`These highlights do not include all the information needed to use
`®
`IXEMPRA
` safely and effectively. See full prescribing information for
`®
`IXEMPRA
`.
`
`®
`IXEMPRA Kit (ixabepilone) for Injection, for intravenous infusion only
`
`
`
`
`Initial U.S. Approval: 2007
`
`
`WARNING: TOXICITY IN HEPATIC IMPAIRMENT
`See full prescribing information for complete boxed warning.
`®
`IXEMPRA
`
` in combination with capecitabine must not be given to
`
`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)
`
`---------------------------INDICATIONS AND USAGE----------------------------
`
`
`IXEMPRA, a microtubule inhibitor, in combination with capecitabine is
`•
`
`
`
`indicated for the treatment of metastatic or locally advanced breast
`
`cancer in patients after failure of an anthracycline and a taxane (1).
`
`
`
`IXEMPRA as monotherapy is indicated for the treatment of metastatic
`or locally advanced breast cancer in patients after failure of an
`anthracycline, a taxane, and capecitabine (1).
`
`
`•
`
`
`------------------------DOSAGE AND ADMINISTRATION----------------------
`
`is 40 mg/m2
`
`
`The
`recommended dose of
`IXEMPRA
`infused
`•
`
`intravenously over 3 hours every 3 weeks (2.1).
`
`Dose reduction is required in certain patients with elevated AST, ALT,
`or bilirubin (2.2, 8.6).
`IXEMPRA (ixabepilone) for injection must be constituted with supplied
`
`DILUENT. The ixabepilone concentration in constituted solution is 2 mg/mL.
`Constituted solution must be diluted with one of the specified fluids, to a final
`ixabepilone concentration of 0.2 mg/mL to 0.6 mg/mL. The final solution
`
`must be used within 6 hours of preparation (2.4).
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`IXEMPRA for
`injection, 15 mg supplied with DILUENT for
`•
`
`IXEMPRA, 8 mL (3)
`IXEMPRA for
`injection, 45 mg supplied with DILUENT for
`
`IXEMPRA, 23.5 mL (3)
`----------------------------CONTRAINDICATIONS-------------------------------
`
`Hypersensitivity to drugs formulated with Cremophor® EL (4).
`•
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: TOXICITY IN HEPATIC IMPAIRMENT
`
`
`1
`INDICATIONS AND USAGE
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`General Dosing Information
`2.1
`
`
`2.2
`Dose Modification
`
`
`2.3
`Premedication
`
`
`2.4
`Instructions for Preparation and IV Administration
`
`
`2.5
`Preparation and Handling Precautions
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1
`Peripheral Neuropathy
`
`
`5.2
`Myelosuppression
`
`
`5.3
`Hepatic Impairment
`
`
`5.4
`Hypersensitivity Reactions
`
`
`5.5
`Pregnancy
`
`
`5.6
`Cardiac Adverse Reactions
`
`
`5.7
`Potential for Cognitive Impairment from Excipients
`
`ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6.1
`
`
`6.2
`Postmarketing Experience
`
`DRUG INTERACTIONS
`
`
`Effect of Other Drugs on Ixabepilone
`7.1
`
`
`7.2
`Effect of Ixabepilone on Other Drugs
`
`
`7.3
`Capecitabine
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`•
`
`
`•
`
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`
`8
`
`Baseline neutrophil count <1500 cells/mm3 or a platelet count
`
`<100,000 cells/mm3 (4).
`Patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN must not
`be treated with IXEMPRA in combination with capecitabine (4).
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`
`Peripheral Neuropathy: Monitor for symptoms of neuropathy, primarily
`
`
`•
`sensory. Neuropathy is cumulative, generally reversible and should be
`
`
`managed by dose adjustment and delays (2.2, 5.1).
`
`
`• Myelosuppression: Primarily neutropenia. Monitor with peripheral blood
`
`cell counts and adjust dose as appropriate (2.2, 5.2).
`
`Hypersensitivity reaction: Must premedicate all patients with an
`H1 antagonist and an H2 antagonist before treatment (2.3, 5.4).
`
`Fetal harm can occur when administered to a pregnant woman. Women
`
`should be advised not to become pregnant when taking IXEMPRA (5.5,
`8.1).
`
`
`
`-------------------------------ADVERSE REACTIONS------------------------------
`
`The most common adverse reactions (≥20%) are peripheral sensory
`•
`fatigue/asthenia, myalgia/arthralgia, alopecia, nausea,
`neuropathy,
`
`vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain.
`
`Additional reactions occurred in ≥20% in combination treatment:
`
`
`palmar-plantar erythrodysesthesia syndrome, anorexia, abdominal pain,
`nail disorder, and constipation (6).
`
`Drug-associated hematologic abnormalities (>40%) include neutropenia,
`leukopenia, anemia, and thrombocytopenia (6).
`
`
`
`•
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`
`--------------------------------DRUG INTERACTIONS-----------------------------
`
`Inhibitors of CYP3A4 may
`increase plasma concentrations of
`•
`ixabepilone; dose of IXEMPRA must be reduced with strong CYP3A4
`
`inhibitors (7.1).
`Inducers of CYP3A4 may decrease plasma concentrations of
`ixabepilone; alternative therapeutic agents with low enzyme induction
`
`potential should be considered (7.1).
`
`
`
`•
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`Approved Patient Labeling
`
`Revised: XX/201X
`
`
`
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`15
`
`16
`
`17
`
`
`
`Nursing Mothers
`8.3
`
`
`Pediatric Use
`8.4
`
`
`Geriatric Use
`8.5
`
`
`Hepatic Impairment
`8.6
`
`
`Renal Impairment
`8.7
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`
`12.4
`Effect of Ixabepilone on QT/QTc Interval
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13.2
`Animal Toxicology
`
`CLINICAL STUDIES
`
`REFERENCES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`
`
`17.1
`Peripheral Neuropathy
`
`
`17.2
`Fever/Neutropenia
`
`
`17.3 Hypersensitivity Reactions
`
`
`17.4
`Pregnancy
`
`
`17.5 Cardiac Adverse Reactions
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`
`
`Reference ID: 3029935
`
`Page 1 of 35
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`IMMUNOGEN 2222, pg. 1
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`
`FULL PRESCRIBING INFORMATION
`
`
` WARNING: TOXICITY IN 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)].
`
`
`
`
` 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.
`
`
`
`Reference ID: 3029935
`
`Page 2 of 35
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` IXEMPRA
`
`Dose Modification
`
`
`
`Decrease the dose by 20%
`
`
`Decrease the dose by 20%
`
`Discontinue treatment
`
`
`
`Decrease the dose by 20%
`
`No change in dose of IXEMPRA
`
`
`
`
`Table 1:
`
`
`
` Dose Adjustment Guidelinesa
`
` IXEMPRA
`
`(Monotherapy or Combination Therapy)
`Nonhematologic:
`
`Grade 2 neuropathy (moderate) lasting ≥7 days
`
`Grade 3 neuropathy (severe) lasting <7 days
`
`Grade 3 neuropathy (severe) lasting ≥7 days or disabling
`
`neuropathy
`
`
`
`Any grade 3 toxicity (severe) other than neuropathy
`
`Transient grade 3 arthralgia/myalgia or fatigue
`
`Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)
`
`Any grade 4 toxicity (disabling)
`
`Hematologic:
`Neutrophil <500 cells/mm3 for ≥7 days
`
`
`Febrile neutropenia
`Platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding
`
`
`Capecitabine
`(when used in combination with IXEMPRA)
`
`Nonhematologic:
`Hematologic:
`
`Platelets <25,000/mm3 or <50,000/mm3 with bleeding
`
`
`Neutrophils <500 cells/mm3 for ≥7 days or febrile neutropenia
`
`
`
`Discontinue treatment
`
`
`
`Decrease the dose by 20%
`
`
`Decrease the dose by 20%
`
`
`Decrease the dose by 20%
`
`
`Capecitabine
`Dose Modification
`
`
`Follow Capecitabine Label
`
`
`
`Hold for concurrent diarrhea or
`
`stomatitis until platelet count
`>50,000/mm3, then continue at
`same dose.
`Hold for concurrent diarrhea or
`
`
`stomatitis until neutrophil count
`>1,000 cells/mm3, then continue
`
`at same dose.
`
` a Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for
`
`
` Adverse Events (CTCAE v3.0).
`
`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
`least 1500 cells/mm3,
`neutrophil count
`is at
`the platelet count
`is at
`least
`100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or
`resolved.
`
`
`
`Reference ID: 3029935
`
`
`Page 3 of 35
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`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 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
`
`Mild
`
`and
`≤1 x ULN
`AST and ALT ≤2.5 x ULN
`
`
`
`
`and
`≤1.5 x ULN
`AST and ALT ≤10 x ULN
`
`
`Moderate
`
`and
`>1.5 x ULN - ≤3 x ULN
`AST and ALT ≤10 x ULN
`
`
`
`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.
`
`
`IXEMPRAb
`(mg/m2)
`40
`32
`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
`
`
`
`Reference ID: 3029935
`
`
`Page 4 of 35
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`
`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 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.
`
` 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
`
`
`
`Reference ID: 3029935
`
`Page 5 of 35
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`
` (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)
`o 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®
`
`
`
`
`
`Reference ID: 3029935
`
`Page 6 of 35
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`
`
`
`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.
`
`
`
`Reference ID: 3029935
`
`Page 7 of 35
`
`IMMUNOGEN 2222, pg. 7
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`
`
`
`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 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 Warnings and
`Precautions (5.3)].
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Peripheral Neuropathy
`
`Peripheral neuropathy was common (see Table 3). Patients treated with IXEMPRA
`should be monitored for symptoms of neuropathy, such as burning sensation,
`hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Neuropathy
`occurred early during treatment; ~75% of new onset or worsening neuropathy occurred
`during the first 3 cycles. Patients experiencing new or worsening symptoms may require
`a reduction or delay in the dose of IXEMPRA [see Dosage and Administration (2.2)]. In
`clinical studies, peripheral neuropathy was managed through dose reductions, dose
`delays, and treatment discontinuation. Neuropathy was the most frequent cause of
`treatment discontinuation due to drug toxicity. In Studies 046 and 081, 80% and 87%,
`respectively, of patients with peripheral neuropathy who received IXEMPRA had
`improvement or no worsening of their neuropathy following dose reduction. For patients
`with grade 3/4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had
`documented improvement to baseline or grade 1, twelve weeks after onset.
`
`
`
`Reference ID: 3029935
`
`Page 8 of 35
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`IMMUNOGEN 2222, pg. 8
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`
`Table 2:
`
`
`
`Treatment-related Peripheral Neuropathy
`
` IXEMPRA with
`
`
`capecitabine
`Study 046
`
` IXEMPRA as
`
`monotherapy
`Study 081
`
`Peripheral neuropathy (all grades)a,b
`
`
`Peripheral neuropathy (grades 3/4)a,b
`
`
` Discontinuation due to neuropathy
`
`
`Median number of cycles to onset of
`
`
`
` grade 3/4 neuropathy
`Median time to improvement of grade 3/4
`
`
` neuropathy to baseline or to grade 1
`
` a Sensory and motor neuropathy combined.
`
`b 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1).
`
`
`
`67%
`
`23%
`21%
`4
`
`63%
`
`14%
`6%
`4
`
`6.0 weeks
`
`4.6 weeks
`
`A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that
`patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased
`
`risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not
`predict the development of neuropathy. Patients with moderate to severe neuropathy
`(grade 2 or greater) were excluded from studies with IXEMPRA. Caution should be used
`when treating patients with diabetes mellitus or preexisting peripheral neuropathy.
`5.2 Myelosuppression
`
`Myelosuppression is dose-dependent and primarily manifested as neutropenia. In
`clinical studies, grade 4 neutropenia (<500 cells/mm3) occurred in 36% of patients treated
`
` with IXEMPRA in combination with capecitabine and 23% of patients treated with
`IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were
`reported in 5% and 6% of patients treated with IXEMPRA in combination with
`capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as
`monotherapy, respectively. Neutropenia-related death occurred in 1.9% of 414 patients
`with normal hepatic function or mild hepatic impairment treated with IXEMPRA in
`combination with capecitabine. The rate of neutropenia-related deaths was higher
`(29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN
`[see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.3)].
`Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as
`monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or
`ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA monotherapy.
`IXEMPRA must not be administered
`to patients with a neutrophil count
`
`
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`Reference ID: 3029935
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`<1500 cells/mm3. To monitor for myelosuppression, frequent peripheral blood cell counts
`are recommended for all patients receiving IXEMPRA. Patients who experience severe
`neutropenia or thrombocytopenia should have their dose reduced [see Dosage and
`
` Administration (2.2)].
`5.3 Hepatic Impairment
`
`Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN
`experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or
`bilirubin ≤1.5 x ULN when treated with IXEMPRA at 40 mg/m2 in combination with
`capecitabine or as monotherapy in breast cancer studies. In combination with
`capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia,
`
` serious adverse reactions, and toxicity-related deaths was greater [see Warnings and
` Precautions (5.2)]. With monotherapy, grade 4 neutropenia, febrile neutropenia, and
`
`serious adverse reactions were more frequent. The safety and pharmacokinetics of
`IXEMPRA as monotherapy were evaluated in a dose escalation study in 56 patients with
`varying degrees of hepatic impairment. Exposure was increased in patients with elevated
`
`
` AST or bilirubin [see Use in Specific Populations (8.6)].
`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 Boxed Warning, Contraindications (4), and Warnings and
`
`Precautions (5.2)]. Patients who are treated with IXEMPRA as monotherapy should
`
` receive a reduced dose depending on the degree of hepatic impairment [see Dosage and
`Administration (2.2)]. 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 AST or ALT >5 x
`
` ULN. Caution should be used when treating these patients [see Dosage and
`Administration (2.2)].
` 5.4 Hypersensitivity Reactions
`
`
`
`Patients with a history of a severe hypersensitivity reaction to agents containing
`Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated
`with IXEMPRA. All patients should be premedicated with an H1 and an H2 antagonist
`approximately 1 hour before IXEMPRA infusion and be observed for hypersensitivity
`reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe
`hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive
`supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients
`treated with IXEMPRA in clinical studies, 9 patients (1%) had experienced severe
`
`
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`Reference ID: 3029935
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`hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be
`retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA
`must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and
`H2 antagonists, and extension of the infusion time should be considered [see Dosage and
`Administration (2.3) and Contraindications (4)].
`
` 5.5 Pregnancy
`
`Pregnancy Category D.
`IXEMPRA may cause fetal harm when administered to pregnant women. There
`are no adequate and well-controlled studies with IXEMPRA in pregnant women. Women
`should be advised not to become pregnant when taking IXEMPRA. If this drug is used
`during pregnancy, or if the patient becomes pregnant while taking this drug, the patient
`should be apprised of the potential hazard to the fetus.
`Ixabepilone was studied for effects on embryo-fetal development in pregnant rats
`and rabbits given IV 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. There were no teratogenic effects. 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
`one-tenth 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 one-tenth the human clinical dose based on body surface area). No
`
`fetuses were available at this dose for evaluation.
`
` 5.6 Cardiac Adverse Reactions
`
`The frequency of cardiac adverse reactions (myocardial ischemia and ventricular
`dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than
` in the capecitabine alone (0.3%) treatment group. Supraventricular arrhythmias were
`
`observed in the combination arm (0.5%) and not in the capecitabine alone arm. Caution
`
`should be exercised in patients with a history of cardiac disease. Discontinuation of
`IXEMPRA should be considered in patients who develop cardiac ischemia or impaired
`cardiac function.
`
`
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`Reference ID: 3029935
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` 5.7 Potential for Cognitive Impairment from Excipients
`
`Since IXEMPRA contains dehydrated alcohol USP, consideration should be given
`to the possibility of central nervous system and other effects of alcohol [see Description
`(11)].
`
`6
`
`ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other sections.
`
`
`• Peripheral neuropathy [see Warnings and Precautions (5.1)]
`
`
`• Myelosuppression [see Warnings and Precautions (5.2)]
`
`
`
`• Hypersensitivity reactions [see Warnings and Precautions (5.4)]
`
`
`
`
`
` 6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, the adverse
`reaction rates observed in the clinical trials of a drug cannot be directly compared to rates
`in other clinical trials and may not reflect the rates observed in clinical practice.
`Unless otherwise specified, assessment of adverse reactions is based on one
`randomized study (Study 046) and one single-arm study (Study 081). In Study 046,
`369 patients with metastatic breast cancer were treated with IXEMPRA 40 mg/m2
`
`administered intravenously over 3 hours every 21 days, combined with capecitabine
`1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated
`with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily
`
`for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced
`breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over
`3 hours every 3 weeks.
`
`The most common adverse reactions (≥20%) reported by patients receiving
`IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia,
`alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The
`following additional reactions occurred in ≥20% in combination treatment: palmar-
`plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder,
`and constipation. The most common hematologic abnormalities (>40%) include
`neutropenia, leukopenia, anemia, and thrombocytopenia.
`Table 4 presents nonhematologic adverse reactions reported in 5% or more of
`
`patients. Hematologic abnormalities are presented separately in Table 5.
`
`
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`Reference ID: 3029935
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`Table 4:
`
`
`
`
`
`System Organ Classa/
`Preferred Term
`Infections and Infestations
`Upper respiratory tract
`infectionb
`
` Blood and Lymphatic System
`Disorders
`
`
`
`Febrile neutropenia
`Immune System Disorders
`Hypersensitivityb
`
` Metabolism and Nutrition
`
`
` Disorders
`Anorexiab
`
` Dehydrationb
`
`Psychiatric
`Insomniab
`
`
` Nervous System Disorders
`
`Peripheral neuropathy
`Sensory neuropathyb,e
`Motor neuropathyb
`
`Headache
`Taste disorderb
`
`
`Dizziness
`Eye Disorders
`
`
`Lacrimation increased
`Vascular Disorders
`
`Hot flushb
`
`
`Nonhematologic Drug-related Adverse Reactions Occurring
`in at Least 5% of Patients with Metastatic or Locally
`Advanced Breast Cancer Treated with