Ixabepilone
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Boxed warning
WARNING: TOXICITY IN PATIENTS WITH HEPATIC IMPAIRMENT 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 Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )]. WARNING: TOXICITY IN PATIENTS WITH HEPATIC IMPAIRMENT See full prescribing information for complete boxed warning. 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. ( 4 , 5.3 )
Handling and access
NIOSH hazardous drug
Table 1NIOSH lists ixabepilone as a hazardous drug. AHFS class: 10:00 antineoplastic agents.
- The package insert includes manufacturer's special handling information (MSHI). Follow it when preparing, administering, and disposing of this drug.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Dosing in kidney impairment
This label has no separate kidney-impairment dosing section. Check warnings and clinical pharmacology in the full label.
Dosing in liver impairment
Dosage Modifications in Patients with Hepatic Impairment Dosage Modifications in Patients with Hepatic Impairment Combination Therapy IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Contraindications] . Single Agent Reduce the dose of IXEMPRA for patients with hepaptic impairment as recommended in Table 2 . [see Warnings and Precautions and Use in Specific Populations]. [See table below.]
| a Excluding patients whose total bilirubin is elevated due to Gilbert's disease. | ||||
| b Dosage recommendations are for first course of therapy; further decreases in subsequent courses should be based on individual tolerance. c For patients with AST and ALT ≤ 10x ULN and lilirubin >1.5 to 3x ULN, consider increasing the dose from 20mg/m 2 to 30mg/m 2 in subsequent cycles if a dose of 20 mg/m 2 is tolerated. | ||||
| Transaminase Levels | Bilirubin Levelsa | IXEMPRAb (mg/m2 | ||
| AST and ALT ≤2.5 x ULN | and | ≤1 x ULN | No Modification | |
| AST and ALT ≤10x ULN | and | ≤1.5 x ULN | 32 | |
| AST and ALT ≤10 x ULN | and | >1.5 to ≤3 x ULN | 20-30 c | |
| AST and ALT > 10 x ULN | or | >3 x ULN | Avoid Use | |
Preparation and administration
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Premedication All patients must be premedicated approximately 1 hour before the infusion of IXEMPRA with: An H 1 antagonist (eg, diphenhydramine 50 mg orally or equivalent) and An H 2 antagonist (eg, ranitidine 150 - 300 mg orally or equivalent). Patients who experienced a hypersensitivity reaction to IXEMPRA require premedication with corticosteroids (eg, dexamethasone 20 mg intravenously, 30 minutes before infusion or orally, 60 minutes before infusion) in addition to pretreatment with H 1 and H 2 antagonists [see Warnings and Precautions] .
Preparation and Administration IXEMPRA is a hazardous drug. Follow aplicable special handling and disposal procedures. 1 IXEMPRA Kit contains two vials, a vial labeled IXEMPRA (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for IXEMPRA. Use only the supplied DILUENT to reconstitute IXEMPRA (ixabepilone) for injection.
Reconstituation 1. Prior to reconstituting, remove the IXEMPRA Kit from the refrigerator and allow it to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature. 2.
With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is reconstituted with 8 mL of DILUENT and the 45-mg IXEMPRA is reconstituted with 23.5 mL of DILUENT. 3. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved. 4.
After reconstituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL. 5. After reconstituting IXEMPRA, dilute the reconstituted with infusion fluid as soon as possible. The reconstituted solution may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. Dilution Before administration, the reconstituted solution must be further diluted with one of the specified infusion fluids listed below.
Other infusion fluids should not be used with IXEMPRA. The IXEMPRA infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag. The following infusion fluids have been qualified for use in the dilution of IXEMPRA: Lactated Ringer’s Injection, USP 0.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP) When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the reconstituted IXEMPRA solution.
PLASMA-LYTE A Injection pH 7.4 ® For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final IXEMPRA infusion concentration of each dose based on the volume of infusion fluid to be used. The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas: Total Infusion Volume = mL of Reconstituted Solution + mL of infusion fluid Final Infusion Concentration = Dose of IXEMPRA (mg)/Total Infusion Volume (mL) 1.
Aseptically, withdraw the appropriate volume of reconstituted solution containing 2 mg of ixabepilone per mL. 2. Aseptically, transfer to an intravenous bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of IXEMPRA. 3. Thoroughly mix the infusion bag by manual rotation. 4. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours.
Administration of diluted IXEMPRA must be completed within this 6-hour period. Administration The infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns. DEHP-free infusion containers and administration sets must be used. Discard any remaining solution according to institutional procedures for hazardous drugs.
Drug interactions
Check ixabepilone against a medication listLabel text (6 paragraphs)
Strong CYP3A4 Inhibitors: Avoid strong CYP3A4 inhibitors. If coadministration cannot be avoided, reduce the dosage of IXEMPRA ( 2.5 , 7.1 ). Strong CYP3A4 Inducers: Avoid strong CYP3A4 inducers. If coadministration cannot be avoided, reduce the dosage of IXEMPRA ( 2.5 , 7.1 ).
7.1 Effect of Other Drugs on IXEMPRA Strong CYP3A4 Inhibitors The coadministration of IXEMPRA with a strong CYP3A4 inhibitor increased ixabepilone plasma concentration, which may increase the incidence and severity of adverse reactions of IXEMPRA. Avoid coadministration of IXEMPRA with strong CYP3A4 inhibitors. If the coadministration of IXEMPRA with strong CYP3A4 cannot be avoided, reduce the dose of IXEMPRA [see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 ]. Moderate or Weak CYP3A4 Inhibitors The coadministration of IXEMPRA with moderate or weak CYP3A4 inhibitors may increase the incidence and severity of adverse reactions of IXEMPRA.
Monitor for adverse reactions and reduce the dose of IXEMPRA as recommended [see Dosage and Administration ( 2.5 ), Adverse Reactions ( 6 )]. Strong CYP3A4 Inducers The coadministration of IXEMPRA with a strong CYP3A4 inducer, decreased plasma concentrations of ixabepilone, which may decrease the efficacy of IXEMPRA [see Clinical Pharmacology ( 12.3 )]. Avoid the coadministration IXEMPRA with strong CYP3A4 inducers. If the coadministration of IXEMPRA with a strong CYP3A4 inducer cannot be avoided, increase the dose of IXEMPRA [see Dosage and Administration ( 2.4 )].
Concomitant Use of IXEMPRA and Capecitabine No clinically meaningful differences in the pharmacokinetics of ixabepilone and capecitabine were observed when IXEMPRA was administered in combination with capecitabine (1000 mg/m 2 ) [see Clinical Pharmacology ( 12.3 )].
7.2 Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs [see Clinical Pharmacology ( 12.3 )].
7.3 Capecitabine In patients with cancer who received ixabepilone (40 mg/m 2 ) in combination with capecitabine (1000 mg/m 2 ), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data.
Contraindications
4 CONTRAINDICATIONS IXEMPRA is contraindicated in patients who have: a neutrophil count <1500 cells/mm 3 or a platelet count <100,000 cells/mm 3 [see Warnings and Precautions ( 5.2 )]. a history of severe hypersensitivity to agents containing Cremophor ® EL or its derivatives (e.g., polyoxyethylated castor oil) [see Warnings and Precautions ( 5.4 )]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning and Warnings and Precautions ( 5.3 )]. Baseline neutrophil count <1500 cells/mm 3 or a platelet count <100,000 cells/mm 3 ( 4 ). Hypersensitivity to drugs formulated with Cremophor ® EL ( 4 ).
IXEMPRA in combination with capecitabine is contraindicated for use in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN.( 4 ).
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
E*Likelihood score E*: Unproven but suspected rare cause of clinically apparent liver injury.
Ixabepilone is a semisynthetic epothilone analogue that acts to stabilize microtubules thereby preventing mitosis and causing growth arrest in cancer cells. Ixabepilone is approved for use in refractory cases of advanced breast cancer. Its use is associated with a low rate of serum enzyme elevation, but ixabepilone has not been linked to cases of clinically apparent liver injury with jaundice.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on the use of IXEMPRA in pregnant women to inform the drug-associated risk. IXEMPRA contains alcohol which can interfere with neurobehavioral development [see Clinical Considerations]. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC (see Data).
Advise females of reproductive potential and pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations IXEMPRA contains alcohol [see Warnings and Precautions ( 5.7 )] . Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.
Data Animal data In embryo-fetal development studies, pregnant rats and rabbits received intravenous 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 during the period of organogenesis. 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 0.1 times 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 0.1 times the human clinical dose based on body surface area).
Lactation
8.2 Lactation Risk Summary There is no data on the presence of IXEMPRA in human milk, the effects on the breastfed child, or the effects on milk production. Ixabepilone and/or its metabolites were present in milk of lactating rats (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IXEMPRA and for 2 weeks after the last dose. Data Animal data 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.
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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