Ixempra

Dosage Form: injection kit
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)].

Indications and Usage for Ixempra

Ixempra (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting.

Ixempra is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Ixempra 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 Guidelinesa

Ixempra (Monotherapy or Combination Therapy)	Ixempra Dose Modification
a Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0).
Nonhematologic:
Grade 2 neuropathy (moderate) lasting ≥7 days	Decrease the dose by 20%
Grade 3 neuropathy (severe) lasting <7 days	Decrease the dose by 20%
Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy	Discontinue treatment
Any grade 3 toxicity (severe) other than neuropathy	Decrease the dose by 20%
Transient grade 3 arthralgia/myalgia or fatigue	No change in dose of Ixempra
Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)
Any grade 4 toxicity (disabling)	Discontinue treatment
Hematologic:
Neutrophil <500 cells/mm3 for ≥7 days	Decrease the dose by 20%
Febrile neutropenia	Decrease the dose by 20%
Platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding	Decrease the dose by 20%
Capecitabine (when used in combination with Ixempra)	Capecitabine Dose Modification
Nonhematologic:	Follow Capecitabine Label
Hematologic:
Platelets <25,000/mm3or <50,000/mm3 with bleeding	Hold for concurrent diarrhea or stomatitis until platelet count >50,000/mm3, then continue at same dose.
Neutrophils <500 cells/mm3 for ≥7 days or febrile neutropenia	Hold for concurrent diarrhea or stomatitis until neutrophil count >1,000 cells/mm3, then continue at same dose.

Re-treatment Criteria:   Dose adjustments at the start of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines in Table 1. Patients should not begin a new cycle of treatment unless the neutrophil count is at least 1500 cells/mm3, the platelet count is at least 100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved.

Dose Adjustments in Special Populations - Hepatic Impairment

Combination Therapy:

Ixempra in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 x ULN and bilirubin ≤1 x ULN may receive the standard dose of ixabepilone (40 mg/m2) [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.6)].

Monotherapy:

Patients with hepatic impairment should be dosed with Ixempra based on the guidelines in Table 2. Patients with moderate hepatic impairment should be started at 20 mg/m2, the dosage in subsequent cycles may be escalated up to, but not exceeding, 30 mg/m2 if tolerated. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 x ULN. Caution should be used when treating these patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

Table 2: Dose Adjustments for Ixempra as Monotherapy in Patients with Hepatic Impairment

	Transaminase Levels		Bilirubin Levelsa	Ixemprab (mg/m2)
a Excluding patients whose total bilirubin is elevated due to Gilbert’s disease.
b Dosage recommendations are for first course of therapy; further decreases in subsequent courses should be based on individual tolerance.
Mild	AST and ALT ≤2.5 x ULN	and	≤1 x ULN	40
	AST and ALT ≤10 x ULN	and	≤1.5 x ULN	32
Moderate	AST and ALT ≤10 x ULN	and	>1.5 x ULN - ≤3 x ULN	20 - 30

Strong CYP3A4 Inhibitors

The use of concomitant strong CYP3A4 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole). Grapefruit juice may also increase plasma concentrations of Ixempra and should be avoided. Based on pharmacokinetic studies, if a strong CYP3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is predicted to adjust the ixabepilone AUC to the range observed without inhibitors and should be considered. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the Ixempra dose is adjusted upward to the indicated dose [see Drug Interactions (7.1)].

Strong CYP3A4 Inducers

The use of concomitant strong CYP3A4 inducers should be avoided (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and phenobarbital). Selection of an alternative concomitant medication with no or minimal enzyme induction potential should be considered. Based on extrapolation from a drug interaction study with rifampin, the following guidance may be considered for dosing in patients requiring coadministration of a strong CYP3A4 inducer, if no alternatives are feasible. Once patients have been maintained on a strong CYP3A4 inducer, the dose of Ixempra may be gradually increased from 40 mg/m2 to 60 mg/m2 depending on tolerance. If the dose is increased, Ixempra should be given as a 4-hour intravenous infusion. This 60 mg/m2 dose given intravenously over 4 hours is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. Patients whose dose is increased above 40 mg/m2 should be monitored carefully for toxicities associated with Ixempra. If the strong inducer is discontinued, the Ixempra dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions (7.1)].

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.

Instructions for Preparation and IV Administration

Ixempra Kit  contains two vials, a vial labeled Ixempra (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for Ixempra. Only supplied DILUENT must be used for constituting Ixempra (ixabepilone) for injection. Ixempra Kit  must be stored in a refrigerator at 2° C - 8° C (36° F - 46° F) in the original package to protect from light. Prior to constituting Ixempra for injection, the Kit  should be removed from the refrigerator and allowed to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature. To allow for withdrawal losses, the vial labeled as 15 mg Ixempra for injection contains 16 mg of ixabepilone and the vial labeled as 45 mg Ixempra for injection contains 47 mg of ixabepilone. The 15-mg Ixempra Kit  is supplied with a vial providing 8 mL of the DILUENT and the 45-mg Ixempra Kit  is supplied with a vial providing 23.5 mL of the DILUENT. After constituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.

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

A. To constitute:

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


2. Gently swirl and invert the vial until the powder in Ixempra is completely dissolved.

B. To dilute:

Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below. The Ixempra infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag.

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

• Lactated Ringer’s Injection, USP


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


• PLASMA-LYTE A Injection pH 7.4®

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

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

 

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

 

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

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


2. Aseptically, transfer to an intravenous (IV) bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of Ixempra.


3. Thoroughly mix the infusion bag by manual rotation.

The infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns. DEHP-free infusion containers and administration sets must be used. Any remaining solution should be discarded according to institutional procedures for antineoplastics.

Stability

After constituting Ixempra, the constituted solution should be further diluted with infusion fluid as soon as possible, but may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted Ixempra must be completed within this 6-hour period. The infusion fluids previously mentioned are specified because their pH is in the range of 6.0 to 9.0, which is required to maintain Ixempra stability. Other infusion fluids should not be used with Ixempra.

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.

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® 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 Study 046	Ixempra as monotherapy Study 081
a Sensory and motor neuropathy combined.
b 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1).
Peripheral neuropathy (all grades)a,b	67%	63%
Peripheral neuropathy (grade 3/4)a,b	23%	14%
Discontinuation due to neuropathy	21%	6%
Median number of cycles to onset of grade 3/4    neuropathy	4	4
Median time to improvement of grade 3/4    neuropathy to baseline or to grade 1	6.0 weeks	4.6 weeks

A pooled analysis of 1540 cancer patients treated with Ixempra indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with Ixempra. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy.

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® EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with Ixempra. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before Ixempra infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of Ixempra should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with Ixempra in clinical studies, 9 patients (1%) had experienced severe 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)].

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)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with Ixempra 40 mg/m2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with Ixempra 40 mg/m2 administered intravenously over 3 hours every 3 weeks.

The most common adverse reactions (≥20%) reported by patients receiving Ixempra were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia.

Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5.

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				Study 081
	Ixempra with capecitabine n=369		Capecitabine n=368		Ixempra monotherapy n=126
System Organ Classa/ Preferred Term	Total (%)	Grade 3/4 (%)	Total (%)	Grade 3/4 (%)	Total (%)	Grade 3/4 (%)
a 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).
b A composite of multiple MedDRA Preferred Terms.
c 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, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1-3 severity scale in Study 046.
Infections and Infestations
Upper respiratory tract infectionb	4	0	3	0	6	0
Blood and Lymphatic System Disorders
Febrile neutropenia	5	4c	1	1d	3	3d
Immune System Disorders
Hypersensitivityb	2	1d	0	0	5	1d
Metabolism and Nutrition Disorders
Anorexiab	34	3d	15	1d	19	2d
Dehydrationb	5	2	2	<1d	2	1d
Psychiatric Disorders
Insomniab	9	<1d	2	0	5	0
Nervous System Disorders
Peripheral neuropathy
Sensory neuropathyb,e	65	21	16	0	62	14
Motor neuropathyb	16	5d	<1	0	10	1d
Headache	8	<1d	3	0	11	0
Taste disorderb	12	0	4	0	6	0
Dizziness	8	1d	5	1d	7	0
Eye Disorders
Lacrimation increased	5	0	4	<1d	4	0
Vascular Disorders
Hot flushb	5	0	2	0	6	0
Respiratory, Thoracic, and Mediastinal Disorders
Dyspneab	7	1	4	1	9	1d
Coughb	6	0	2	0	2	0
Gastrointestinal Disorders
Nausea	53	3d	40	2d	42	2d
Vomitingb	39	4d	24	2	29	1d
Stomatitis/mucositisb	31	4	20	3d	29	6
Diarrheab	44	6d	39	9	22	1d
Constipation	22	0	6	<1d	16	2d
Abdominal painb	24	2d	14	1d	13	2d
Gastroesophageal reflux diseaseb	7	1d	8	0	6	0
Skin and Subcutaneous Tissue Disorders
Alopeciab	31	0	3	0	48	0
Skin rashb	17	1d	7	0	9	2d
Nail disorderb	24	2d	10	<1d	9	0
Palmar-plantar erythrodysesthesia syndromeb,f	64	18d	63	17d	8	2d
Pruritus	5	0	2	0	6	1d
Skin exfoliationb	5	<1d	3	0	2	0
Skin hyperpigmentationb	11	0	14	0	2	0
Musculoskeletal, Connective Tissue, and Bone Disorders
Myalgia/arthralgiab	39	8d	5	<1d	49	8d
Musculoskeletal painb	23	2d	5	0	20	3d
General Disorders and Administration Site Conditions
Fatigue/astheniab	60	16	29	4	56	13
Edemab	8	0	5	<1d	9	1d
Pyrexia	10	1d	4	0	8	1d
Painb	9	1d	2	0	8	3d
Chest painb	4	1d	<1	0	5	1d
Investigations
Weight decreased	11	0	3	0	6	0

Table 5: Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with Ixempra

	Study 046				Study 081
	Ixempra with capecitabine n=369		Capecitabine n=368		Ixempra monotherapy n=126
Hematology Parameter	Grade 3 (%)	Grade 4 (%)	Grade 3 (%)	Grade 4 (%)	Grade 3 (%)	Grade 4 (%)
a G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage colony stimulating factor) was used in 20% and 17% of patients who received Ixempra in Study 046 and Study 081, respectively.
Neutropeniaa	32	36	9	2	31	23
Leukopenia (WBC)	41	16	5	1	36	13
Anemia (Hgb)	8	2	4	1	6	2
Thrombocytopenia	5	3	2	2	5	2

The following serious adverse reactions were also reported in 1323 patients treated with Ixempra as monotherapy or in combination with other therapies in Phase 2 and 3 studies.

Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection

Blood and Lymphatic System Disorders: coagulopathy, lymphopenia

Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia

Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy

Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial f