Pharmacy & Therapeutics - September 2008 - (Page 527)

DRUG FORECAST pleted enrollment, and data are now being analyzed. Patients received a maximum of two prior antineoplastic regimens, or if they had been treated for metastatic disease, they relapsed within one year of treatment. The primary outcome measure is overall survival; secondary outcome measures include time to progression, ORR, duration of response in patients with measurable disease, and quality of life. stored in a refrigerator at 2°C to 8°C (36°F–46°F). The diluent used with ixabepilone contains Cremophor EL (BASF Aktiengesellschaft) and dehydrated alcohol. After constitution with the diluent, the concentration of ixabepilone is 2 mg/mL. The constituted solution must be further diluted with lactated Ringer’s solution USP in non-di(2-ethylhexyl)phthalate (DEHP) IV bags to a final concentration of between 0.2 and 0.6 mg/ mL. The infusion solution must be administered with a non-DEHP infusion set via an in-line filter with a microporous membrane of 0.2 to 1.2 microns. Diluted solutions are stable at room temperature and remain stable in light for up to six hours. 18 Because of the potential for neurotoxicity, ixabepilone should be infused over three or more hours.60 Dose modifications are required for patients with liver impairment (Table 3). Ixabepilone was evaluated in 56 patients with mild-to-severe hepatic impairment, as defined by bilirubin and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels. Compared with patients with normal hepatic function (n = 17), the AUC0–∞ of ixabepilone increased by 22% in patients with either bilirubin 1 to 1.5 times above the upper limit of normal (ULN) or an AST level above the ULN but with bilirubin below 1.5 times the ULN. The AUC concentration increased by 30% in patients with bilirubin above 1.5 to 3 times the ULN and any AST level and by 81% in patients with bilirubin greater than 3 times the ULN and any AST level.61 Hepatic impair ment results in increased exposure to ixabepilone and greater toxicity when ixabepilone is given with capecitabine or as mono therapy. Dose modification of ixabepilone used as monotherapy is based on the degree of hepatic impairment (see Table 1). Patients should not receive ixabepilone monotherapy if AST or ALT levels are more than 10 times the ULN or if bilirubin is 3 times the ULN.18 DOSAGE, ADMINISTRATION, AND DOSE MODIFICATIONS The FDA-approved dose of ixabepilone is 40 mg/m2 given intravenously over three hours every three weeks. In clinical studies of ixabepilone, doses for patients with a body surface area (BSA) greater than 2.2 m2 were to have been based on a BSA of 2.2 m2. Because few patients in the clinical studies of ixabepilone had a BSA greater than 2.2 m2, data on these patients are limited. Ixabepilone is commercially available as 15-mg and 45-mg kits; each kit contains two vials consisting of lyophilized drug and diluent for constitution. Ixabepilone kits must be CONTRAINDICATIONS The most commonly described adverse effect of drugs formulated with Cremophor EL is hypersensitivity. Ixabepilone diluent contains a highly puri- Table 3 Dose Adjustments for Ixabepilone Adjustment Nonhematological toxicity* Grade 2 neuropathy (moderate) lasting ≥7 days Grade 3 neuropathy (severe) lasting <7 days Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy Any grade 3 toxicity (severe) Transient grade 3 arthralgia/myalgia or fatigue Grade 3 hand–foot syndrome Any grade 4 toxicity (disabling) Hematological toxicity* Neutrophils <500 cells/mm3 for ≥7 days Febrile neutropenia Platelets <25,000/mm3 or platelets 1.5 × ULN ≤3 × ULN Ixabepilone + capecitabine combination therapy AST or ALT >2.5 × ULN or bilirubin >1 × ULN Coadministration with other drugs Strong inhibitors of CYP 3A4†‡ Suggested Dose or Dose Modification Decrease dose by 20% Decrease dose by 20% Discontinue treatment Decrease dose by 20% No change in ixabepilone dose No change in ixabepilone dose Discontinue treatment Decrease dose by 20% Decrease dose by 20% Decrease dose by 20% Recommended dose: 40 mg/m2 Recommended dose: 32 mg/m2 Recommended dose: 20–30 mg/m2 Contraindicated Starting dose: 20 mg/m2 ALT = alanine aminotransferase; AST = aspartate aminotransferase; CYP 3A4 = cytochrome P450 isoenzyme 3A4; ULN = upper limit of normal. * Toxicities graded in accordance with the National Cancer Institute Common Toxicity Criteria (CTC) for adverse events. † Inhibiting oxidative metabolism of ixabepilone may significantly increase its plasma concentrations. ‡ Examples of strong cytochrome CYP 3A4 inhibitors: ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, and voriconazole. Vol. 33 No. 9 • September 2008 • P&T® 527

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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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