IXEMPRA

2 DOSAGE AND ADMINISTRATION The recommended dosage of IXEMPRA is 40 mg/m 2 administered as a 3-hour intravenous infusion once every 3 weeks ( 2.2 ). Dose reduction is required in patients with elevated AST, ALT, or bilirubin.( 2.3, 8.6 ) IXEMPRA must be reconstituted with the supplied DILUENT and further diluted to a concentration of 0.2 mg/mL to 0.6 mg/mL prior to administration ( 2.6 ). 2.1 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 ( 5.4 )] . 2.2 Recommended Dosage The recommended dosage of IXEMPRA is 40 mg/m 2 administered intravenously over 3 hours every 3 weeks. Calculate doses for patients with body surface area (BSA) greater than 2.2 m 2 should be calculated based on 2.2 m 2 . 2.3 Dosage Modification for Adverse Reactions Evaluate patients during treatment by periodic clinical observation and laboratory tests including complete blood cell counts [see the Warnings and Precautions ( 5 )]. Dosage modifications for IXEMPRA for adverse reactions are shown in Table 1. If adverse reactions recur, reduce dose by an additional 20%. Re-treatment Criteria: Determine dosage modifications at the start of each cycle based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines in Table 1 . Do not begin a new cycle of treatment unless the neutrophil count is at least 1500 cells/mm 3 , the platelet count is at least 100,000 cells/mm 3 [see Contraindictions]. Withhold IXEMPRA until nonhematologic toxicities have improved to grade 1 (mild) or resolved prior to beginning a new cycle of treatment. Evaluate patients during treatment by periodic clinical observation and laboratory tests including complete blood cell counts [see the Warnings and Precautions ( 5 )] . Dosage modifications for IXEMPRA for adverse reactions are shown in Table 1 . If adverse reactions recur, reduce dose by an additional 20%. Table 1: Dosage for Modification for Adverse Reactions a a Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events(CTCAE v3.0). IXEMPRA IXEMPRA (Single Agent or Combination Therapy) Dosage Modification Nonhematologic: Grade 2 neuropathy (moderate) lasting ≥7 days Decrease the dose by 20% Grade 3 neuropathy (severe) lasting 50,000/mm 3 , then continue at same dose. Neutrophils 1,000 cells/mm 3 , then continue at same dose. Combination Therapy: IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 x ULN and bilirubin ≤1 x ULN [see Contraindictions ( 4 )]. 2.4 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 ( 4 )] . Single Agent Reduce the dose of IXEMPRA for patients with hepaptic impairment as recommended in Table 2 . [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )]. Table 2: Dose Modifications for IXEMPRA as a Single Agent for Patients with Hepatic Impairment 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 Levels a IXEMPRA b (mg/m 2 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 2.5 Dosage Modification for Drug Interactions Strong CYP3A4 Inhibitors Avoid the use of concomitant use of strong CYP3A4 inhibitors. If coadministration of a strong CYP3A4 inhibitor with IXEMPRA cannot be avoided, reduce the dose of IXEMPRA to 20 mg/m 2 . If the strong inhibitor is discontinued, increase the IXEMPRA dose (at 1 week after discontinuing the inhibitor) to that was used before starting the strong inhibitor [see Clinical Pharmacology ( 12.3 )]. Strong CYP3A4 Inducers Avoid the concomitant use of strong CYP3A4 inducers. If coadministration of a strong CYP3A4 inducer with IXEMPRA cannot be avoided, gradually increase the dose from 40 mg/m2 to 60 mg/m 2 as tolerated once a patient has been maintained on a strong CYP3A4 inducer. Administer IXEMPRA as a 4-hour intravenous infusion and monitor patients carefully for adverse reactions. If the strong inducer is discontinued, reduce the IXEMPRA dose to that before that before starting the strong CYP3A4 inducer [see Clinical Pharmacology ( 12.3 )]. 2.6 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.

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1 INDICATIONS AND USAGE IXEMPRA is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.