Important Safety Information

Toxicity in hepatic impairment

• IXEMPRA (ixabepilone) in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death
• In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater in patients with hepatic impairment
• Caution should be used when using IXEMPRA as monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended
• With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent in patients with hepatic impairment

Contraindications

• IXEMPRA is contraindicated in patients:
  • with a known history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor^® EL or its derivatives such as polyoxyethylated castor oil
  • who have a baseline neutrophil count <1500 cells/mm³ or a platelet count <100,000 cells/mm³

Peripheral neuropathy

• Peripheral neuropathy was common. Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain
• Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening peripheral neuropathy may require changes in the dose or discontinuation of IXEMPRA
• Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. Caution should be used when treating patients with diabetes mellitus or existing moderate to severe neuropathy

Myelosuppression

• Myelosuppression is dose-dependent and primarily manifested as neutropenia
• Patients should be monitored for myelosuppression; frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA
• Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced. Neutropenia-related deaths occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. Neutropenia-related death occurred in 0.4% of 240 patients with IXEMPRA as monotherapy

Hypersensitivity reaction

• Premedicate with an H₁ and an H₂ antagonist approximately 1 hour before IXEMPRA infusion and observe for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm)
• In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started
• Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H₁ and H₂ antagonists, and extension of the infusion time should be considered

Pregnancy

• Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy or the patient becomes pregnant, the patient should be apprised of the potential hazard to the fetus

Cardiac adverse reactions

• Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function due to reports of cardiovascular adverse reactions (eg, myocardial ischemia, supraventricular arrhythmia, and ventricular dysfunction). The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group

Potential for cognitive impairment from excipients

• IXEMPRA contains dehydrated alcohol USP. Consideration should be given to the possibility of central nervous system and other effects of alcohol

Adverse reactions

• The most common adverse reactions (≥ 20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain.  The following additional events occurred in ≥ 20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. Drug-associated hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia

Cremophor is a registered trademark of BASF AG.

AST = aspartate aminotransferase; ALT = alanine aminotransferase
ULN = upper limit of normal; CTC = common terminology criteria