Ixabepilone, a microtubule inhibitor that is a semisynthetic derivative of epothilone B, is an epothilone antineoplastic agent.1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 15, 17, 18, 19
Ixabepilone is used in combination with oral capecitabine for the treatment of metastatic or locally advanced breast cancer in patients whose disease is resistant to treatment with an anthracycline and a taxane or in patients whose cancer is taxane-resistant and for whom further anthracycline therapy is contraindicated.1, 2, 8, 11, 13, 17 Anthracycline resistance is defined as progression during therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting.1 Taxane resistance is defined as progression during therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting.1
The current indication for ixabepilone and capecitabine combination therapy is based mainly on the results of an open-label, multicenter, multinational, randomized, phase 3 trial comparing the efficacy and safety of ixabepilone in combination with capecitabine and capecitabine given as monotherapy in patients with metastatic or locally advanced breast cancer.1, 3, 11 In this trial, 752 patients received ixabepilone (40 mg/m2 IV every 3 weeks) in combination with capecitabine (1000 mg/m2 orally given twice daily for 2 weeks followed by a 1-week rest period) or capecitabine monotherapy (1250 mg/m2 orally given twice daily for 2 weeks followed by a 1-week rest period).1, 3, 19 All patients were previously treated with and demonstrated tumor progression or resistance to anthracyclines and taxanes.1, 3, 11, 19 Patients who had received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible.1, 3, 11 Patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine monotherapy treatment group received a median of 4 cycles of treatment.1, 3, 11
Patients receiving combination therapy with ixabepilone and capecitabine in this study demonstrated a longer progression-free survival (5.7 versus 4.1 months, respectively) and a higher objective tumor response rate (approximately 35 versus 14%, respectively) compared with patients receiving capecitabine monotherapy.1, 3, 4, 8, 18, 19 No difference in overall survival (12.9 versus 11.1 months, respectively) between patients receiving combination therapy with ixabepilone and capecitabine and patients receiving capecitabine monotherapy was observed.1, 23
A second open-label, multicenter, multinational, randomized, phase 3 trial compared the efficacy and safety of ixabepilone in combination with capecitabine and capecitabine given as monotherapy in patients with metastatic or locally advanced breast cancer.1, 22 In this trial, 1221 patients received ixabepilone (40 mg/m2 IV every 3 weeks) in combination with capecitabine (1000 mg/m2 orally given twice daily for 2 weeks followed by a 1-week rest period) or capecitabine monotherapy (1250 mg/m2 orally given twice daily for 2 weeks followed by a 1-week rest period).22 All patients were previously treated with, but not necessarily resistant to, anthracyclines and taxanes.22 In the 79% of patients with measurable disease, patients receiving combination therapy with ixabepilone and capecitabine in this study demonstrated longer progression-free survival (6.2 versus 4.4 months, respectively) and a higher objective tumor response rate (approximately 43 versus 29%, respectively) compared with patients receiving capecitabine monotherapy.22 No significant difference in overall survival (16.4 versus 15.6 months, respectively) between patients receiving combination therapy with ixabepilone and capecitabine and patients receiving capecitabine monotherapy was observed.1, 22
Ixabepilone is used as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.1, 2, 5, 7, 11, 13, 17
The current indication for use of ixabepilone as a single agent is based primarily on the results of a multicenter, single-arm study involving 126 women with metastatic or locally advanced breast cancer.1, 5 The study enrolled patients whose tumors had recurred or progressed following 2 or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine; patients who had received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible.1, 5 The patients in this study were heavily pretreated (88% had previously received 2 or more chemotherapy regimens for metastatic disease) and 86% had liver and/or lung metastases.1, 5 Ixabepilone 40 mg/m2 was given as a 3-hour IV infusion every 3 weeks; patients received a median of 4 cycles (range: 1-18 cycles) of therapy with the drug.1, 5, 11 The objective tumor response rates based on independent radiologic review and investigator assessments were approximately 12% (with all partial responses) and 18%, respectively.1, 5, 8, 11 The median time to response was approximately 6 weeks, median duration of response was approximately 6 months, and median progression-free survival was approximately 3 months.1, 5, 11, 17, 18
The possible role of ixabepilone in theinitial therapy of advanced breast cancer† also is being studied.11, 13
To minimize risk of hypersensitivity reactions, the manufacturer states that all patients should be premedicated with diphenhydramine hydrochloride 50 mg orally (or similar antihistamine) and a histamine H2-receptor antagonist (e.g., ranitidine 150-300 mg orally) approximately 1 hour before beginning the ixabepilone infusion.1, 2 Patients who experienced a prior hypersensitivity reaction to the drug must also be premedicated with corticosteroids (e.g., dexamethasone 20 mg, given either IV 30 minutes prior to infusion or orally 60 minutes prior to infusion).1, 2
Reconstitution and Administration
Ixabepilone is administered by IV infusion only over 3 hours.1, 2
Ixabepilone is commercially available as the Ixempra® kit, which contains 2 single-use vials: one of the vials contains ixabepilone powder for injection and the other vial contains diluent.1, 17 Ixabepilone powder for injection must be reconstituted and diluted prior to administration.1 The kit should be removed from the refrigerator and allowed to stand at room temperature for approximately 30 minutes prior to reconstitution. A white precipitate may be observed in the diluent vial when first removed from the refrigerator, but this precipitate will dissolve to form a clear solution once the diluent warms to room temperature.1, 2
Procedures for proper handling and disposal of antineoplastic drugs should be followed.1, 14 To minimize risk of dermal exposure, impervious gloves should be worn when handling vials containing ixabepilone, regardless of the setting, including unpacking and inspection, transport within a facility, and dose preparation and administration.1 For additional information on proper procedures for handling antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Ixabepilone powder for injection is reconstituted by adding 8 mL of the supplied diluent to the vial labeled as containing 15 mg of ixabepilone or 23.5 mL of the supplied diluent to the vial labeled as containing 45 mg of ixabepilone to provide a solution containing 2 mg/mL; only the supplied diluent should be used when reconstituting the powder.1, 2 The vial should be gently swirled and inverted until the powder completely dissolves.1 Following reconstitution, the solution should be diluted with an appropriate infusion fluid as soon as possible, but may be stored in the vial for up to one hour at room temperature and room light.1, 2 The appropriate dose should then be withdrawn and diluted in the appropriate volume of infusion fluid supplied in diethylhexylphthalate (DEHP)-free bags.1 Acceptable infusion fluids for dilution of reconstituted ixabepilone solution include lactated Ringer's injection, Plasma-Lyte A Injection pH 7.4®, or 0.9% sodium chloride injection with 2 mEq sodium bicarbonate injection (i.e., 2 mL of 8.4% w/v sodium bicarbonate solution or 4 mL of 4.2% w/v sodium bicarbonate solution) added to adjust the pH to between 6 and 9.1 For most doses, a 250-mL bag of infusion fluid is sufficient; however, it is necessary to check the final infusion concentration of each dose based on the volume of infusion fluid to be used; the final infusion concentration must be between 0.2-0.6 mg/mL.1, 2 The infusion bag should be mixed thoroughly by manual rotation.1 Once diluted, the solution is stable at room temperature and room light for up to 6 hours; administration of diluted ixabepilone must be completed within this 6-hour period.1, 2 Diluents other than those specified by the manufacturer should not be used.1
The drug should be administered through an appropriate 0.2- to 1.2- µ m inline filter.1, 2 Only DEHP-free infusion containers and administration sets should be used.1, 2
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.1, 2, 7, 17, 18 Dosages for patients with a body surface area greater than 2.2 m2 should be calculated based on 2.2 m2.1
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.1, 7 If concomitant administration of a potent CYP3A4 inhibitor is necessary during ixabepilone therapy, a dosage reduction to 20 mg/m2 should be considered.1, 17 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/m2.1 (See Drug Interactions.)
The use of potent inducers of CYP3A4, including carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, and rifampin, should be avoided during ixabepilone therapy.1 The use of an alterative concomitant medication with no or minimal enzyme induction potential should be considered.1 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.1 If the dosage is increased, ixabepilone should be administered as a 4-hour IV infusion.1 Upon discontinuance of the CYP3A4 inducer, the ixabepilone dosage should be returned to the dosage used prior to initiation of the inducer.1 (See Drug Interactions.)
Dosage Modification for Toxicity
Patients receiving ixabepilone should be evaluated during treatment by periodic clinical observation and laboratory tests, including complete blood cell counts.1 If toxicities are present, treatment should be delayed to allow recovery.1 Dosage adjustment guidelines for monotherapy and combination therapy with ixabepilone are shown in Table 1.1 If toxicities recur, an additional 20% dosage reduction should be made.1
Ixabepilone (Monotherapy or Combination Therapy) | Ixabepilone Dosage Modification |
|---|---|
Nonhematologic: | |
Grade 2 neuropathy (moderate) lasting ≥7 days | Decrease dosage by 20% |
Grade 3 neuropathy (severe) lasting <7 days | Decrease dosage by 20% |
Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy | Discontinue treatment |
Any grade 3 toxicity (severe) other than neuropathy | Decrease dosage by 20% |
Transient grade 3 arthralgia/myalgia or fatigue | No change in ixabepilone dosage |
Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia) | No change in ixabepilone dosage |
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 <50,000/mm3 with bleeding | Decrease dosage by 20% |
Capecitabine (when used in combination with ixabepilone) | Capecitabine Dosage Modification |
|---|---|
Nonhematologic: | |
All types and grades of nonhematologic toxicities | Consult the full prescribing information for capecitabine |
Hematologic: | |
Platelets <25,000/mm3 or <50,000/mm3 with bleeding | Hold for concurrent diarrhea or stomatitis until platelet count >50,000/mm3, then continue at same dosage |
Neutrophils <500/mm3 for ≥7 days or febrile neutropenia | Hold for concurrent diarrhea or 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 1.1 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.1
Severity | Transaminase and Bilirubin Concentrationsa | Ixabepilone Dosageb |
|---|---|---|
Mild | AST and ALT ≤2.5 × ULN and bilirubin ≤1 × ULN | 40 mg/m2 |
AST and ALT ≤10 × ULN and bilirubin ≤1.5 × ULN | 32 mg/m2 | |
Moderate | AST and ALT ≤10 × ULN and bilirubin >1.5 × ULN to ≤3 × ULN | 20-30 mg/m2 |
aExcluding patients whose total bilirubin is elevated due to Gilbert's disease.
bDosage recommendations are for first course of therapy; further dosage decreases in subsequent courses should be made based on individual tolerance.
Ixabepilone in combination with capecitabine is contraindicated in patients with serum AST or ALT concentrations exceeding 2.5 times the upper limit of normal (ULN) or serum bilirubin concentrations elevated above the upper limit of normal (i.e., exceeding 1 times the upper limit of normal).1, 2 Patients receiving combination treatment who have serum AST and ALT concentrations not exceeding 2.5 times the upper limit of normal and serum bilirubin concentrations not exceeding the upper limit of normal may receive the usual dosage of ixabepilone (40 mg/m2).1
For ixabepilone monotherapy, patients with hepatic impairment should be dosed based on the guidelines in Table 2.1 In patients with moderate hepatic impairment, the manufacturer recommends an initial ixabepilone dosage of 20 mg/m2, which may then be increased up to a maximum dosage of 30 mg/m2 in subsequent cycles, if tolerated.1 Ixabepilone monotherapy in patients with serum AST or ALT concentrations exceeding 10 times the upper limit of normal or serum bilirubin concentrations exceeding 3 times the upper limit of normal is not recommended.1 Limited data are available for patients with baseline AST or ALT concentrations exceeding 5 times the upper limit of normal; the drug should be used with caution in such patients.1
History of severe (grade 3 or 4) hypersensitivity reaction to agents containing polyoxyl 35 castor oil (Cremophor® EL, polyoxyethylated castor oil).1, 2
Neutrophil count less than 1500/mm3 or platelet count less than 100,000/mm3.1
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).1, 7
Toxicity in Hepatic Impairment
Patients with baseline serum AST or ALT concentrations exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations exceeding 1.5 times the upper limit of normal experienced greater toxicity than patients with baseline AST or ALT concentrations not exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations not exceeding 1.5 times the upper limit of normal when treated with ixabepilone 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer clinical studies.1, 9 In patients with hepatic impairment receiving combined ixabepilone and capecitabine, the overall frequency of grade 3 or 4 adverse effects, febrile neutropenia, serious adverse effects, and toxicity-related deaths was greater.1 In patients with hepatic impairment receiving ixabepilone monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse effects were more frequent.1 Safety and pharmacokinetics of ixabepilone monotherapy were evaluated in patients with varying degrees of hepatic impairment, and exposure was found to be increased in patients with elevated serum AST or bilirubin concentrations.1
Ixabepilone in combination with capecitabine is contraindicated in patients with baseline 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).1 Patients with hepatic impairment who are treated with ixabepilone monotherapy should receive a reduced dosage depending on the degree of hepatic impairment (see Table 2 under Dosage and Administration: Special Populations).1 Ixabepilone monotherapy in patients with serum AST or ALT concentrations exceeding 10 times the upper limit of normal or serum bilirubin concentrations exceeding 3 times the upper limit of normal is not recommended.1 Limited data are available for patients with serum AST or ALT concentrations exceeding 5 times the upper limit of normal; caution should be used when treating these patients.1
Other Warnings and Precautions
Peripheral neuropathy, mostly sensory in nature but also motor neuropathy, occurs commonly in ixabepilone-treated patients and was reported in over 60% of patients receiving the drug in controlled studies.1, 2, 3, 7, 11, 13, 15, 16, 19 Although generally mild to moderate in severity15 , grade 3 or 4 neuropathy was reported in 14 and 23% of patients receiving ixabepilone monotherapy and ixabepilone combined with capecitabine, respectively, in controlled trials.1, 2, 3, 15, 19 Neuropathy generally develops early during treatment, with approximately 75% of new-onset or worsening neuropathy occurring during the first 3 cycles.1, 3, 16, 17 Peripheral neuropathy was often characterized as paresthesia or dysesthesia and manifested as a symmetrical, stocking-and-glove distribution with more pronounced effects in the lower extremities.13
All patients receiving ixabepilone should therefore be monitored for symptoms of neuropathy, including burning sensation, hyperesthesia or hypoesthesia, paresthesia, discomfort, and neuropathic pain.1, 2 In clinical trials, peripheral neuropathy was managed through dosage reductions, treatment delays, and treatment discontinuance.1, 3, 15, 19 Patients experiencing new or worsening neuropathic symptoms may require a dosage reduction and/or treatment delay.1, 15, 19 (See Dosage and Administration: Dosage Modification for Toxicity.) Neuropathy was the most frequent cause of treatment discontinuance due to drug toxicity, but generally was reversible.1, 2, 11, 13, 19 In clinical studies involving ixabepilone monotherapy or combined ixabepilone and capecitabine therapy, peripheral neuropathy improved or did not worsen in at least 80% of patients following dosage reduction.1, 15 In patients with grade 3 or 4 neuropathy, documented improvement to baseline or grade 1 neuropathy was reported in 76-79% of patients 12 weeks after onset of the neuropathy.1
Patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of developing severe neuropathy.1 The manufacturer states that prior therapy with neurotoxic chemotherapeutic agents did not predict the development of neuropathy.1 However, some evidence suggests that previous exposure to other neurotoxic drugs (including taxanes) may increase the risk of ixabepilone-associated neuropathy.13 The manufacturer states that ixabepilone should be used with caution in patients with diabetes mellitus or preexisting peripheral neuropathy.1
Myelosuppression is one of the major and dose-limiting adverse effects of ixabepilone and is primarily manifested as neutropenia.1, 18 In clinical studies, grade 4 neutropenia (less than 500 cells/mm3) occurred in 36% of patients treated with ixabepilone plus capecitabine and 23% of patients treated with ixabepilone monotherapy.1 Febrile neutropenia and infection with neutropenia were reported in 5 and 6%, respectively, of patients treated with ixabepilone plus capecitabine, and 3 and 5%, respectively, of patients treated with ixabepilone monotherapy.1 Neutropenia-related death occurred in 1.9% of patients with normal hepatic function or mild hepatic impairment treated with ixabepilone plus capecitabine.1 The incidence of neutropenia-related death was higher (29%) in patients with serum AST or ALT concentrations exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations exceeding 1.5 times the upper limit of normal.1 Neutropenia-related death occurred in 0.4% of patients receiving ixabepilone monotherapy.1 No neutropenia-related deaths were reported in patients with serum AST or ALT concentrations exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations exceeding 1.5 times the upper limit of normal treated with ixabepilone monotherapy.1
Ixabepilone should not be administered to patients with a neutrophil count less than 1500/mm3.1 Frequent determinations of peripheral blood cell counts are recommended for all patients receiving the drug to monitor for myelosuppression.1 Patients who experience severe neutropenia or thrombocytopenia should have their dosage reduced.1 (See Dosage and Administration: Dosage Modification for Toxicity.)
Patients with a history of severe hypersensitivity reaction to agents containing polyoxyl 35 castor oil (Cremophor® EL, polyoxyethylated castor oil), such as paclitaxel, should not be treated with ixabepilone.1, 2 All patients receiving ixabepilone should be premedicated with an antihistamine and a histamine H2-receptor antagonist approximately 1 hour before beginning the ixabepilone infusion and should also be observed for hypersensitivity reactions (e.g., flushing, rash, dyspnea, bronchospasm).1, 2, 17 (See Dosage and Administration: General.) If a severe hypersensitivity reaction develops, the infusion of ixabepilone should be stopped and aggressive supportive treatment (e.g., epinephrine, corticosteroids) instituted.1 Severe hypersensitivity reactions (including anaphylaxis) have occurred in 9 out of 1323 (approximately 1%) of patients receiving the drug in clinical trials; 3 out of 9 of these were able to be retreated.1, 17 The manufacturer states that patients who experience a hypersensitivity reaction in one cycle of ixabepilone treatment must be premedicated in subsequent cycles with a corticosteroid in addition to the antihistamine and a histamine H2-receptor antagonist, and extension of the infusion time should be considered.1 (For more information on hypersensitivity reactions associated with the polyoxyl 35 castor oil vehicle, see Cautions: Sensitivity Reactions, in Cyclosporine 92:44.)
The incidence of adverse cardiovascular effects (myocardial ischemia and ventricular dysfunction) was higher in patients receiving combined ixabepilone and capecitabine therapy (1.9%) than in those receiving capecitabine alone (0.3%).1 Supraventricular arrhythmias were observed in patients receiving combination treatment (0.5%) but not those receiving capecitabine alone.1 The manufacturer recommends that ixabepilone be used with caution in patients with a history of cardiac disease.1 Discontinuance of the drug should be considered in patients who develop cardiac ischemia or impaired cardiac function.1
Potential for Cognitive Impairment from Excipient
Since the diluent in the commercially available Ixempra® kit contains dehydrated alcohol, the possibility of adverse CNS effects, including cognitive impairment, and other effects of alcohol should be considered.1 (See Advice to Patients.)
Radiation recall has been reported in patients receiving ixabepilone.1
Category D.1 (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.1 Discontinue nursing or the drug, taking into account the importance of the drug to the woman.1, 21
Safety and efficacy not established in pediatric patients younger than 18 years of age.20
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.1 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.1 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.1 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.1 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.1 No overall differences in safety were observed in these patients compared with those younger than 65 years of age.1
Patients with baseline serum AST or ALT concentrations exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations exceeding 1.5 times the upper limit of normal experienced greater toxicity than patients with baseline AST or ALT concentrations not exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations not exceeding 1.5 times the upper limit of normal when treated with ixabepilone 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer clinical studies.1, 9 Ixabepilone and capecitabine combination therapy 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).1, 7 (See Toxicity in Hepatic Impairment under Warnings/Precautions: Warnings, in Cautions.)
Dosage reduction depending on the degree of hepatic impairment is recommended if ixabepilone is used as monotherapy in patients with hepatic impairment.1 Because there is a need for dosage adjustment based on hepatic function, assessment of hepatic function is recommended before initiation of ixabepilone and periodically thereafter.1 (See Dosage and Administration: Special Populations.) Caution is also advised if ixabepilone monotherapy is used in patients with hepatic impairment.1
Ixabepilone is minimally excreted via the kidneys.1 No controlled pharmacokinetic studies have been conducted with the drug in patients with renal impairment.1 In addition, ixabepilone and capecitabine combination therapy has not been evaluated in patients with a calculated creatinine clearance of less than 50 mL/minute.1, 2 Ixabepilone given as monotherapy has not been evaluated in patients with serum creatinine concentrations exceeding 1.5 times the upper limit of normal.1 In a population pharmacokinetic analysis of ixabepilone monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (creatinine clearance exceeding 30 mL/minute) on the pharmacokinetics of the drug.1, 2, 7 The manufacturer does not make specific dosage adjustment recommendations for ixabepilone in renal impairment.1, 2
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.1, 2, 5, 13, 15, 17 Incidence of adverse effects was generally higher in patients receiving both ixabepilone and capecitabine than in those receiving ixabepilone alone.1, 3, 17 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.1, 3, 13 Adverse hematologic effects reported in 40% or more of patients include neutropenia, leukopenia, anemia, and thrombocytopenia. 1, 2, 3, 13, 17
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Inhibitors of Cytochrome P-450 (CYP) 3A4 Isoenzyme
Pharmacokinetic interaction (increased plasma ixabepilone concentrations) may occur during concomitant administration of potent CYP3A4 inhibitors (e.g., amprenavir [no longer commercially available in the US], atazanavir, clarithromycin, delavirdine, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); concomitant use of ixabepilone with these drugs should be avoided.1, 7, 12, 13 Concurrent administration of ixabepilone with ketoconazole increased the area under the plasma concentration-time curve (AUC) of ixabepilone by 79% compared with ixabepilone treatment alone.1, 2, 12, 17 Close monitoring for toxicity and reduction of ixabepilone dosage to 20 mg/m2 should be considered if concomitant therapy with a potent CYP3A4 inhibitor and ixabepilone is needed.1, 2 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/m2.1, 2
Because the effect of mild or moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, verapamil) on exposure to ixabepilone has not been studied, caution should be used during concomitant administration of these drugs and use of alternative therapeutic agents that do not inhibit CYP3A4 should be considered.1, 11 Patients receiving CYP3A4 inhibitors during ixabepilone therapy should be closely monitored for acute toxicity (e.g., frequent monitoring of peripheral blood counts between cycles of ixabepilone).1
Pharmacokinetic interaction (decreased and possibly subtherapeutic plasma ixabepilone concentrations) may occur during concomitant use with potent CYP3A4 inducers (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin); concomitant use of ixabepilone with these drugs should be avoided.1, 17 Concurrent administration of ixabepilone with rifampin decreased the AUC of ixabepilone by 43% compared with ixabepilone treatment alone.1 If concurrent administration of other drugs is indicated during ixabepilone therapy, drugs with no or minimal enzyme induction potential should be considered.1 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/m2,1 and patients should be monitored carefully for toxicity.1 (See Dosage and Administration: Dosage.) A dosage of 60 mg/m2 over 4 hours is predicted to result in an AUC of ixabepilone in the range observed at the usual recommended dosage without concomitant enzyme inducers.1 Upon discontinuance of the CYP3A4 inducer, the ixabepilone dosage should be returned to the dosage used prior to initiation of the inducer.1
Since St. John's wort ( Hypericum perforatum ) may cause unpredictable decreases in plasma ixabepilone concentrations, such concomitant use should be avoided.1
Substrates of CYP3A4 and other CYP Isoenzymes
At clinically relevant plasma concentrations, ixabepilone does not inhibit CYP isoenzymes 3A4, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2D6 and does not induce CYP isoenzymes 3A4, 1A2, 2B6, or 2C9; pharmacokinetic interaction is unlikely when ixabepilone is used with substrates of these isoenzymes.1, 9, 17
Drugs Affecting the P-glycoprotein Transport System
In vitro studies indicate that ixabepilone is a weak inhibitor and a substrate for the P-glycoprotein transport system.1
Concomitant administration of ixabepilone with capecitabine has decreased peak ixabepilone and capecitabine concentrations by 19 and 27%, respectively, and increased fluorouracil AUC by 14% compared with separate administration of these drugs.1 This pharmacokinetic interaction is unlikely to be clinically important and effectiveness of combination therapy with these drugs has been demonstrated in clinical trials.1, 3, 7, 11
Grapefruit juice and other grapefruit products should be avoided because of the potential for increased plasma ixabepilone concentrations.1, 2
Ixabepilone is a microtubule inhibitor belonging to the epothilone class of antineoplastic agents.1, 2, 6, 7, 9, 10, 11, 13, 15, 17, 18, 19 Epothilones are naturally occurring products of fermentation from the myxobacterium Sorangium cellulosum .3, 7, 11, 13, 18, 19 Ixabepilone is a semisynthetic derivative of epothilone B, a 16-membered polyketide macrolide, with a chemically modified lactam substitution for the naturally existing lactone.1, 6, 7, 13, 17, 18 Ixabepilone binds to β-tubulin subunits on microtubules and stabilizes and suppresses microtubule activity resulting in mitotic arrest and apoptosis.1, 13, 15, 17, 18, 19 Although ixabepilone appears to share a similar antimicrotubule mechanism of action with taxanes, the drug differs structurally from taxanes and does not appear to be affected by common mechanisms of taxane resistance.1, 17, 18, 19
Ixabepilone is active in xenografts that are resistant to multiple antineoplastic agents, including taxanes, anthracyclines, and vinca alkaloids.1, 13, 19 The drug has also demonstrated synergistic antitumor activity in combination with capecitabine in vivo.1 In addition to direct antitumor activity, ixabepilone possesses antiangiogenic activity.1
Ixabepilone is extensively metabolized in the liver, principally by oxidative metabolism via the cytochrome P-450 (CYP) isoenzyme 3A4.1, 2, 13, 17 The drug is eliminated primarily as metabolized drug, with more than 30 inactive metabolites eliminated in urine and feces.1, 2 No single metabolite accounted for more than 6% of the administered dose.1, 2 Following IV administration of a single dose of radiolabeled drug, approximately 86% of the dose was eliminated within 7 days, 65% in feces and 21% in urine.1, 9, 17 Unchanged ixabepilone accounted for less than 2 and 6% of the dose in feces and urine, respectively.1, 2, 9 The drug has a terminal elimination half-life of approximately 52 hours (range: 20-72 hours).1, 2, 11, 13, 17 No accumulation in plasma is expected when the drug is administered once every 3 weeks.1, 2
Importance of reading the patient information provided by the manufacturer.1, 21
Risk of neuropathy.1, 2 Importance of patients notifying clinicians if they develop any numbness, tingling, or burning of the hands or feet.1, 2, 21
Importance of patients notifying clinicians if they develop a fever of 100.5°F or higher or other signs and symptoms of potential infection (e.g., chills, cough, burning or pain upon urination).1, 2, 21
Importance of patients notifying clinicians if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness, and/or other hypersensitivity-related symptoms following IV infusion of ixabepilone.1, 21
Importance of patients notifying clinicians if they notice chest pain, difficulty breathing, palpitations, or unusual weight gain.1, 21
Importance of patients informing clinicians if they are allergic to a drug such as paclitaxel that contains polyoxyl 35 castor oil (Cremophor® EL, polyethoxylated castor oil).1, 2, 21
Importance of patients informing clinicians if they have hepatic impairment.21 Importance of undergoing blood tests to determine liver function before and during ixabepilone therapy.21 Importance of not taking ixabepilone in combination with capecitabine if hepatic impairment is present.21
Importance of not drinking grapefruit juice while receiving ixabepilone therapy.1, 2, 21
Importance of informing patients that Ixempra® contains alcohol and may cause drowsiness or dizziness.1, 21 Importance of avoiding certain activities (e.g., operating machinery, driving a motor vehicle) if patient feels drowsy or dizzy.1, 21
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses (e.g., diabetes mellitus, liver disease).1, 2
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1, 21 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1, 21
Importance of informing patients of other important precautionary information.1, 21 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion only | 15 mg | ||
45 mg | Ixempra® | Bristol-Myers Squibb |
1. Bristol-Myers Squibb Company. Ixempra® (ixabepilone) Kit for injection prescribing information. Princeton, NJ: 2010 May. Available at [Web]. Accessed 2011 Sep 4.
2. Bhushan S, Walko CM. Ixabepilone: a new antimitotic for the treatment of metastatic breast cancer. Ann Pharmacother . 2008; 42:1252-61. [PubMed 18648018]
3. Thomas ES, Gomez HL, Li RK et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol . 2007; 25:5210-7. [PubMed 17968020]
4. Thomas ES. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol . 2008; 26:2223. [PubMed 18445853]
5. Perez EA, Lerzo G, Pivot X et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol . 2007; 25:3407-14. [PubMed 17606974]
6. Thomas E, Tabernero J, Fornier M et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol . 2007; 25:3399-406. [PubMed 17606975]
7. Moulder SL. Ixabepilone for the treatment of taxane-refractory breast cancer. Future Oncol . 2008; 4:333-40. [PubMed 18518758]
8. Lechleider RJ, Kaminskas E, Jiang X et al. Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies. Clin Cancer Res . 2008; 14:4378-84. [PubMed 18628451]
9. Higa GM, Abraham J. Ixabepilone: a new microtubule-targeting agent for breast cancer. Expert Rev Anticancer Ther . 2008; 8:671-81. [PubMed 18471040]
10. Pivot X, Villanueva C, Chaigneau L et al. Ixabepilone, a novel epothilone analog in the treatment of breast cancer. Expert Opin Investig Drugs . 2008; 17:593-9. [PubMed 18363523]
11. Denduluri N, Swain SM. Ixabepilone for the treatment of solid tumors: a review of clinical data. Expert Opin Investig Drugs . 2008; 17:423-35. [PubMed 18321240]
12. Goel S, Cohen M, Cömezoglu SN et al. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res . 2008; 25:2701-9.
13. Trivedi M, Budihardjo I, Loureiro K et al. Epothilones: a novel class of microtubule-stabilizing drugs for the treatment of cancer. Future Oncol . 2008; 4:483-500. [PubMed 18684060]
14. Institute for Safe Medication Practices. ISMP's list of high-alert medications. Horsham, PA; 2008. From ISMP website ([Web]). Accessed 2008 Sep 23.
15. Swain SM, Arezzo JC. Neuropathy associated with microtubule inhibitors: diagnosis, incidence, and management. Clin Adv Hematol Oncol . 2008; 6:455-67. [PubMed 18567992]
16. Lee JJ, Low JA, Croarkin E et al. Changes in neurologic function tests may predict neurotoxicity caused by ixabepilone. Expert Opin Investig Drugs . 2006; 24:2084-91.
17. Anon. Ixabepilone (Ixempra) for breast cancer. Med Lett Drugs Ther . 2008; 50:7-8. [PubMed 18219261]
18. Goodin S. Novel cytotoxic agents: epothilones. Am J Health-Syst Pharm . 2008; 65 (Suppl 3):S10-5.
19. Pronzato P. New therapeutic options for chemotherapy-resistant metastatic breast cancer: the epothilones. Drugs . 2008; 68:139-46. [PubMed 18197722]
20. Bristol-Myers Squibb Company. Princeton, NJ: Personal communication.
21. Bristol-Myers Squibb Company. Ixempra® (ixabepilone) Kit for injection patient information. Princeton, NJ; 2010 May.
22. Sparano JA, Vrdoljak E, Rixe O et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol . 2010; 28:3256-63. [PubMedCentral][PubMed 20530276]
23. Hortobagyi GN, Gomez HL, Rubi KL et al. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat . 2010; 122:409-18. [PubMed 20454927]