Икземпра

Икземпра (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.

Икземпра 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.

General Dosing Information

The recommended dosage of Икземпра 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^a

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: Икземпра 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).

Monotherapy: Patients with hepatic impairment should be dosed with Икземпра 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.

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

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 Икземпра 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 Икземпра dose is adjusted upward to the indicated dose.

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 Икземпра may be gradually increased from 40 mg/m² to 60 mg/m² depending on tolerance. If the dose is increased, Икземпра 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 Икземпра. If the strong inducer is discontinued, the Икземпра dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.

Premedication

To minimize the chance of occurrence of a hypersensitivity reaction, all patients must be premedicated approximately 1 hour before the infusion of Икземпра 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 Икземпра 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

Икземпра Kit contains two vials, a vial labeled Икземпра (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for Икземпра. Only supplied DILUENT must be used for constituting Икземпра (ixabepilone) for injection. Икземпра Kit must be stored in a refrigerator at 2° C - 8° CÂ (36° F - 46° F) in the original package to protect from light. Prior to constituting Икземпра 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 Икземпра for injection contains 16 mg of ixabepilone and the vial labeled as 45 mg Икземпра for injection contains 47 mg of ixabepilone. The 15-mg Икземпра Kit is supplied with a vial providing 8 mL of the DILUENT and the 45-mg Икземпра 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 before preparation.

To constitute:

1. With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the Икземпра for injection vial. The 15-mg Икземпра is constituted with 8 mL of DILUENT and the 45-mg Икземпра is constituted with 23.5 mL of DILUENT.
2. Gently swirl and invert the vial until the powder in Икземпра is completely dissolved.

To dilute:

Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below. The Икземпра 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 Икземпра:

• 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 Икземпра 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 Икземпра 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 Икземпра (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 Икземпра.
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 Икземпра, 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 Икземпра 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 Икземпра stability. Other infusion fluids should not be used with Икземпра.

Preparation and Handling Precautions

Procedures for proper handling and disposal of antineoplastic drugs should be followed. To minimize the risk of dermal exposure, impervious gloves should be worn when handling vials containing Икземпра, regardless of the setting, including unpacking and inspection, transport within a facility, and dose preparation and administration.

Икземпра 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).

Икземпра is contraindicated in patients who have a neutrophil count < 1500 cells/mm³ or a platelet count < 100,000 cells/mm³.

Икземпра in combination with capecitabine is contraindicated in patients with AST or ALT > 2.5 x ULN or bilirubin > 1 x ULN.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Peripheral Neuropathy

Peripheral neuropathy was common (see Table 3). Patients treated with Икземпра 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 Икземпра. 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 Икземпра 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 2: Treatment-related Peripheral Neuropathy

A pooled analysis of 1540 cancer patients treated with Икземпра 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 Икземпра. 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 Икземпра in combination with capecitabine and 23% of patients treated with Икземпра monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with Икземпра in combination with capecitabine, respectively, and 3% and 5% of patients treated with Икземпра as monotherapy, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with Икземпра 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. Neutropenia-related death occurred in 0.4% of 240 patients treated with Икземпра 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 Икземпра monotherapy. Икземпра 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 Икземпра. Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced.

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 Икземпра 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. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of Икземпра 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.

Икземпра 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. Patients who are treated with Икземпра as monotherapy should receive a reduced dose depending on the degree of hepatic impairment. 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.

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 Икземпра. All patients should be premedicated with an H₁ and an H₂ antagonist approximately 1 hour before Икземпра infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of Икземпра should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with Икземпра 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 Икземпра 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.

Pregnancy

Pregnancy Category D

Икземпра may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with Икземпра in pregnant women. Women should be advised not to become pregnant when taking Икземпра. 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 Икземпра 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 Икземпра should be considered in patients who develop cardiac ischemia or impaired cardiac function.

Potential for Cognitive Impairment from Excipients

Since Икземпра contains dehydrated alcohol USP, consideration should be given to the possibility of central nervous system and other effects of alcohol.

Patient Counseling Information

Peripheral Neuropathy

Patients should be advised to report to their physician any numbness and tingling of the hands or feet.

Fever/Neutropenia

Patients should be instructed to call their physician 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 develops.

Hypersensitivity Reactions

Patients should be advised to call their physician if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness or other hypersensitivity-related symptoms following an infusion of Икземпра.

Pregnancy

Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid nursing during treatment with Икземпра.

Cardiac Adverse Reactions

Patients should be advised to report to their physician chest pain, difficulty breathing, palpitations or unusual weight gain.

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).

Use In Specific Populations

Pregnancy

Pregnancy Category D.

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 Икземпра taking into account the importance of the drug to the mother.

Pediatric Use

The effectiveness of Икземпра in pediatric patients has not been established. Икземпра was evaluated in one Phase 1 and one Phase 2 trial. The pediatric patients had a safety profile consistent with that seen in adults, and no new safety signals were identified.

In the Phase 1 open-label, dose-finding trial, the safety of Икземпра was evaluated in 19 pediatric patients with advanced or refractory solid tumors and 2 with acute leukemias. Икземпра was administered as a one-hour IV infusion daily for the first five days of a 21-day cycle at one of 5 dose levels, ranging from 3 to 10 mg/m². Among the 21 patients, 12 ranged in age from 2 to 12 years and 9 ranged from 13 to 18 years. The maximum tolerated dose was 8 mg/m² IV daily for 5 days every 21 days. No significant anti-tumor activity was observed. The pharmacokinetics of ixabepilone were characterized by population pharmacokinetic analysis of data for 16 patients from this trial, who were aged 2 to 18 years (median 12 years). The pharmacokinetic parameters of ixabepilone in these pediatric patients were compared to the corresponding parameters of 130 adult patients enrolled in clinical trials using the same dosing schedule. The median BSA normalized clearance of ixabepilone in pediatric patients (17 L/h/m²) was similar to that in adult patients (20 L/h/m²).

In the Phase 2 trial of 59 patients with advanced or refractory solid tumors, 28 ranged in age from 3 to 12 years and 19 ranged in age from 13 to 18 years. Twelve additional patients over the age of 18 were treated in this trial. Икземпра was administered at a dose of 8 mg/m² IV daily for 5 days every 21 days. This trial was terminated early due to lack of efficacy.

Geriatric Use

Clinical studies of Икземпра 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 Икземпра in combination with capecitabine were ≥ 65 years of age and 3 patients were ≥ 75. Overall, the incidence of grade 3/4 adverse reactions was 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 Икземпра 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

Икземпра 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 < 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).

Икземпра in combination with capecitabine must not be given to patients with AST or ALT > 2.5 x ULN or bilirubin > 1 x ULN. Dose reduction is recommended when administering Икземпра as monotherapy to patients with hepatic impairment. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of Икземпра and periodically thereafter.

Renal Impairment

Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with Икземпра in patients with renal impairment. Икземпра in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of < 50 mL/min. Икземпра as monotherapy has not been evaluated in patients with creatinine > 1.5 times ULN. In a population pharmacokinetic analysis of Икземпра as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL > 30 mL/min) on the pharmacokinetics of ixabepilone.

The following adverse reactions are discussed in greater detail in other sections.

• Peripheral neuropathy
• Myelosuppression
• Hypersensitivity reactions

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 Икземпра 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 Икземпра 40 mg/m² administered intravenously over 3 hours every 3 weeks.

The most common adverse reactions ( ≥ 20%) reported by patients receiving Икземпра 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 Икземпра

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

The following serious adverse reactions were also reported in 1323 patients  treated with Икземпра 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 flutter, cardiomyopathy, myocardial ischemia

Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis

Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain

Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage

Hepatobiliary Disorders: acute hepatic failure, jaundice

Skin and Subcutaneous Tissue Disorders: erythema multiforme

Musculoskeletal, Connective Tissue Disorders, and Bone Disorders: muscular weakness, muscle spasms, trismus

Renal and Urinary Disorders: nephrolithiasis, renal failure

General Disorders and Administration Site Conditions: chills

Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase

Postmarketing Experience

Radiation recall has been reported during postmarketing use of Икземпра. Because this reaction was 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.

Experience with overdose of Икземпра is limited to isolated cases. The adverse reactions reported in these cases included peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, stomatitis). The highest dose mistakenly received was 100 mg/m² (total dose 185 mg).

There is no known antidote for overdosage of Икземпра. 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.

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 βIII 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.

Absorption

Following administration of a single 40 mg/m² dose of Икземпра 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.

Drug Transport Systems

Ixabepilone is a substrate and a weak inhibitor for the drug efflux transporter P-glycoprotein (P-gp) in vitro .

Ixabepilone is not a substrate for the breast cancer resistance protein (BCRP) in vitro .

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.

Effect of Ixabepilone on QT/QTc 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 Икземпра 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 Икземпра administration. However, small increases in QTc interval with the use of ixabepilone cannot be excluded due to study design limitations.