Ixempra

Ixempra Manufacturers

• E.r. Squibb & Sons, L.l.c.
  

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  Ixempra | E.r. Squibb & Sons, L.l.c.

  

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  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.

  Table 1: Dose Adjustment Guidelinesa IXEMPRA
  (Monotherapy or Combination Therapy) IXEMPRA
  Dose Modification a  Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0).

  Nonhematologic:

  Grade 2 neuropathy (moderate) lasting ≥7 days

  Decrease the dose by 20%

  Grade 3 neuropathy (severe) lasting <7 days

  Decrease the dose by 20%

  Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy

  Discontinue treatment

  Any grade 3 toxicity (severe) other than neuropathy

  Decrease the dose by 20%

  Transient grade 3 arthralgia/myalgia or fatigue

  No change in dose of IXEMPRA

  Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)

  Any grade 4 toxicity (disabling)

  Discontinue treatment

  Hematologic:

  Neutrophil <500 cells/mm3 for ≥7 days

  Decrease the dose by 20%

  Febrile neutropenia

  Decrease the dose by 20%

  Platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding

  Decrease the dose by 20%

  Capecitabine
  (when used in combination with IXEMPRA)

  Capecitabine
  Dose Modification

  Nonhematologic:

  Follow Capecitabine Label

  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 dose.

  Neutrophils <500 cells/mm3 for ≥7 days or febrile neutropenia

  Hold for concurrent diarrhea or stomatitis until neutrophil count >1,000 cells/mm3, then continue at same dose.

  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 × ULN or bilirubin >1 × ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 × ULN and bilirubin ≤1 × 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 × ULN or bilirubin >3 × ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 × ULN. Caution should be used when treating these patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

  Table 2: Dose Adjustments for IXEMPRA as Monotherapy in Patients with Hepatic Impairment Transaminase
  Levels Bilirubin
  Levelsa IXEMPRAb
  (mg/m2) 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.

  Mild

  AST and ALT ≤2.5 × ULN

  and

  ≤1 × ULN

  40

  AST and ALT ≤10 × ULN

  and

  ≤1.5 × ULN

  32

  Moderate

  AST and ALT ≤10 × ULN

  and

  >1.5 × ULN - ≤3 × ULN

  20 - 30

  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 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 Drug Interactions (7.1)].

  2.3 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 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 H1 and H2 antagonists.

  2.4 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.

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

  A. To constitute:

  1. 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. 2. 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) 1. Aseptically, withdraw the appropriate volume of constituted solution containing 2 mg of ixabepilone per mL. 2. Aseptically, transfer to an intravenous (IV) 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.

  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.

  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.

  Table 1: Dose Adjustment Guidelinesa IXEMPRA
  (Monotherapy or Combination Therapy) IXEMPRA
  Dose Modification a  Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0).

  Nonhematologic:

  Grade 2 neuropathy (moderate) lasting ≥7 days

  Decrease the dose by 20%

  Grade 3 neuropathy (severe) lasting <7 days

  Decrease the dose by 20%

  Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy

  Discontinue treatment

  Any grade 3 toxicity (severe) other than neuropathy

  Decrease the dose by 20%

  Transient grade 3 arthralgia/myalgia or fatigue

  No change in dose of IXEMPRA

  Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)

  Any grade 4 toxicity (disabling)

  Discontinue treatment

  Hematologic:

  Neutrophil <500 cells/mm3 for ≥7 days

  Decrease the dose by 20%

  Febrile neutropenia

  Decrease the dose by 20%

  Platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding

  Decrease the dose by 20%

  Capecitabine
  (when used in combination with IXEMPRA)

  Capecitabine
  Dose Modification

  Nonhematologic:

  Follow Capecitabine Label

  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 dose.

  Neutrophils <500 cells/mm3 for ≥7 days or febrile neutropenia

  Hold for concurrent diarrhea or stomatitis until neutrophil count >1,000 cells/mm3, then continue at same dose.

  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 × ULN or bilirubin >1 × ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 × ULN and bilirubin ≤1 × 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 × ULN or bilirubin >3 × ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 × ULN. Caution should be used when treating these patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

  Table 2: Dose Adjustments for IXEMPRA as Monotherapy in Patients with Hepatic Impairment Transaminase
  Levels Bilirubin
  Levelsa IXEMPRAb
  (mg/m2) 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.

  Mild

  AST and ALT ≤2.5 × ULN

  and

  ≤1 × ULN

  40

  AST and ALT ≤10 × ULN

  and

  ≤1.5 × ULN

  32

  Moderate

  AST and ALT ≤10 × ULN

  and

  >1.5 × ULN - ≤3 × ULN

  20 - 30

  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 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 Drug Interactions (7.1)].

  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.

  Table 1: Dose Adjustment Guidelinesa IXEMPRA
  (Monotherapy or Combination Therapy) IXEMPRA
  Dose Modification a  Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0).

  Nonhematologic:

  Grade 2 neuropathy (moderate) lasting ≥7 days

  Decrease the dose by 20%

  Grade 3 neuropathy (severe) lasting <7 days

  Decrease the dose by 20%

  Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy

  Discontinue treatment

  Any grade 3 toxicity (severe) other than neuropathy

  Decrease the dose by 20%

  Transient grade 3 arthralgia/myalgia or fatigue

  No change in dose of IXEMPRA

  Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)

  Any grade 4 toxicity (disabling)

  Discontinue treatment

  Hematologic:

  Neutrophil <500 cells/mm3 for ≥7 days

  Decrease the dose by 20%

  Febrile neutropenia

  Decrease the dose by 20%

  Platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding

  Decrease the dose by 20%

  Capecitabine
  (when used in combination with IXEMPRA)

  Capecitabine
  Dose Modification

  Nonhematologic:

  Follow Capecitabine Label

  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 dose.

  Neutrophils <500 cells/mm3 for ≥7 days or febrile neutropenia

  Hold for concurrent diarrhea or stomatitis until neutrophil count >1,000 cells/mm3, then continue at same dose.

  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 × ULN or bilirubin >1 × ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 × ULN and bilirubin ≤1 × 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 × ULN or bilirubin >3 × ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 × ULN. Caution should be used when treating these patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

  Table 2: Dose Adjustments for IXEMPRA as Monotherapy in Patients with Hepatic Impairment Transaminase
  Levels Bilirubin
  Levelsa IXEMPRAb
  (mg/m2) 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.

  Mild

  AST and ALT ≤2.5 × ULN

  and

  ≤1 × ULN

  40

  AST and ALT ≤10 × ULN

  and

  ≤1.5 × ULN

  32

  Moderate

  AST and ALT ≤10 × ULN

  and

  >1.5 × ULN - ≤3 × ULN

  20 - 30

  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 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 Drug Interactions (7.1)].

  2.3 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 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 H1 and H2 antagonists.

  2.4 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.

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

  A. To constitute:

  1. 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. 2. 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) 1. Aseptically, withdraw the appropriate volume of constituted solution containing 2 mg of ixabepilone per mL. 2. Aseptically, transfer to an intravenous (IV) 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.

  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.

  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.

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