2.1 Premedication

All patients must be premedicated approximately 1 hour before the infusion of IXEMPRA with:

• An H 1 antagonist (eg, diphenhydramine 50 mg orally or equivalent) and
• An H 2 antagonist (eg, ranitidine 150 - 300 mg orally or equivalent).

Patients who experienced a hypersensitivity reaction to IXEMPRA require premedication with corticosteroids (eg, dexamethasone 20 mg intravenously, 30 minutes before infusion or orally, 60 minutes before infusion) in addition to pretreatment with H 1 and H 2 antagonists [see Warnings and Precautions (5.4)].

2.2 Recommended Dosage

The recommended dosage of IXEMPRA is 40 mg/m 2 administered intravenously over 3 hours every 3 weeks. Calculate doses for patients with body surface area (BSA) greater than 2.2 m 2 should be calculated based on 2.2 m 2.

2.3 Dosage Modification for Adverse Reactions

Evaluate patients during treatment by periodic clinical observation and laboratory tests including complete blood cell counts [see the Warnings and Precautions ( 5)].

Dosage modifications for IXEMPRA for adverse reactions are shown in Table 1.

If adverse reactions recur, reduce dose by an additional 20%.

2.4 Dosage Modifications in Patients with Hepatic Impairment

Dosage Modifications in Patients with Hepatic Impairment

2.5 Dosage Modification for Drug Interactions

Strong CYP3A4 Inhibitors

Avoid the use of concomitant use of strong CYP3A4 inhibitors. If coadministration of a strong CYP3A4 inhibitor with IXEMPRA cannot be avoided, reduce the dose of IXEMPRA to 20 mg/m 2. If the strong inhibitor is discontinued, increase the IXEMPRA dose (at 1 week after discontinuing the inhibitor) to that was used before starting the strong inhibitor [see Clinical Pharmacology ( 12.3)].

2.6 Preparation and Administration

IXEMPRA is a hazardous drug. Follow aplicable special handling and disposal procedures. 1

IXEMPRA Kit contains two vials, a vial labeled IXEMPRA (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for IXEMPRA. Use only the supplied DILUENT to reconstitute IXEMPRA (ixabepilone) for injection.

Reconstituation

1. Prior to reconstituting, remove the IXEMPRA Kit from the refrigerator and allow it 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.

2. With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is reconstituted with 8 mL of DILUENT and the 45-mg IXEMPRA is reconstituted with 23.5 mL of DILUENT.

3. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved.

4. After reconstituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.

5. After reconstituting IXEMPRA, dilute the reconstituted with infusion fluid as soon as possible. The reconstituted solution may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light.

Dilution

Before administration, the reconstituted solution must be further diluted with one of the specified infusion fluids listed below. Other infusion fluids should not be used with IXEMPRA.

The IXEMPRA infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag.

The following infusion fluids have been qualified for use in the dilution of IXEMPRA:

Lactated Ringer’s Injection, USP

0.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP)

When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the reconstituted IXEMPRA solution.

• PLASMA-LYTE A Injection pH 7.4 ®

For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final IXEMPRA infusion concentration of each dose based on the volume of infusion fluid to be used.

The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas:

Total Infusion Volume = mL of Reconstituted Solution + mL of infusion fluid

Final Infusion Concentration = Dose of IXEMPRA (mg)/Total Infusion Volume (mL)

1. Aseptically, withdraw the appropriate volume of reconstituted solution containing 2 mg of ixabepilone per mL.

2. Aseptically, transfer to an intravenous 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.

4. 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.

Administration

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.

Discard any remaining solution according to institutional procedures for hazardous drugs.

5.2 Myelosuppression

Severe, life-threatening, or fatal myelosuppression can occur in patients treated with IXEMPRA. Myelosuppression is dose-dependent and primarily manifests as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm 3) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with single agent 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 a single agent, 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 a single agent. 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 as a single agent.

IXEMPRA is contraindicated for use in patients with a neutrophil count of <1500 cells/mm 3. [see Contraindications (4)].

Monitor patients receiving IXEMPRA for myelosuppression with frequent peripheral blood cell counts. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of myelosuppression [see Dosage and Administration (2.3)].

5.1 Peripheral Neuropathy

Peripheral neuropathy (sensory and motor neuropathy) occurred in patients treated with IXEMPRA in combination with capecitabine and in patients treated with single agent IXEMPRA as shown in Table (see Table 3).

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 or 4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset.

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. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA.

Monitor patients for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of peripheral neuropathy [ see Dosage and Administration (2.3)].

5.3 Increased Toxicities in Patients with 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/m 2 in combination with capecitabine or as single agent 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 increased oin patients with 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 Boxed Warning, Contraindications ( 4), and Warnings and Precautions ( 5.2)].

With IXEMPRA single agent therapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reatcitons were increased in patients with hepatic impairment [see Warnings and Precautions ( 5.2) and Adverse Reactions (6.1). Reduce the dose IXEMPRA based in the degree of hepatic impairment. Avoid use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN [see Dosage and Administration ( 2.4)]

5.4 Hypersensitivity Reactions

IXEMPRA is contraindicated in patients with a history of a severe hypersensitivity reaction to agents containing Cremophor ® EL or its derivatives (eg, polyoxyethylated castor oil) [ see Contraindications (4)].

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 H 1 and H 2 antagonists, and extension of the infusion time should be considered [see Dosage and Administration ( 2.3) and Contraindications ( 4)]

Administer an H 1 and H 2antagonist approximately 1 hour before IXEMPRA infusion and observe patients for hypersensitivity reaction occur, stop the infusion of IXEMPRA provide supportive treatment as clinically indicated (e.g.. epinephrine, corticosteriods).

5.5 Cardiac Adverse Reactions

Cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) occurred in patients receiving IXEMPRA in combination with capecitabine (1.9%) and as a single agent (0.3%). Supraventricular arrhythmias were observed in the combination arm (0.5%).

Closely monitor patients with a history of cardiac disease during treatment with IXEMPRA. Consider discontinuation of IXEMPRA in patients who develop cardiac ischemia or impaired cardiac function [see Dosage and Administration (2.3)].

5.6 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC. Advise females of reproductive potential and pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

5.7 Alcohol Content

The alcohol content in a dose of IXEMPRA may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in IXEMPRA on the ability to drive or use machines immediately after the infusion. Each administration of IXEMPRA at the recommended dosage of 40 mg/m 2 delivers approximately 8.4 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2, this would deliver approximately 16.8 grams of ethanol [see Description ( 11)].

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/m 2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as a single agent (n=368) in this study received 1250 mg/m 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/m 2 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.

6.2 Postmarketing Experience

The following adverse reaction has been identified during postapproval use of IXEMPRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Procedural Complications: Radiation recall

7.1 Effect of Other Drugs on IXEMPRA

7.2 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)].

7.3 Capecitabine

In patients with cancer who received ixabepilone (40 mg/m 2) in combination with capecitabine (1000 mg/m 2), 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.

8.1 Pregnancy

Risk Summary

Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IXEMPRA in pregnant women to inform the drug-associated risk. IXEMPRA contains alcohol which can interfere with neurobehavioral development [see Clinical Considerations]. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC (see Data). Advise females of reproductive potential and pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

IXEMPRA contains alcohol [see Warnings and Precautions (5.7)]. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.

Data

Animal data

In embryo-fetal development studies, pregnant rats and rabbits received intravenous 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 during the period of organogenesis. 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 0.1 times 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 0.1 times the human clinical dose based on body surface area).

8.2 Lactation

Risk Summary

There is no data on the presence of IXEMPRA in human milk, the effects on the breastfed child, or the effects on milk production. Ixabepilone and/or its metabolites were present in milk of lactating rats (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IXEMPRA and for 2 weeks after the last dose.

Data

Animal data

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.

8.3 Females and Males of Reproductive Potential

Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with IXEMPRA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose.

Males

Based on genotoxicity and animal studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on findings in animals, IXEMPRA may impair male and female fertility [see Nonclinical Toxicology (13.1)].

.

8.4 Pediatric Use

The alcohol content of IXEMPRA should be taken into account when given to pediatric patients [see Warnings and Precautions (5.6)].

The safety and effectiveness of IXEMPRA in pediatric patients have not been established. Safety and efficacy were assessed, but not established for IXEMPRA across two studies: an open-label, dose-finding trial in 21 patients aged 2 to 18 years with advanced or refractory solid tumors and hematologic malignancies [NCT00030108] and a trial with 28 patients aged 3 to 18 years with advanced or refractory solid tumors [NCT00331643] that was terminated early due to lack of efficacy. No new safety signals were identified. The median BSA normalized clearance of ixabepilone in 16 patients aged 2 to 18 years (17 L/h/m 2) was within range of that of patients greater than 18 years (20 L/h/m 2).

8.5 Geriatric Use

Clinical studies of IXEMPRA did not include sufficient numbers of patients aged sixty-five and over to determine whether they respond differently from younger patients.

Of the 431 patients treated with IXEMPRA in combination with capecitabine, 10% were 65 years of age and over, and 0.1% were 75 years of age and over. The incidence of grade 3/4 adverse reactions was higher in patients ³65 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%). Deaths due to adverse reactions occurred in 2 (4.7%) of 43 patients ³65 years with normal baseline hepatic function or mild impairment.

Of the 240 patients with breast cancer treated with IXEMPRA as a single agent, 13% were 65 years of age and over, and 0.2% were 75 years of age and over.

8.6 Hepatic Impairment

Monitor hepatic function before initiation of IXEMPRA and periodically thereafter.

Dose reduction is recommended when administering IXEMPRA as a single agent to patients with hepatic impairment [see Dosage and Administration ( 2.4)].

IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Contraindications ( 4)].

The alcohol content of IXEMPRA should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions ( 5.7)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Ixabepilone has a plasma concentration-dependent effect on tubulin dynamics in peripheral blood mononuclear cells that is observed as the formation of microtubule bundles.

Cardiac Electrophysiology

At the recommended dosage, IXEMPRA does not cause large mean increases (i.e., >20 msec) in the QT interval. The QT prolongation potential of ixabepilone was assessed as part of an uncontrolled, open-label, single-dose study in advanced cancer patients. Fourteen patients received a single dose of IXEMPRA 40 mg/m2 intravenously over 3 hours and serial ECGs were collected over 24 hours. The maximum mean ΔQTcF was observed 1 hour after the end of infusion and was 8 ms (upper 95% CI: 12 ms). No patients had a QTcF interval >450 ms or ΔQTcF >30 ms after IXEMPRA administration. However, small increases in QTc interval with the use of ixabepilone cannot be excluded due to study design limitations

12.3 Pharmacokinetics

Following administration of a single 40 mg/m 2 dose of IXEMPRA, the mean (% coefficient of variation) maximum plasma concentration (Cmax) was 252 ng/mL (56%), and the mean (%CV) area under the curve (AUC) was 2,143 ng·hr/mL (48%). The pharmacokinetics of ixabepilone were linear at doses of 15 (0.375 times the approved recommended dosage) to 57 mg/m 2 (1.425 times the approved recommended dosage).

Distribution

The mean (%CV) volume of distribution at steady-state was greater than1,000 L (x CV%). Serum protein binding of ixabepilone ranged from 67% to 77% and the blood-to-plasma concentration ratios ranged from 0.65 to 0.85.

Elimination

Ixabepilone has a terminal elimination half-life of approximately 52 hours (x CV%).

Metabolism

Ixabepilone is metabolized by CYP3A4.

Excretion

Ixabepilone is eliminated primarily as metabolites 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.

Specific Populations

Based upon a population pharmacokinetic analysis in 676 cancer patients, gender, race, age, mild and moderate renal insufficiency (creatinine clearance [CLcr]CrCL >30 mL/min) do not have clinically meaningful effects on the pharmacokinetics of ixabepilone.

Patients with 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 (AUC 0-infinity) of ixabepilone AUC increased by:

• 22% in patients with mild hepatic impairment [a) bilirubin >1 to 1.5 x ULN and AST < ULN or b) AST >ULN but bilirubin <1.5 x ULN];
• 30% in patients with moderate hepatic impairment (bilirubin >1.5 to 3 x ULN and any AST level);
• 81% in patients with severe hepatic impairment (bilirubin >3 x ULN and any AST level).

Drug Interaction Studies

Clinical Studies

Effect of Strong CYP3A4 Inhibitors on IXEMPRA:

Coadministration of ixabepilone with ketoconazole, a strong CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone.

Effect of Strong CYP3A4 Inducers on IXEMPRA:

Coadministration of IXEMPRA with rifampin, a strong CYP3A4 inducer, decreased ixabepilone AUC by 43% compared to IXEMPRA treatment alone.

Capecitabine:

In patients with cancer who received ixabepilone (40 mg/m 2) in combination with capecitabine decreased (1000 mg/m 2), ixabepilone Cmax decreased by 19% and capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%; as compared to ixabepilone or capecitabine administered separately.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes:

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.

Transporter Systems:

Ixabepilone is a substrate of P-gp but is not a substrate of BCRP. Ixabepilone is an inhibitor of P-gp for the drug efflux transporter P‑glycoprotein (P-gp).

13.1 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 0.1 times 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/m 2) 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/m 2) in dogs (approximately 0.2 and 0.4 times the expected clinical exposure based on AUC).

13.2 Animal Toxicology and/or Pharmacology

Overdosage

In rats, single intravenous doses of ixabepilone from 60 to 180 mg/m 2 (mean AUC values ≥8156ng·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/m 2 (mean AUC value of 6925 ng·h/mL) was markedly toxic, inducing severe gastrointestinal toxicity and death 3 days after dosing.

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/m 2 every 3 weeks) in combination with capecitabine (at 1000 mg/m 2 twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as a single agent (at 1250 mg/m 2 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/m 2 of doxorubicin or 360 mg/m 2 of epirubicin were also eligible.

In this study, the median age of patients was 53 years, 67% were White, 23% were Asian, and 3% were Black; Karnofsky performance status was 70-100%, and 75% had received prior adjuvant or neo-adjuvant chemotherapy. 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.

The patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine single-agent treatment group received a median of 4 cycles of treatment.

The major efficacy outcome measures 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. Additional efficacy outcome measures included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), response duration, and overall survival.

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.

Figure 1: Progression-free Survival Kaplan Meier Curves

There was no statistically significant difference in overall survival between treatment arms in this study, as well as in a second similar study. In the study described above, the median overall survivals were 12.9 months (95% Cl: 11.5, 14.2) in the combination therapy arm and 11.1 months (95% Cl: 10.0,12.5) in the capecitabine alone arm [Hazard Ratio 90 (95% Cl: 0.77,1.05), p-value=0.19j.

In the second trial, comparing IXEMPRA in combination with capecitabine versus capecitabine alone, conducted in 1221 patients pretreated with an anthracycline and a taxane, the median overall survival was 16.4 months (95% Cl: 15.0,17.9) in the combination therapy arm and 15.6 months (95% Cl: 13.9,17.0), in the capecitabine alone arm [Hazard Ratio 0.90 (95% Cl: 0.78,1.03), p-value=0.12.

IXEMPRA as a Single Agent

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/m 2 of doxorubicin or 360 mg/m 2 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, Kamofsky 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/m 2 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.

17.1 Peripheral Neuropathy

Advice patients to report any numbness and tingling of the hands or feet to their healthcare provider [see Warnings and Precautions ( 5.1)].

17.2 Fever/Neutropenia

Instruct patients to immediately contact their healthcare provider if a fever of 100.5° F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination occur [see Warnings and Precautions ( 5.2)].

17.3 Hypersensitivity Reactions

Advise patients to immediately contact their healthcare provider if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness, or other hypersensitivity-related symptoms following an infusion of IXEMPRA [see Warnings and Precautions ( 5.4)].

17.4 Cardiac Adverse Reactions

Advise patients to immediately contact call their healthcare provider if they experience chest pain, difficulty breathing, palpitations, or unusual weight gain [see Warnings and Precautions ( 5.5)].

17.5 Embryo-Fetal Toxicity

Advise females of reproductive potential and pregnant women of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose [see Warnings and Precautions ( 5.6) and Use in Specific Populations ( 8.1, 8.3)].

17.6 Lactation

Advise women not to breastfeed during treatment with IXEMPRA and for 2 weeks after the last dose [see Use in Specific Populations ( 8.2)].

17.7 Infertility

Advise males and females of reproductive potential that IXEMPRA may impair fertility [see Use in Specific Populations ( 8.2)].

17.8 Alcohol Content in IXEMPRA

Explain to patients the possible effects of the alcohol content in IXEMPRA, including possible effects on the central nervous system [see Warnings and Precautions ( 5.7)].