Ixempra (ixabepilone)

For the management of breast cancer in adults, 40 mg/m2 of ixabepilone is administered IV over 3 hours every 3 weeks, either as monotherapy or in combination with capecitabine. Dosages for patients with a body surface area greater than 2.2 m2 should be calculated based on 2.2 m2.

The use of potent inhibitors of cytochrome P-450 isoenzyme 3A4 (CYP3A4), including amprenavir (no longer commercially available in the US), atazanavir, clarithromycin, delavirdine, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole, should be avoided during ixabepilone therapy. If concomitant administration of a potent CYP3A4 inhibitor is necessary during ixabepilone therapy, a dosage reduction to 20 mg/m2 should be considered. Upon discontinuance of the CYP3A4 inhibitor, approximately 1 week should elapse before adjusting the ixabepilone dosage back to the usual recommended dosage of 40 mg/m2. (See Drug Interactions.)

The use of potent inducers of CYP3A4, including carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, and rifampin, should be avoided during ixabepilone therapy. The use of an alterative concomitant medication with no or minimal enzyme induction potential should be considered. If concomitant administration of a potent CYP3A4 inducer is necessary during ixabepilone therapy, dosage may be gradually increased from 40 mg/m2 to 60 mg/m2, based on individual tolerance. If the dosage is increased, ixabepilone should be administered as a 4-hour IV infusion. Upon discontinuance of the CYP3A4 inducer, the ixabepilone dosage should be returned to the dosage used prior to initiation of the inducer. (See Drug Interactions.)

Patients receiving ixabepilone should be evaluated during treatment by periodic clinical observation and laboratory tests, including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. Dosage adjustment guidelines for monotherapy and combination therapy with ixabepilone are shown in Table 1. If toxicities recur, an additional 20% dosage reduction should be made.

Table 1. Dosage Adjustment Guidelines for Nonhematologic and Hematologic Toxicities

Ixabepilone (Monotherapy or Ixabepilone Dosage Modification Combination Therapy) Nonhematologic: Grade 2 neuropathy (moderate) Decrease dosage by 20% lasting >=7 days Grade 3 neuropathy (severe) lasting Decrease dosage by 20% <7 days Grade 3 neuropathy (severe) lasting Discontinue treatment >=7 days or disabling neuropathy Any grade 3 toxicity (severe) other Decrease dosage by 20% than neuropathy Transient grade 3 arthralgia/myalgia No change in ixabepilone dosage or fatigue Grade 3 hand-foot syndrome No change in ixabepilone dosage (palmar-plantar erythrodysesthesia) Any grade 4 toxicity (disabling) Discontinue treatment Hematologic: Neutrophils <500/mm3 for >=7 days Decrease dosage by 20% Febrile neutropenia Decrease dosage by 20% Platelets <25,000/mm3 or platelets Decrease dosage by 20% <50,000/mm3 with bleeding Capecitabine (when used in Capecitabine Dosage Modification combination with ixabepilone) Nonhematologic: All types and grades of Consult the full prescribing nonhematologic toxicities information for capecitabine Hematologic: Platelets <25,000/mm3 or <50,000/mm3 Hold for concurrent diarrhea or with bleeding stomatitis until platelet count >50,000/mm3, then continue at same dosage Neutrophils <500/mm3 for >=7 days or Hold for concurrent diarrhea or febrile neutropenia stomatitis until neutrophil count >1000/mm3, then continue at same dosage

Dosage adjustments at the start of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines in Table 1. Patients should not begin a new cycle of treatment unless the neutrophil count is at least 1500/mm3, platelet count is at least 100,000/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved.

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There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

History of severe (grade 3 or 4) hypersensitivity reaction to agents containing polyoxyl 35 castor oil (Cremophor(R) EL, polyoxyethylated castor oil).

Neutrophil count less than 1500/mm3 or platelet count less than 100,000/mm3.

Ixabepilone in combination with capecitabine is contraindicated in patients with serum AST or ALT concentrations exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations elevated above the upper limit of normal (i.e., exceeding 1 times the upper limit of normal).

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Adverse effects reported in 20% or more of patients receiving ixabepilone included peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. Incidence of adverse effects was generally higher in patients receiving both ixabepilone and capecitabine than in those receiving ixabepilone alone. Adverse effects reported in 20% or more of patients receiving ixabepilone in combination with capecitabine included palmar-plantar erythrodysesthesia (hand-foot syndrome), anorexia, abdominal pain, nail disorder, and constipation. Adverse hematologic effects reported in 40% or more of patients include neutropenia, leukopenia, anemia, and thrombocytopenia.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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Safety and efficacy not established in pediatric patients younger than 18 years of age.

Category D. (See Users Guide.)

Not known whether ixabepilone is distributed into human milk; however, in lactating rats given radiolabeled ixabepilone, concentrations of radioactivity in milk were comparable to those in plasma and declined in parallel with plasma concentrations of the drug. Discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Clinical studies of ixabepilone did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. In clinical studies, 45 out of 431 breast cancer patients receiving ixabepilone and capecitabine in combination were 65 years of age or older and 3 patients were 75 years of age or older. Overall, the incidence of grade 3 or 4 adverse reactions was higher in geriatric patients 65 years of age and older compared with younger patients (82 and 68%, respectively); these reactions included stomatitis, diarrhea, palmar-plantar erythrodysesthesia syndrome, peripheral neuropathy, febrile neutropenia, fatigue, and asthenia. Toxicity-related deaths occurred in 2 out of 43 (4.7%) patients 65 years of age or older with normal baseline hepatic function or mild hepatic impairment. In clinical studies, 32 out of 240 breast cancer patients receiving ixabepilone as monotherapy were 65 years of age or older and 6 patients were 75 years of age or older. No overall differences in safety were observed in these patients compared with those younger than 65 years of age.