythro mycin, fluconazole (Diflucan, Pfizer), and verapamil (e.g., Calan, Pfizer) are given.18 The use of strong CYP 3A4 inducers, such as dexamethasone, phenytoin (Dilantin, Pfizer), carbamazepine (Tegretol, Novartis), rifampin, and phenobarbital, may lead to subtherapeutic levels of ixabepilone; caution is advised if concomitant enzyme inducers must be administered. Ixabepilone does not induce or inhibit CYP 3A4 or other liver microsomal enzymes by clinically relevant amounts; therefore, plasma levels of other drugs that are substrates for CYP enzymes should not be affected by ixabepilone.18 COST As of November 2007, the average wholesale price (AWP) of ixabepilone, according to the manufacturer, was $921.96 for the 15-mg kit and $2,765.89 for the 45-mg kit.67 The AWP for a typical 75-mg dose of ixabepilone would be $4,609.81. These prices do not take into account other pharmacoeconomic parameters, such as specialist equipment or nurse time, that may influence the overall cost of administration of ixabepilone. For example, because of the presence of Cremophor EL, non-DEHP bags and tubing are required to prevent the plasticizer from leaching into the solution. Currently, lactated Ringer’s solution in non-DEHP IV bags is available only through a single manufacturer. ADVERSE EFFECTS In phase 2 monotherapy trials, ixabepilone demonstrated a manageable safety profile when given at the recommended schedule of a 40-mg/m2 IV infusion over three hours every three weeks to appropriately selected patients.36,37,39,60 Adverse events commonly reported with ixabepilone monotherapy are summarized in Table 4. Grade 3 and 4 treatment-related adverse events included peripheral sensory neuropathy, fatigue and asthenia, myalgia, stomatitis, mucositis, and neutropenia, although febrile neutropenia was uncommon. Among lower-grade CONCLUSION DRUG INTERACTIONS In vitro studies have identified CYP 3A4 as the main route of oxidative metabolism of ixabepilone.18 Inhibition of this enzyme may decrease metabolism and Ixabepilone is minimally susceptible to resistance mechanisms that have a detrimental impact on the efficacy of taxanes and anthracyclines. Ixabepilone thus represents a clinically useful addi- 528 P&T® • September 2008 • Vol. 33 No. 9

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Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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