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Peripheral neuropathy was common (see Table 3). 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 symptoms may require a reduction or delay in the dose of IXEMPRA [see DOSAGE AND ADMINISTRATION]. In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and treatment discontinuation. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3/4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset.
Table 2: Treatment-related Peripheral Neuropathy
|IXEMPRA with capecitabine
|IXEMPRA as monotherapy
|Peripheral neuropathy (all grades) a,b||67%||63%|
|Peripheral neuropathy (grades 3/4) a,b||23%||14%|
|Discontinuation due to neuropathy||21%||6%|
|Median number of cycles to onset of grade 3/4 neuropathy||4||4|
|Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1||6.0 weeks||4.6 weeks|
|a Sensory and motor neuropathy
b 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1).
A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy.
Myelosuppression is dose-dependent and primarily manifested as neutropenia. In clinical studies, grade 4 neutropenia ( < 500 cells/mm³) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as monotherapy, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT > 2.5 x ULN or bilirubin > 1.5 x ULN [see BOXED WARNING, and CONTRAINDICATIONS]. Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or ALT > 2.5 x ULN or bilirubin > 1.5 x ULN treated with IXEMPRA monotherapy. IXEMPRA must not be administered to patients with a neutrophil count < 1500 cells/mm³. To monitor 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 [see DOSAGE AND ADMINISTRATION].
Patients with baseline AST or ALT > 2.5 x ULN or bilirubin > 1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤ 2.5 x ULN or bilirubin ≤ 1.5 x ULN when treated with IXEMPRA at 40 mg/m² in combination with capecitabine or as monotherapy in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of IXEMPRA as monotherapy were evaluated in a dose escalation study in 56 patients with varying degrees of hepatic impairment. Exposure was increased in patients with elevated AST or bilirubin [see Use In Specific Populations].
IXEMPRA 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 [see BOXED WARNING and CONTRAINDICATIONS]. Patients who are treated with IXEMPRA as monotherapy should receive a reduced dose depending on the degree of hepatic impairment [see DOSAGE AND ADMINISTRATION]. Use in patients with AST or ALT > 10 x ULN or bilirubin > 3 x ULN is not recommended. Limited data are available for patients with AST or ALT > 5 x ULN. Caution should be used when treating these patients [see DOSAGE AND ADMINISTRATION].
Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with IXEMPRA. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before IXEMPRA infusion and be observed 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. Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1%) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. 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 [see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].
Pregnancy Category D
IXEMPRA may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with IXEMPRA in pregnant women. Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Ixabepilone was studied for effects on embryo-fetal development in pregnant rats and rabbits given IV doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively. There were no teratogenic effects. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally toxic dose of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately one-tenth the human clinical dose based on body surface area). No fetuses were available at this dose for evaluation.
Cardiac Adverse Reactions
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. Supraventricular arrhythmias were observed in the combination arm (0.5%) and not in the capecitabine alone arm. 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.
Potential for Cognitive Impairment from Excipients
Patient Counseling Information
[see FDA-Approved Patient Labeling]
Patients should be advised to report to their physician any numbness and tingling of the hands or feet [see WARNINGS AND PRECAUTIONS].
Patients should be instructed to call their physician if a fever of 100.5° F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination develops [see WARNINGS AND PRECAUTIONS].
Patients should be advised to call their physician if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness or other hypersensitivity-related symptoms following an infusion of IXEMPRA [see WARNINGS AND PRECAUTIONS].
Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid nursing during treatment with IXEMPRA [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Cardiac Adverse Reactions
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with ixabepilone have not been conducted. Ixabepilone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in an in vitro cytogenetic assay using primary human lymphocytes. Ixabepilone was clastogenic (induction of micronuclei) in the in vivo rat micronucleus assay at doses ≥ 0.625 mg/kg/day.
There were no effects on male or female rat mating or fertility at doses up to 0.2 mg/kg/day in both males and females (approximately one-fifteenth the expected human clinical exposure based on AUC). The effect of ixabepilone on human fertility is unknown. However, when rats were given an IV infusion of ixabepilone during breeding and through the first 7 days of gestation, a significant increase in resorptions and pre- and post-implantation loss and a decrease in the number of corpora lutea was observed at 0.2 mg/kg/day. Testicular atrophy or degeneration was observed in 6-month rat and 9-month dog studies when ixabepilone was given every 21 days at intravenous doses of 6.7 mg/kg (40 mg/m²) in rats (approximately 2.1 times the expected clinical exposure based on AUC) and 0.5 and 0.75 mg/kg (10 and 15 mg/m²) in dogs (approximately 0.2 and 0.4 times the expected clinical exposure based on AUC).
Use In Specific Populations
Pregnancy Category D [see WARNINGS AND PRECAUTIONS].
It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue IXEMPRA taking into account the importance of the drug to the mother.
The effectiveness of IXEMPRA in pediatric patients has not been established. IXEMPRA was evaluated in one Phase 1 and one Phase 2 trial. The pediatric patients had a safety profile consistent with that seen in adults, and no new safety signals were identified.
In the Phase 1 open-label, dose-finding trial, the safety of IXEMPRA was evaluated in 19 pediatric patients with advanced or refractory solid tumors and 2 with acute leukemias. IXEMPRA was administered as a one-hour IV infusion daily for the first five days of a 21-day cycle at one of 5 dose levels, ranging from 3 to 10 mg/m². Among the 21 patients, 12 ranged in age from 2 to 12 years and 9 ranged from 13 to 18 years. The maximum tolerated dose was 8 mg/m² IV daily for 5 days every 21 days. No significant anti-tumor activity was observed. The pharmacokinetics of ixabepilone were characterized by population pharmacokinetic analysis of data for 16 patients from this trial, who were aged 2 to 18 years (median 12 years). The pharmacokinetic parameters of ixabepilone in these pediatric patients were compared to the corresponding parameters of 130 adult patients enrolled in clinical trials using the same dosing schedule. The median BSA normalized clearance of ixabepilone in pediatric patients (17 L/h/m²) was similar to that in adult patients (20 L/h/m²).
In the Phase 2 trial of 59 patients with advanced or refractory solid tumors, 28 ranged in age from 3 to 12 years and 19 ranged in age from 13 to 18 years. Twelve additional patients over the age of 18 were treated in this trial. IXEMPRA was administered at a dose of 8 mg/m² IV daily for 5 days every 21 days. This trial was terminated early due to lack of efficacy.
Clinical studies of IXEMPRA did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects.
Forty-five of 431 patients treated with IXEMPRA in combination with capecitabine were ≥ 65 years of age and 3 patients were ≥ 75. Overall, the incidence of grade 3/4 adverse reactions was higher in patients ≥ 65 years of age versus those < 65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients ≥ 65 years with normal baseline hepatic function or mild impairment.
Thirty-two of 240 breast cancer patients treated with IXEMPRA as monotherapy were ≥ 65 years of age and 6 patients were ≥ 75. No overall differences in safety were observed in these patients compared to those < 65 years of age.
IXEMPRA was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC0-infinity) of ixabepilone increased by:
- 22% in patients with a) bilirubin > 1 – 1.5 x ULN or b) AST > ULN but bilirubin < 1.5 x ULN;
- 30% in patients with bilirubin > 1.5 – 3 x ULN and any AST level; and
- 81% in patients with bilirubin > 3 x ULN and any AST level.
Doses of 10 and 20 mg/m² as monotherapy were tolerated in 17 patients with severe hepatic impairment (bilirubin > 3 x ULN).
IXEMPRA in combination with capecitabine must not be given to patients with AST or ALT > 2.5 x ULN or bilirubin > 1 x ULN [see BOXED WARNING, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]. Dose reduction is recommended when administering IXEMPRA as monotherapy to patients with hepatic impairment [see DOSAGE AND ADMINISTRATION]. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter.
Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with IXEMPRA in patients with renal impairment. IXEMPRA in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of < 50 mL/min. IXEMPRA as monotherapy has not been evaluated in patients with creatinine > 1.5 times ULN. In a population pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL > 30 mL/min) on the pharmacokinetics of ixabepilone.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 10/27/2011
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