•
`
`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
`neuropathy,
`fatigue/asthenia, myalgia/arthralgia, alopecia, nausea,
`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: Month/Year
`
`
`
`10
`11
`12
`
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Hepatic Impairment
`8.6
`Renal Impairment
`8.7
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Actio n
`12.2 Pharmacodynami s c
`12.3 Pharmacokinetics
`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
`Injection Site Reactions
`17.2
`Fever/Neutropenia
`17.3 Peripheral Neuropathy
`17.4 Pregnancy
`17.5 Cardiac Adverse Reactions
`17.6
`FDA-Approved Patient Labeling
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`13
`
`14
`15
`16
`17
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`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: Year
`
`
`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 infused
`•
`The
`recommended dose of
`IXEMPRA
`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 Lactated Ringer’s Injection, USP, 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---------------------
`•
`injection, 15 mg supplied with DILUENT for
`IXEMPRA for
`IXEMPRA, 8 mL (3)
`injection, 45 mg supplied with DILUENT for
`IXEMPRA for
`IXEMPRA, 23.5 mL (3)
`
`•
`
`•
`
`
`----------------------------CONTRAINDICATIONS-------------------------------
`•
`Hypersensitivity to drugs formulated with Cremophor® EL (4).
`Baseline neutrophil count <1500 cells/mm3 or a platelet count <100,000
`•
`cells/mm3 (4).
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: TOXICITY IN HEPATIC IMPAIRMENT
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`General Dosing Information
`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 PRECAU IONS
`T
`5.1
`Peripheral Neuropathy
`5.2
`Myelosuppression
`5.3
`Hepatic Impairment
`5.4
`Hypersensitivity Reaction
`5.5
`Pregnancy
`5.6
`Cardiac Adverse Reactions
`5.7
`Potential for Cognitive Impairment from Excipients
`ADVERSE REACTIONS
`DRUG INTERACTIONS
`7.1
`Effect of Other Drugs on Ixabepilone
`7.2
`Effect of Ixabepilone on Other Drugs
`7.3
`Capecitabine
` POPULATIONS
`USE IN SPECIFI
`C
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`
`3
`4
`5
`
`6
`7
`
`8
`
`October 14, 2007
`
`Page 1 of 33
`
`AVENTIS EXHIBIT 2066
`Mylan v. Aventis, IPR2016-00712
`
`T
`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
` 1
`
`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)].
`
`
`
`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. 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.
`
`October 16, 2007
`
`Page 2 of 33
`
`

`
`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 Guidelines
`
`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.
` 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
`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:
`
`October 16, 2007
`
`Page 3 of 33
`
`

`
`
`
`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), 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 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), Use in Specific Populations (8.6).]
`
`
`Dose Adjustments for IXEMPRA as Monotherapy in Patients with
`Table 2:
`Hepatic Impairment
`Transaminase
`Levels
`
`
`
`
`
`Mild
`and
`AST and ALT ≤2.5 x ULN
`
`and
`AST or ALT ≤ 10 x ULN
`Moderate AST and ALT ≤10 x ULN
`and
`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.
`
`
`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).]
`
`October 16, 2007
`
`Page 4 of 33
`
`Bilirubin
`Levelsa
`≤1 x ULN
`≤1 x ULN
`>1.5 x ULN - ≤3 x ULN
`
`IXEMPRAb
`(mg/m2)
`40
`32
`20 - 30
`
`

`
`
`
`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
`(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.
`
`October 16, 2007
`
`Page 5 of 33
`
`

`
`
`
`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 only with Lactated
`Ringer’s Injection, USP (LRI) supplied in DEHP [di-(2-ethylhexyl)phthalate] free bags.
`For most doses, a 250 mL bag of Lactated Ringer’s Injection is sufficient. However, it is
`necessary to check the final infusion concentration of each dose based on the volume of
`Lactated Ringer’s Injection 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 LRI
`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
`Lactated Ringer’s Injection, USP to achieve the final desired concentration of
`ixabepilone.
`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 ixabepilone for injection, the constituted solution should be
`further diluted with Lactated Ringer’s Injection 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 Lactated Ringer’s Injection, USP the solution is stable at room
`temperature and room light for a maximum of 6 hours. Administration of diluted
`
`October 16, 2007
`
`Page 6 of 33
`
`

`
`
`
`IXEMPRA must be completed within this 6-hour period. Lactated Ringer’s Injection
`USP is specified because it has a pH range of 6 to 7.5, which is required to maintain
`IXEMPRA stability. Other diluents 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 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
`
`October 16, 2007
`
`Page 7 of 33
`
`

`
`
`
`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.
`
`Table 3:
`
`
`
`Treatment-related Peripheral Neuropathy
`
`IXEMPRA with
`capecitabine
`Study 046
` 67%
`
`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
` Sensory and motor neuropathy combined.
` 24% and 27 % of patients in 046 and 081, respectively had preexisting neuropathy (grade 1).
`
`
`23%
`
`21%
`4
`
`6.0 weeks
`
`IXEMPRA as
`monotherapy
`Study 081
` 63%
`
`14%
`
`6%
`4
`
`4.6 weeks
`
`A pooled analysis of 945 cancer patients treated with IXEMPRA indicated that
`patients with diabetes mellitus may be at increased risk of severe neuropathy. The
`presence of grade 1 neuropathy and prior therapy with neurotoxic chemotherapy agents
`did not predict either the development or worsening 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
`existing moderate to severe 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
`
`October 16, 2007
`
`Page 8 of 33
`
`

`
`
`
`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 <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
`
`October 16, 2007
`
`Page 9 of 33
`
`

`
`
`
`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 (e.g., 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
`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
`
`October 16, 2007
`
`Page 10 of 33
`
`

`
`
`
`IXEMPRA should be considered in patients who develop cardiac ischemia or impaired
`cardiac function.
`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)]
`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.
`
`October 16, 2007
`
`Page 11 of 33
`
`

`
`
`
`Table 4:
`
`
`
`
`
`System Organ Class/
`Preferred Term
`
`Infections and Infestations
`Upper respiratory tract
`infection
`Blood and Lymphatic System
`Disorders
`Febrile neutropenia
`
`Immune System Disorders
`Hypersensitivity
`
`Metabolism and Nutrition
`Disorders
`Anorexia
`
`Dehydration
`
`Psychiatric
`Insomnia
`
`Nervous System Disorders
`Peripheral neuropathy
`Sensory neuropathyb,e
`Motor neuropathy
`
`Headache
`
`Taste disorder
`Dizziness
`
`Eye Disorders
`Lacrimation increased
`
`Vascular Disorders
`Hot flush
`Respiratory, Thoracic, and
`Mediastinal Disorders
`
`Nonhematologic Drug-related Adverse Reactions Occurring
`in at Least 5% of Patients with Metastatic or Locally
`Advanced Breast Cancer Treated with IXEMPRA
`
`Study 081
`IXEMPRA
`monotherapy
`n=126
`Total
`Grade 3/4
`(%)
`(%)
`
`6
`
`
`0
`
`
`
`3
`
`
`5
`
`
`
`19
`
`2
`
`
`5
`
`
`
`62
`10
`
`11
`
`6
`7
`
`
`4
`
`
`6
`
`
`
`
`3d
`
`1d
`
`
`2d
`1d
`
`0
`
`
`
`14
`1d
`0
`
`0
`0
`
`
`0
`
`
`0
`
`
`Study 046
`IXEMPRA with
`Capecitabine
`capecitabine
`
`n=369
`n=368
`
`Grade 3/4
`(%)
`
`
`0
`
`
`
`1
`
`
`0
`
`
`
`1d
`<1d
`
`0
`
`
`
` 0
`
`
`0
`
`0
`
`0
`1d
`
`<1d
`
`0
`
`
`Total
`(%)
`
`4
`
`
`
`5
`
`
`2
`
`
`
`34
`
`5
`
`
`9
`
`
`
`65
`16
`
`8
`
`12
`8
`
`
`5
`
`
`5
`
`
`Grade 3/4
`(%)
`
`
`0
`
`
`
`4
`
`
`1d
`
`
`3d
`2
`
`
`<1d
`
`
`21
`5d
`<1d
`0
`1d
`
`0
`
`
`0
`
`
`Total
`(%)
`
`3
`
`
`
`1
`
`
`0
`
`
`
`15
`
`2
`
`
`2
`
`
`
`16
`<1
`
`3
`
`4
`5
`
`
`4
`
`
`2
`
`
`October 16, 2007
`
`Page 12 of 33
`
`

`
`
`
`Table 4:
`
`
`
`
`
`Nonhematologic Drug-related Adverse Reactions Occurring
`in at Least 5% of Patients with Metastatic or Locally
`Advanced Breast Cancer Treated with IXEMPRA
`
`Study 046
`IXEMPRA with
`Capecitabine
`capecitabine
`
`n=369
`n=368
`
`System Organ Class/
`Preferred Term
`
`Dyspnea
`
`Cough
`Gastrointestinal Disorders
`Nausea
`
`Vomiting
`
`Stomatitis/mucositis
`
`Diarrhea
`
`Constipation
`
`Abdominal pain
`
`Gastroesophageal reflux
`disease
`Skin and Subcutaneous Tissue
`Disorders
`Alopecia
`Skin rash
`
`Nail disorder
`
`Palmar-plantar
`erythrodysesthesia
`syndromeb,f
`Pruritus
`
`Skin exfoliation
`
`Skin hyperpigmentation
`Musculoskeletal, Connective
`Tissue, and Bone Disorders
`Myalgia/arthralgia
`
`Musculoskeletal pain
`
`Total
`(%)
`7
`
`6
`
`53
`
`39
`
`31
`
`44
`
`22
`
`24
`
`7
`
`
`
`31
`17
`
`24
`
`64
`
`5
`
`5
`
`11
`
`
`39
`
`23
`
`Grade 3/4
`(%)
`
`1
`
`0
`
`3d
`4d
`4
`6d
`0
`2d
`1d
`
`
`
`0
`1d
`2d
`18d
`
`0
`<1d
`0
`
`
`8d
`2d
`
`Total
`(%)
`4
`
`2
`
`40
`
`24
`
`20
`
`39
`
`6
`
`14
`
`8
`
`
`
`3
`7
`
`10
`
`63
`
`2
`
`3
`
`14
`
`
`5
`
`5
`
`October 16, 2007
`
`Page 13 of 33
`
`Grade 3/4
`(%)
`
`1
`
`0
`
`2d
`2
`3d
`9
`<1d
`1d
`0
`
`
`
`0
`0
`<1d
`17d
`
`0
`
`0
`
`0
`
`
`<1d
`0
`
`Study 081
`IXEMPRA
`monotherapy
`n=126
`Total
`Grade 3/4
`(%)
`(%)
`1d
`9
`0
`
`2d
`1d
`6
`1d
`2d
`2d
`0
`
`2
`
`42
`
`29
`
`29
`
`22
`
`16
`
`13
`
`6
`
`
`
`48
`9
`
`9
`
`8
`
`6
`
`2
`
`2
`
`
`49
`
`20
`
`
`
`0
`2d
`0
`2d
`
`1d
`0
`
`0
`
`
`8d
`3d
`
`

`
`
`
`Table 4:
`
`
`
`
`
`Nonhematologic Drug-related Adverse Reactions Occurring
`in at Least 5% of Patients with Metastatic or Locally
`Advanced Breast Cancer Treated with IXEMPRA
`
`Study 046
`IXEMPRA with
`Capecitabine
`capecitabine
`
`n=369
`n=368
`
`Total
`(%)
`
`
`Grade 3/4
`(%)
`
`
`
`Total
`(%)
`
`
`Grade 3/4
`(%)
`
`
`
`Study 081
`IXEMPRA
`monotherapy
`n=126
`Total
`Grade 3/4
`(%)
`(%)
`
`
`
`
`System Organ Class/
`Preferred Term
`
`General Disorders and
`Administrative Site Conditions
`Fatigue/asthenia
`Edema
`
`Pyrexia
`
`Pain
`
`Chest pain
`
`60
`8
`
`10
`
`9
`
`4
`
`29
`5
`
`4
`
`2
`
`<1
`
`4
`<1d
`0
`
`0
`
`0
`
`56
`9
`
`8
`
`8
`
`5
`
`13
`16
`1d
`0
`1d
`1d
`3d
`1d
`1d
`1d
`Investigations
`
`
`
`
`
`
`0
`6
`0
`3
`0
`11
`Weight decreased
` System organ class presented as outlined in Guidelines for Preparing Core Clinical Safety Information on Drugs by the Council for
`International Organizations of Medical Sciences (CIOMS).
` A composite of multiple MedDRA Preferred Terms.
`
` NCI CTC grading for febrile neutropenia ranges from Grade 3 to 5. Three patients (1%) experienced Grade 5 (fatal) febrile
`neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and
`Precautions (5.2)].
`d No grade 4 reports.
`e Peripheral sensory neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: areflexia,
`burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hypore