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)].

DOSAGE AND ADMINISTRATION

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.

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 Guidelines

IXEMPRA (Monotherapy or Combination Therapy) IXEMPRA Dose Modification

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

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

No change in dose of IXEMPRA

Any grade 4 toxicity (disabling) Discontinue treatment

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)

Decrease the dose by 20% Decrease the dose by 20% Decrease the dose by 20%

Capecitabine Dose Modification

Nonhematologic:

Follow Capecitabine Label

Hematologic:

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

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

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:

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).]

IXEMPRA

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).]

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).

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 2deg C - 8deg C (36deg F - 46deg 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.

1. 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.

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 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.

Preparation and Handling Precautions

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. 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.

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.

CONTRAINDICATIONS

IXEMPRA is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor(r) 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)].

WARNINGS AND PRECAUTIONS

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.

Table 3: Treatment-related Peripheral Neuropathy

IXEMPRA with capecitabine

IXEMPRA as

monotherapy Study 081

es)

Peripheral neuropathy (all grad a,b 67% 63%

Peripheral neuropathy (grades 3/4) a,b 23% 14%

Discontinuation due to neuropathy 21% 6%

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.

4 4

6.0 weeks 4.6 weeks

24% and 27 % of patients in 046 and 081, respectively had preexisting neuropathy (grade 1). 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.

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 <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)].

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)].

Hypersensitivity Reactions

Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor(r) 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 (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)].

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.

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.

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)].

DRUG INTERACTIONS

Effect of Other Drugs on Ixabepilone

Drugs That May Increase Ixabepilone Plasma Concentrations

CYP3A4 Inhibitors: Co-administration of ixabepilone with ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered. The effect of mild or moderate inhibitors (eg, erythromycin, fluconazole, or verapamil) on exposure to ixabepilone has not been studied. Therefore, caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment with IXEMPRA, and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during treatment with IXEMPRA should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood counts between cycles of IXEMPRA). [See Dosage and Administration (2.2).]

Drugs That May Decrease Ixabepilone Plasma Concentrations

CYP3A4 Inducers:

IXEMPRA is a CYP3A4 substrate. Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifampicin, rifabutin, and phenobarbital) may decrease ixabepilone concentrations leading to subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction potential should be considered for coadministration with IXEMPRA. St. John's Wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided.

Effect of Ixabepilone on Other Drugs

Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs [see Clinical Pharmacology (12.3)].

Capecitabine

In patients with cancer who received ixabepilone (40 mg/m2) in combination with capecitabine (1000 mg/m2), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [See Warnings and Precautions (5.5)]

Nursing Mothers

It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue IXEMPRA taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of IXEMPRA in pediatric patients have not been established.

Geriatric Use

Clinical studies of IXEMPRA did not include sufficient numbers of subjects aged sixty five and over to determine whether they respond differently from younger subjects. Forty-five of 431 patients treated with IXEMPRA in combination with capecitabine were >=65 years of age and 3 patients were >=75. Overall, the incidence of grade 3/4 adverse reactions were higher in patients >=65 years of age versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients >=65 years with normal baseline hepatic function or mild impairment. Thirty-two of 240 breast cancer patients treated with IXEMPRA as monotherapy were >=65 years of age and 6 patients were >=75. No overall differences in safety were observed in these patients compared to those <65 years of age.

Hepatic Impairment

IXEMPRA was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC0-infinity) of ixabepilone increased by:

• 22% in patients with a) bilirubin >1 - 1.5 x ULN or b) AST >ULN but bilirubin

Renal Impairment

<1.5 x ULN; 30% in patients with bilirubin >1.5 - 3 x ULN and any AST level; and 81% in patients with bilirubin >3 x ULN and any AST level. Doses of 10 and 20 mg/m2 as monotherapy were tolerated in 17 patients with severe hepatic impairment (bilirubin >3 x ULN). IXEMPRA in combination with capecitabine must not be given to patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.3)]. Dose reduction is recommended when administering IXEMPRA as monotherapy to patients with hepatic impairment [see Dosage and Administration (2.3)]. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter. Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with IXEMPRA in patients with renal impairment. IXEMPRA in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of <50 mL/min. IXEMPRA as monotherapy has not been evaluated in patients with creatinine >1.5 times ULN. In a population pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 mL/min) on the pharmacokinetics of ixabepilone.

OVERDOSAGE

One case of overdose of IXEMPRA has been reported. The patient mistakenly received 100 mg/m2 (total dose 185 mg) and was admitted to the hospital for observation. The patient experienced myalgia (grade 1) and fatigue (grade 1) one day after infusion and was treated with a centrally acting analgesic. The patient recovered and was discharged without incident. There is no known antidote for overdosage of IXEMPRA. In case of overdosage, the patient should be closely monitored, and supportive treatment should be administered. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations.

DESCRIPTION

IXEMPRA (ixabepilone) is a microtubule inhibitor belonging to a class of antineoplastic agents, the epothilones and their analogs. The epothilones are isolated from the myxobacterium Sorangium cellulosum. Ixabepilone is a semisynthetic analog of epothilone B, a 16-membered polyketide macrolide, with a chemically modified lactam substitution for the naturally existing lactone. The chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-7,11- dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]- 17-oxa-4-azabicyclo[14.1.0] heptadecane-5,9-dione, and it has a molecular weight of 506.7. Ixabepilone has the following structural formula:

O

S

N

HN

O OH O

IXEMPRA (ixabepilone) for Injection is intended for intravenous infusion only after constitution with the supplied DILUENT and after further dilution with Lactated Ringer's Injection, USP. IXEMPRA (ixabepilone) for injection is supplied as a sterile, non-pyrogenic single-use vial containing 15 mg or 45 mg ixabepilone as lyophilized white powder. The DILUENT for IXEMPRA is a sterile, non-pyrogenic solution of 52.8% (w/v) purified polyoxyethylated castor oil and 39.8% (w/v) dehydrated alcohol, USP. The IXEMPRA (ixabepilone) for injection and the DILUENT for IXEMPRA are co-packaged and supplied as IXEMPRA Kit.

CLINICAL PHARMACOLOGY

Mechanism of Action

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

Pharmacodynamics

In cancer patients, ixabepilone has a plasma concentration-dependent effect on tubulin dynamics in peripheral blood mononuclear cells that is observed as the formation of microtubule bundles. Ixabepilone has antitumor activity in vivo against multiple human tumor xenografts, including drug-resistant types that overexpress P-gp, MRP-1, and bIII tubulin isoforms, or harbor tubulin mutations. Ixabepilone is active in xenografts that are resistant to multiple agents including taxanes, anthracyclines, and vinca alkaloids. Ixabepilone demonstrated synergistic antitumor activity in combination with capecitabine in vivo. In addition to direct antitumor activity, ixabepilone has antiangiogenic activity.

Pharmacokinetics

Absorption

Following administration of a single 40 mg/m2 dose of TRADNAME in patients with cancer, the mean Cmax was 252 ng/mL (coefficient of variation, CV = 56%) and the mean AUC was 2143 ng hr/mL (CV 48%). Typically Cmax occurred at the end of the 3 hour infusion. In cancer patients, the pharmacokinetics of ixabepilone were linear at doses of 15 to 57 mg/m2.

Distribution

The mean volume of distribution of 40 mg/m2 ixabepilone at steady-state was in excess of 1000 L. In vitro, the binding of ixabepilone to human serum proteins ranged from 67 to 77%, and the blood-to-plasma concentration ratios in human blood ranged from 0.65 to 0.85 over a concentration range of 50 to 5000 ng/mL.

Metabolism

Ixabepilone is extensively metabolized in the liver. In vitro studies indicated that the main route of oxidative metabolism of ixabepilone is via CYP3A4. More than 30 metabolites of ixabepilone are excreted into human urine and feces. No single metabolite accounted for more than 6% of the administered dose. The biotransformation products generated from ixabepilone by human liver microsomes were not active when tested for in vitro cytotoxicity against a human tumor cell line.

In vitro

studies using human liver microsomes indicate that clinically relevant concentrations of ixabepilone do not inhibit CYP3A4, CYP1A2, CYP2A6, CYP2B6,

CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Ixabepilone does not induce the activity or the corresponding mRNA levels of CYP1A2, CYP2B6, CYP2C9, or CYP3A4 in cultured human hepatocytes at clinically relevant concentrations. Therefore, it is unlikely that ixabepilone will affect the plasma levels of drugs that are substrates of CYP enzymes.

Elimination

Ixabepilone is eliminated primarily as metabolized drug. After an intravenous 14[C]-ixabepilone dose to patients, approximately 86% of the dose was eliminated within 7 days in feces (65% of the dose) and in urine (21% of the dose). Unchanged ixabepilone accounted for approximately 1.6% and 5.6% of the dose in feces and urine, respectively. Ixabepilone has a terminal elimination half-life of approximately 52 hours. No accumulation in plasma is expected for ixabepilone administered every 3 weeks.

Effects of Age, Gender, and Race

Based upon a population pharmacokinetic analysis in 676 cancer patients, gender, race, and age do not have meaningful effects on the pharmacokinetics of ixabepilone.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with ixabepilone have not been conducted. Ixabepilone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in an in vitro cytogenetic assay using primary human lymphocytes. Ixabepilone was clastogenic (induction of micronuclei) in the in vivo rat micronucleus assay at doses >0.625 mg/kg/day. There were no effects on male or female rat mating or fertility at doses up to 0.2 mg/kg/day in both males and females (approximately one-fifteenth the expected human clinical exposure based on AUC). The effect of ixabepilone on human fertility is unknown. However, when rats were given an IV infusion of ixabepilone during breeding and through the first 7 days of gestation, a significant increase in resorptions and pre- and post-implantation loss and a decrease in the number of corpora lutea was observed at 0.2 mg/kg/day. Testicular atrophy or degeneration was observed in 6-month rat and 9-month dog studies when ixabepilone was given every 21 days at intravenous doses of 6.7 mg/kg (40 mg/m2) in rats (approximately 2.1 times the expected clinical exposure based on AUC) and 0.5 and 0.75 mg/kg (10 and 15 mg/m2) in dogs (approximately 0.2 and 0.4 times the expected clinical exposure based on AUC).

Animal Toxicology

Overdose

In rats, single intravenous doses of ixabepilone from 60 to 180 mg/m2 (mean AUC values >=8156 ng *h/mL) were associated with mortality occurring between 5 and 14 days after dosing, and toxicity was principally manifested in the gastrointestinal, hematopoietic (bone-marrow), lymphatic, peripheral-nervous, and male-reproductive systems. In dogs, a single intravenous dose of 100 mg/m2 (mean AUC value of 6925 ng *h/mL) was markedly toxic, inducing severe gastrointestinal toxicity and death 3 days after dosing.

CLINICAL STUDIES

Combination Therapy

In an open-label, multicenter, multinational, randomized trial of 752 patients with metastatic or locally advanced breast cancer, the efficacy and safety of IXEMPRA (40 mg/m2 every 3 weeks) in combination with capecitabine (at 1000 mg/m2 twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as monotherapy (at 1250 mg/m2 twice daily for 2 weeks followed by 1 week rest). Patients were previously treated with anthracyclines and taxanes. Patients were required to have demonstrated tumor progression or resistance to taxanes and anthracyclines as follows:

• tumor progression within 3 months of the last anthracycline dose in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting, and

• tumor progression within 4 months of the last taxane dose in the metastatic setting or recurrence within 12 months in the adjuvant or neoadjuvant setting.

For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible. Sixty-seven percent of patients were White, 23% were Asian and 3% were Black. Both arms were evenly matched with regards to race, age (median 53 years), baseline performance status (Karnofsky 70-100%), and receipt of prior adjuvant or neo-adjuvant chemotherapy (75%). Tumors were ER-positive in 47% of patients, ER-negative in 43%, HER2-positive in 15%, HER2-negative in 61%, and ER-negative, PR-negative, HER2- negative in 25%. The baseline disease characteristics and previous therapies for all patients (n=752) are shown in Table 6.

For IXEMPRA plus capecitabine versus capecitabine only, prior treatment in the metastatic setting included cyclophosphamide

(25% vs. 23%), fluorouracil (22% vs. 16%), vinorelbine (11% vs. 12%), gemcitabine (9% each arm), carboplatin (9% vs. 7%), liposomal doxorubicin (3% each arm), and cisplatin (2% vs. 3%).

Tumor progression within 3 months in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting. 24% and 21% of patients had received 2 or more taxane-containing regimens in the combination and single agent treatment groups,

respectively.

The patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine monotherapy treatment group received a median of 4 cycles of treatment. The primary endpoint of the study was progression-free survival (PFS) defined as time from randomization to radiologic progression as determined by Independent Radiologic Review (IRR), clinical progression of measurable skin lesions or death from any cause. Other study endpoints included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), time to response, response duration, and overall survival. The data for overall survival analysis are not mature. IXEMPRA in combination with capecitabine resulted in a statistically significant improvement in PFS compared to capecitabine. The results of the study are presented in Table 7 and Figure 1.

a

Patients were censored for PFS at the last date of tumor assessment prior to the start of subsequent therapy. In patients where

independent review was not available PFS was censored at the randomization date.

b

For the hazard ratio, a value less than 1.00 favors combination treatment, CI adjusted for interim analysis.

c

Stratified by visceral metastasis in liver/lung, prior chemotherapy in metastatic setting, and anthracycline resistance.

d

Cochran-Mantel-Haenszel test

Figure 1: Progression-free Survival Kaplan Meier Curves

1.0

0.9

PROPORTION NOT PROGRESSED

IXABEPILONE + CAPECITABINE CAPECITABINE

0.7

0.6

0.5

STRATIFIED LOGRANK P-VALUE= < 0.0001

0.2

0.1

0.0

0 4 8 12 16 20 24 28 32

MONTHS

Monotherapy

IXEMPRA was evaluated as a single agent in a multicenter single-arm study in 126 women with metastatic or locally advanced breast cancer. The study enrolled patients whose tumors had recurred or had progressed following two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Patients who had received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible. Tumor progression or recurrence were prospectively defined as follows: Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose), Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane), HER2 positive patients must also have progressed during or after discontinuation of trastuzumab. In this study, the median age was 51 years (range, 30-78), and 79% were White, 5% Black, and 2% Asian, Karnofsky performance status was 70-100%, 88% had received two or more prior chemotherapy regimens for metastatic disease, and 86% had liver and/or lung metastases. Tumors were ER-positive in 48% of patients, ER-negative in 44%, HER2-positive in 7%, HER2-negative in 72%, and ER-negative, PR-negative, HER2-negative in 33%. IXEMPRA was administered at a dose of 40 mg/m2 intravenously over 3 hours every 3 weeks. Patients received a median of 4 cycles (range 1 to 18) of IXEMPRA therapy. Objective tumor response was determined by independent radiologic and investigator review using RECIST. Efficacy results are presented in Table 8.

Table 8: Efficacy of IXEMPRA in Metastatic and Locally Advanced Breast Cancer

Endpoint Result

Objective tumor response rate (95% CI)

IRR Assessment a (n = 113) Investigator Assessment (n = 126)

b

12.4% (6.9 - 19.9)

18.3% (11.9 - 26.1)

Time to response

(n = 14)

Median, weeks (min - max) 6.1 (5 - 54.4)

b

Duration of response

(n = 14)

Median, months (95% CI) 6.0 (5.0 - 7.6)

a All responses were partial. b

As assessed by IRR.

REFERENCES

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

HOW SUPPLIED/STORAGE AND HANDLING

IXEMPRA is supplied as a Kit containing one vial of IXEMPRA(tm) (ixabepilone) for injection and one vial of DILUENT for IXEMPRA. NDC 0015-1910-12 IXEMPRA(tm) Kit containing one vial of IXEMPRA(tm) (ixabepilone) for injection, 15 mg and one vial of DILUENT for IXEMPRA, 8 mL NDC 0015-1911-13 IXEMPRA(tm) Kit containing one vial of IXEMPRA(tm) (ixabepilone) for injection, 45 mg and one vial of DILUENT for IXEMPRA, 23.5 mL IXEMPRA Kit must be stored in a refrigerator at 2deg C to 8deg C (36deg F to 46deg F). Retain in original package until time of use to protect from light. Procedures for proper handling and disposal of antineoplastic drugs [see References (15)] should be followed. To minimize the risk of dermal exposure, impervious gloves should be worn when handling vials containing TRADENAME, regardless of the setting, including unpacking and inspection, transport within a facility, and dose preparation and administration.