Ixabepilone – Ixempra™

Ixabepilone - Ixempra™

Usual Diluents

Dilution Data

Premedication:
To minimize the chance of occurrence of a hypersensitivity reaction, all patients must be premedicated approximately 1 hour before the infusion of IXEMPRA with: An H1 antagonist (eg, diphenhydramine 50 mg orally or equivalent) and An H2 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 H1 and H2 antagonists.

Instructions for Preparation and IV Administration:
IXEMPRA Kit contains two vials, a vial labeled IXEMPRA (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for IXEMPRA. Only supplied DILUENT must be used for constituting IXEMPRA (ixabepilone) for injection. IXEMPRA Kit must be stored in a refrigerator at 2° C - 8° C (36° F - 46° F) in the original package to protect from light. Prior to constituting IXEMPRA for injection, the Kit should be removed from the refrigerator and allowed 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. To allow for withdrawal losses, the vial labeled as 15 mg IXEMPRA for injection contains 16 mg of ixabepilone and the vial labeled as 45 mg IXEMPRA for injection contains 47 mg of ixabepilone. The 15-mg IXEMPRA Kit is supplied with a vial providing 8 mL of the DILUENT and the 45-mg IXEMPRA Kit is supplied with a vial providing 23.5 mL of the DILUENT. After constituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.

To constitute: With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is constituted with 8 mL of DILUENT and the 45-mg IXEMPRA is constituted with 23.5 mL of DILUENT. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved To dilute:
Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below. 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 constituted 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 Constituted Solution + mL of infusion fluid
  Final Infusion Concentration = Dose of IXEMPRA (mg)/Total Infusion Volume (mL) . Aseptically, withdraw the appropriate volume of constituted solution containing 2 mg of ixabepilone per mL. Aseptically, transfer to an intravenous (IV) bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of IXEMPRA. Thoroughly mix the infusion bag by manual rotation. 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. Any remaining solution should be discarded according to institutional procedures for antineoplastics.

----------------------------- Stability -----------------------------
After constituting IXEMPRA, the constituted solution should be further diluted with infusion fluid as soon as possible, but may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. 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. The infusion fluids previously mentioned are specified because their pH is in the range of 6.0 to 9.0, which is required to maintain IXEMPRA stability. Other infusion fluids should not be used with IXEMPRA.

DESCRIPTION

IXEMPRA (ixabepilone) is a microtubule inhibitor belonging to a class of antineoplastic agents, the epothilones and their analogs. The epothilones are isolated from the myxobacterium Sorangium cellulosum. Ixabepilone is a semisynthetic analog of epothilone B, a 16-membered polyketide macrolide, with a chemically modified lactam substitution for the naturally existing lactone.

IXEMPRA (ixabepilone) for injection is intended for intravenous infusion only after constitution with the supplied DILUENT and after further dilution with a specified infusion fluid [see Instructions for Preparation and IV Administration (2.4)]. IXEMPRA (ixabepilone) for injection is supplied as a sterile, non-pyrogenic single-use vial providing 15 mg or 45 mg ixabepilone as a lyophilized white powder. The DILUENT for IXEMPRA is a sterile, non-pyrogenic solution of 52.8% (w/v) purified polyoxyethylated castor oil and 39.8% (w/v) dehydrated alcohol, USP. The IXEMPRA (ixabepilone) for injection and the DILUENT for IXEMPRA are co-packaged and supplied as IXEMPRA Kit.

CLINICAL PHARMACOLOGY
Mechanism of Action
Ixabepilone is a semi-synthetic analog of epothilone B. Ixabepilone binds directly to β-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of αβ-II and αβ-III microtubules. Ixabepilone possesses low in vitro susceptibility to multiple tumor resistance mechanisms including efflux transporters, such as MRP-1 and P-glycoprotein (P-gp). Ixabepilone blocks cells in the mitotic phase of the cell division cycle, leading to cell death.

1.  INDICATIONS AND USAGE

IXEMPRA (ixabepilone) 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. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting.

IXEMPRA is indicated 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.

2. DOSAGE AND ADMINISTRATION

2.1 General Dosing Information
The recommended dosage of IXEMPRA is 40 mg/m2 administered intravenously over 3 hours every 3 weeks. Doses for patients with body surface area (BSA) greater than 2.2 m2 should be calculated based on 2.2 m2.

2.2 Dose Modification

Dose Adjustments During Treatment
Patients should be evaluated during treatment by periodic clinical observation and laboratory tests including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. Dosing adjustment guidelines for monotherapy and combination therapy are shown in Table 1. If toxicities recur, an additional 20% dose reduction should be made.

Re-treatment Criteria:
Dose 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. Patients should not begin a new cycle of treatment unless the neutrophil count is at least 1500 cells/mm3, the platelet count is at least 100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved.

Dose Adjustments in Special Populations - 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. Patients receiving combination treatment who have AST and ALT ≤2.5 x ULN and bilirubin ≤1 x ULN may receive the standard dose of ixabepilone (40 mg/m2) [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.6)].

Monotherapy:
Patients with hepatic impairment should be dosed with IXEMPRA based on the guidelines in Table 2. Patients with moderate hepatic impairment should be started at 20 mg/m2, the dosage in subsequent cycles may be escalated up to, but not exceeding, 30 mg/m2 if tolerated. 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 baseline AST or ALT >5 x ULN. Caution should be used when treating these patients [see PACKAGE INSERT FOR Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

Strong CYP3A4 Inhibitors
The use of concomitant strong CYP3A4 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole). Grapefruit juice may also increase plasma concentrations of IXEMPRA and should be avoided. Based on pharmacokinetic studies, if a strong CYP3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is predicted to adjust the ixabepilone AUC to the range observed without inhibitors and should be considered. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the IXEMPRA dose is adjusted upward to the indicated dose [see PACKAGE INSERT FOR Drug Interactions (7.1)].

Strong CYP3A4 Inducers
The use of concomitant strong CYP3A4 inducers should be avoided (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and phenobarbital). Selection of an alternative concomitant medication with no or minimal enzyme induction potential should be considered. Based on extrapolation from a drug interaction study with rifampin, the following guidance may be considered for dosing in patients requiring coadministration of a strong CYP3A4 inducer, if no alternatives are feasible. Once patients have been maintained on a strong CYP3A4 inducer, the dose of IXEMPRA may be gradually increased from 40 mg/m2 to 60 mg/m2 depending on tolerance. If the dose is increased, IXEMPRA should be given as a 4 hour intravenous infusion. This 60 mg/m2 dose given intravenously over 4 hours is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. Patients whose dose is increased above 40 mg/m2 should be monitored carefully for toxicities associated with IXEMPRA. If the strong inducer is discontinued, the IXEMPRA dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see PACKAGE INSERT FOR Drug Interactions (7.1)].

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2.3  Premedication
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To minimize the chance of occurrence of a hypersensitivity reaction, all patients must be premedicated approximately 1 hour before the infusion of IXEMPRA with: An H1 antagonist (eg, diphenhydramine 50 mg orally or equivalent) and An H2 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 H1 and H2 antagonists.

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2.4  Instructions for Preparation and IV Administration
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IXEMPRA Kit contains two vials, a vial labeled IXEMPRA (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for IXEMPRA. Only supplied DILUENT must be used for constituting IXEMPRA (ixabepilone) for injection. IXEMPRA Kit must be stored in a refrigerator at 2° C - 8° C (36° F - 46° F) in the original package to protect from light. Prior to constituting IXEMPRA for injection, the Kit should be removed from the refrigerator and allowed 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. To allow for withdrawal losses, the vial labeled as 15 mg IXEMPRA for injection contains 16 mg of ixabepilone and the vial labeled as 45 mg IXEMPRA for injection contains 47 mg of ixabepilone. The 15-mg IXEMPRA Kit is supplied with a vial providing 8 mL of the DILUENT and the 45-mg IXEMPRA Kit is supplied with a vial providing 23.5 mL of the DILUENT. After constituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.

Please refer to Preparation and Handling Precautions [see Dosage and Administration (2.5)] before preparation.

A. To constitute: With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is constituted with 8 mL of DILUENT and the 45-mg IXEMPRA is constituted with 23.5 mL of DILUENT. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved B. To dilute:

Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below. 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 constituted 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 Constituted Solution + mL of infusion fluid

  Final Infusion Concentration = Dose of IXEMPRA (mg)/Total Infusion Volume (mL) .
Aseptically, withdraw the appropriate volume of constituted solution containing 2 mg of ixabepilone per mL. Aseptically, transfer to an intravenous (IV) bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of IXEMPRA. Thoroughly mix the infusion bag by manual rotation.
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. Any remaining solution should be discarded according to institutional procedures for antineoplastics.

----------------------------- Stability -----------------------------
After constituting IXEMPRA, the constituted solution should be further diluted with infusion fluid as soon as possible, but may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. 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. The infusion fluids previously mentioned are specified because their pH is in the range of 6.0 to 9.0, which is required to maintain IXEMPRA stability. Other infusion fluids should not be used with IXEMPRA.

2.5 Preparation and Handling Precautions
Procedures for proper handling and disposal of antineoplastic drugs [see References (15)] should be followed. To minimize the risk of dermal exposure, impervious gloves should be worn when handling vials containing IXEMPRA, regardless of the setting, including unpacking and inspection, transport within a facility, and dose preparation and administration.

3.  DOSAGE FORMS AND STRENGTHS

IXEMPRA for injection, 15 mg supplied with DILUENT for IXEMPRA, 8 mL.

IXEMPRA for injection, 45 mg supplied with DILUENT for IXEMPRA, 23.5 mL.

4. CONTRAINDICATIONS

IXEMPRA is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) [see Warnings and Precautions (5.4)].

IXEMPRA is contraindicated in patients who have a neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3[see PACKAGE INSERT FOR Warnings and Precautions (5.2)] .

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 PACKAGE INSERT FOR Warnings and Precautions (5.3)].

HOW SUPPLIED/STORAGE AND HANDLING

IXEMPRA is supplied as a Kit containing one vial of IXEMPRA® (ixabepilone) for injection and one vial of DILUENT for IXEMPRA.

IXEMPRA Kit must be stored in a refrigerator at 2° C to 8° C (36° F to 46° F). Retain in original package until time of use to protect from light.

Procedures for proper handling and disposal of antineoplastic drugs [see References (15)] should be followed. To minimize the risk of dermal exposure, impervious gloves should be worn when handling vials containing IXEMPRA, regardless of the setting, including unpacking and inspection, transport within a facility, and dose preparation and administration.