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IXABEPILONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ixabepilone, a microtubule inhibitor, is used in the treatment of metastatic or locally advanced breast cancer.

Specific Substances

    1) BMS -247550
    2) CAS 219989-84-1

Available Forms Sources

    A) FORMS
    1) Ixabepilone is available as a kit which contains a diluent. It is supplied for injection as 15 mg or 45 mg of ixabepilone and a vial of diluent containing either 8 mL or 23.5 mL, respectively (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) USES
    1) Ixabepilone is indicated as monotherapy for the treatment of locally advanced or metastatic breast cancer in patients whose tumors are refractory or resistant to anthracyclines, taxanes, and capecitabine. It is also indicated in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer that is anthracycline- and taxane-resistant (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ixabepilone is indicated as monotherapy for the treatment of locally advanced or metastatic breast cancer in patients whose tumors are refractory or resistant to anthracyclines, taxanes, and capecitabine. It is also indicated in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer that is anthracycline- and taxane-resistant.
    B) PHARMACOLOGY: Ixabepilone, an epothilone B analog, is an antimicrotubule agent. Ixabepilone inhibits microtubules, halting cell division in the mitotic phase and resulting in subsequent cell death. Ixabepilone stabilizes the microtubules by directly binding to the beta-tubulin subunits (alpha-beta-II and alpha-beta-III).
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (20% or greater): Peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. OTHER EFFECTS (20% or greater, occurring in combination with capecitabine): Palmar-plantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, and constipation. HEMATOLOGIC ABNORMALITIES (40% or greater): Neutropenia, leukopenia, anemia, and thrombocytopenia. Other potentially serious events with therapeutic use: left ventricular dysfunction, myocardial ischemia and hypersensitivity reaction.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (eg, nausea, anorexia, diarrhea, abdominal pain, and stomatitis) have been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone.
    0.2.20) REPRODUCTIVE
    A) Ixabepilone is classified as FDA pregnancy category D. There are no adequate and well-controlled studies with ixabepilone in pregnant women. However, as ixabepilone may cause fetal harm in pregnant women, advise women to not become pregnant while receiving ixabepilone. If ixabepilone is initiated during pregnancy or if the patient becomes pregnant while receiving ixabepilone, inform the patient of the potential hazard to the fetus. It is not known if ixabepilone is excreted into human milk.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor for symptoms of burning sensation, paresthesia, discomfort or neuropathic pain. Nerve conduction studies may be useful.
    D) Obtain an ECG and institute continuous cardiac monitoring.
    E) Monitor serial CBC with differential and platelet count.
    F) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract. Monitor serum electrolytes in patients with prolonged vomiting and/or diarrhea.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) in patients who develop severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or anemia. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) INTRATHECAL INJECTION
    1) No clinical reports of intrathecal injection of ixabepilone are available. This information was derived from experience with other antineoplastics. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Fresh frozen plasma (25 mL FFP/liter normal saline or lactated ringers) or 5% albumin have also been used for perfusion, and may be useful because of the high degree of protein binding of ixabepilone. Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; ixabepilone is only available parenterally.
    E) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    F) ANTIDOTE
    1) None.
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors to patients who develop severe neutropenia following a significant overdose. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or anemia. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    K) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. In patients with an ixabepilone overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    M) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of ixabepilone. Some toxic effects of overdose may be delayed (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking ixabepilone may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    N) PHARMACOKINETICS
    1) Protein binding: 67% to 77%. Vd: At least 1000 L. Metabolism: The liver is the primary site of metabolism via CYP3A4. Excretion: Renal: 21% of the dose was recovered in the urine. Fecal: 65% of the dose was recovered in the feces. Elimination half-life: 52 hours.
    O) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or peripheral neuropathy.

Range Of Toxicity

    A) TOXICITY: Limited overdose data exists. An adult inadvertently received a total dose of 185 mg and developed myalgia (grade 1) and fatigue (grade 1). Recovery was uneventful. Peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (eg, nausea, anorexia, diarrhea, abdominal pain, and stomatitis) have been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone.
    B) THERAPEUTIC DOSE: ADULT: 40 mg/m(2) administered intravenously over 3 hours every 3 weeks. For patients with a body surface area greater than 2.2 m(2) the dose should be calculated based on 2.2 m(2). Dose adjustments may be necessary based on clinical and laboratory monitoring. CHILD: Safety and efficacy of ixabepilone use has not been determined in pediatric patients. The safety profile of ixabepilone in children was consistent with that seen in adults and the maximum tolerated dose was 8 mg/m(2) IV daily for 5 days every 21 days in a phase 1 trial evaluating the safety of ixabepilone in 21 pediatric patients 2 to 18 years of age.

Clinical Effects

Summary Of Exposure

    A) USES: Ixabepilone is indicated as monotherapy for the treatment of locally advanced or metastatic breast cancer in patients whose tumors are refractory or resistant to anthracyclines, taxanes, and capecitabine. It is also indicated in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer that is anthracycline- and taxane-resistant.
    B) PHARMACOLOGY: Ixabepilone, an epothilone B analog, is an antimicrotubule agent. Ixabepilone inhibits microtubules, halting cell division in the mitotic phase and resulting in subsequent cell death. Ixabepilone stabilizes the microtubules by directly binding to the beta-tubulin subunits (alpha-beta-II and alpha-beta-III).
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (20% or greater): Peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. OTHER EFFECTS (20% or greater, occurring in combination with capecitabine): Palmar-plantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, and constipation. HEMATOLOGIC ABNORMALITIES (40% or greater): Neutropenia, leukopenia, anemia, and thrombocytopenia. Other potentially serious events with therapeutic use: left ventricular dysfunction, myocardial ischemia and hypersensitivity reaction.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (eg, nausea, anorexia, diarrhea, abdominal pain, and stomatitis) have been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) MYOCARDIAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) The incidence of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in women with metastatic or locally advanced breast cancer receiving ixabepilone and capecitabine (1.9%) than in women receiving capecitabine alone (0.3%) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) In women with metastatic or locally advanced breast cancer, 0.5% of patients treated with ixabepilone and capecitabine (n=369) experienced supraventricular arrhythmias (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy was the major dose-limiting toxicity and the most common reason for the discontinuation of therapy (Prod Info IXEMPRA(R)Kit IV injection, 2011; Pivot et al, 2007; Tan, 2006).
    b) ONSET: The median onset of grade 2 or greater peripheral neuropathy occurs after 5 to 6 cycles of therapy (every 3 weeks or daily x 5 every 3 weeks). Potential risk factors for developing peripheral neuropathy include diabetes mellitus, concurrent administration of cisplatin, or advanced age (Lee & Swain, 2006).
    c) The incidence of peripheral neuropathy was 63% with ixabepilone monotherapy and 67% with ixabepilone plus capecitabine therapy (Prod Info IXEMPRA(R)Kit IV injection, 2011). In a phase II study of men with metastatic prostate cancer, ixabepilone was used as a first-line therapy with 29% of the participants reporting significant neuropathy (Tan, 2006). Severe grade 3 or 4 peripheral neuropathy may occur in up to 30% of patients treated with microtublue-stabilizing agents, including taxanes and epothilones (Lee & Swain, 2006).
    d) CASE REPORT: A 62-year-old woman with a history of locally advanced invasive ductal carcinoma of the breast had a recurrence of disease in her lung and bones and was started on ixabepilone therapy of 40 mg/m(2) IV over 3 hours every 3 weeks. By the fifth dose, the patient complained of severe peripheral neuropathic symptoms in both her fingers and dorsum of her feet, which resulted in the discontinuation of therapy (Conlin & Vahdat, 2006).
    2) WITH POISONING/EXPOSURE
    a) Peripheral neuropathy has been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 56% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced fatigue/asthenia (any grade) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    b) In women with metastatic or locally advanced breast cancer, 60% of patients treated with ixabepilone and capecitabine (n=369) experienced fatigue/asthenia (any grade) as compared to 29% of patients treated with capecitabine alone (n=368) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    c) In phase II studies of women with metastatic breast cancer receiving a combination of ixabepilone/capecitabine, nonhematologic toxicities included grade 3 or 4 fatigue (Fornier, 2007a).
    2) WITH POISONING/EXPOSURE
    a) Fatigue has been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone (Prod Info IXEMPRA(R)Kit IV injection, 2011)

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are common events reported with ixabepilone therapy (Prod Info IXEMPRA(R)Kit IV injection, 2011; Perez et al, 2007; Fornier, 2007a).
    b) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 42% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced nausea (any grade), and 29% developed vomiting (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    c) In the same study, abdominal pain was reported in 13% of patients and constipation occurred in 16% (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    d) In phase II studies of women with metastatic breast cancer receiving a combination of ixabepilone/capecitabine, nonhematologic toxicities included grade 3/4 vomiting (Fornier, 2007a).
    2) WITH POISONING/EXPOSURE
    a) Gastrointestinal symptoms (eg, nausea, anorexia, diarrhea, abdominal pain, and stomatitis) have been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone (Prod Info IXEMPRA(R)Kit IV injection, 2011)
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is commonly reported with therapeutic use (Prod Info IXEMPRA(R)Kit IV injection, 2011; Perez et al, 2007; Fornier, 2007a).
    b) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 22% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced diarrhea (any grade) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    c) In phase II studies of women with metastatic breast cancer receiving a combination of ixabepilone/capecitabine, nonhematologic toxicities included grade 3/4 diarrhea (Fornier, 2007a).
    C) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis/mucositis are commonly reported with therapeutic use (Prod Info IXEMPRA(R)Kit IV injection, 2011; Perez et al, 2007; Fornier, 2007a; Agrawal et al, 2003).
    b) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 29% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced stomatitis/mucositis (any grade) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    1) In phase II studies of women with metastatic breast cancer receiving a combination of ixabepilone/capecitabine, nonhematologic toxicities included grade 3/4 mucositis (Fornier, 2007a).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) A dose-dependent myelosuppression, primarily neutropenia, has been reported in patients receiving ixabepilone in clinical studies. As a consequence of severe myelosuppression, febrile neutropenia, neutropenia with infection, and neutropenic-related deaths have occurred (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia is relatively common adverse event, and neutropenia-related deaths were found to be higher among patients with elevated liver enzymes (ie, AST or ALT > 2.5 x ULN or bilirubin > 1.5 x ULN) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    b) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years) evaluating the use of ixabepilone in women with metastatic or locally advanced breast cancer, 31% and 23% of patients experienced grade 3 and grade 4 neutropenia, respectively (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    1) FEBRILE NEUTROPENIA: In the same study, 3% of patients treated with ixabepilone experienced grade 3 febrile neutropenia. No patient experienced grade 4 or higher febrile neutropenia (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    c) In another study of women with stage IIA/IIIB breast cancer treated with a combination of ixabepilone/capecitabine, grade 4 neutropenia was reported in 16 (26%) patients (Fornier, 2007a)
    d) In women with metastatic or locally advanced breast cancer, grade 3 and grade 4 neutropenia was experienced by 32% and 36%, respectively, of patients treated with ixabepilone plus capecitabine (n=369) as compared to 9% and 2%, respectively, of patients treated with capecitabine alone (n=368) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years) evaluating the use of ixabepilone in women with metastatic or locally advanced breast cancer, 5% and 2% of patients experienced grade 3 and 4 thrombocytopenia, respectively (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    b) In women with metastatic or locally advanced breast cancer, grade 3 and 4 thrombocytopenia was experienced by 5% and 3%, respectively, of patients treated with ixabepilone plus capecitabine (n=369) as compared to 2% and 2%, respectively, of patients treated with capecitabine alone (n=368) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    D) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years) evaluating the use of ixabepilone in women with metastatic or locally advanced breast cancer, 36% and 13% of patients experienced grade 3 and 4 leukopenia, respectively (Prod Info IXEMPRA(R)Kit IV injection, 2011). In another study of women with stage IIA/IIIB breast cancer treated with a combination of ixabepilone/capecitabine, 7 (12%) patients developed grade 4 leukopenia (Fornier, 2007a).
    b) In women with metastatic or locally advanced breast cancer, grade 3 and grade 4 leukopenia was experienced by 41% and 16%, respectively, of patients treated with ixabepilone plus capecitabine (n=369) as compared to 5% and 1%, respectively, of patients treated with capecitabine alone (n=368) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    E) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years) evaluating the use of ixabepilone in women with metastatic or locally advanced breast cancer, 6% and 2% of patients experienced grade 3 and grade 4 anemia, respectively (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    b) In women with metastatic or locally advanced breast cancer, grade 3 and grade 4 anemia was experienced by 8% and 2%, respectively, of patients treated with ixabepilone plus capecitabine (n=369) as compared to 4% and 1%, respectively, of patients treated with capecitabine alone (n=368) (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 9% of patients with metastatic or locally advanced breast cancer developed a rash (any grade) with ixabepilone therapy (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    b) In women with metastatic or locally advanced breast cancer, 17% of patients treated with ixabepilone and capecitabine (n=369) had a rash (any grade) as compared to 7% of patients treated with capecitabine alone (n=368) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) ACRAL ERYTHEMA DUE TO CYTOTOXIC THERAPY
    1) WITH THERAPEUTIC USE
    a) Hand-foot Syndrome
    1) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 8% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced palmar-plantar erythrodysesthesia (hand-foot syndrome) (Prod Info IXEMPRA(R)Kit IV injection, 2011). In another study of women with stage IIA/IIIB breast cancer treated with a combination of ixabepilone/capecitabine, 34% of patients experienced hand-foot syndrome (Fornier, 2007a).
    2) CASE REPORT: A 62-year-old woman with a history of locally advanced invasive ductal carcinoma of the breast had a recurrence of disease in her lung and bones and was started on ixabepilone therapy of 40 mg/m(2) IV over 3 hours every 3 weeks. During the third dose the patient was noted to have some erythema and dryness of her feet. Following the fifth dose pronounced erythematous, hyperpigmentation of her feet, ankles, lower calves, hands and wrists were noted bilaterally. She also complained of severe peripheral neuropathies in her hands and feet and therapy was discontinued. The rash resolved over 4 weeks without intervention (Conlin & Vahdat, 2006).
    3) In women with metastatic or locally advanced breast cancer, 64% of patients treated with ixabepilone and capecitabine (n=369) experienced palmar-plantar erythrodysesthesia (hand-foot syndrome) as compared to 63% of patients treated with capecitabine alone (n=368) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    C) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 48% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced alopecia (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    D) DISORDER OF NAIL
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 9% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced a nail disorder (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    b) CASE REPORT: A 59 year-old woman with a history of breast cancer developed a recurrence of disease in the lung and was treated with ixabepilone (40 mg/m(2) day every 21 days). After 6 cycles of therapy, onycholysis and subungual hemorrhagic bullas of the fingernails were observed. Because the nail symptoms were not severe, the patient completed a total of 8 courses of ixabepilone with disease stabilization. The nail disorders resolved 5 months after therapy had been completed (Alimonti et al, 2005).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 20% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced musculoskeletal pain (any grade) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    b) In women with metastatic or locally advanced breast cancer, 23% of patients treated with ixabepilone and capecitabine (n=369) experienced musculoskeletal pain (any grade) as compared to 5% of patients treated with capecitabine alone (n=368) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    2) WITH POISONING/EXPOSURE
    a) Musculoskeletal pain/myalgia has been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 49% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced myalgia/arthralgia (any grade) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    C) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 49% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced myalgia/arthralgia (any grade) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    2) WITH POISONING/EXPOSURE
    a) Musculoskeletal pain/myalgia has been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) In a multicenter, single-arm study (n=126; median age, 51 years; range, 30 to 78 years), 5% of patients with metastatic or locally advanced breast cancer treated with ixabepilone experienced hypersensitivity (any grade) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    b) In women with metastatic or locally advanced breast cancer, 2% of patients treated with ixabepilone and capecitabine (n=369) experienced hypersensitivity (any grade) (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Ixabepilone is classified as FDA pregnancy category D. There are no adequate and well-controlled studies with ixabepilone in pregnant women. However, as ixabepilone may cause fetal harm in pregnant women, advise women to not become pregnant while receiving ixabepilone. If ixabepilone is initiated during pregnancy or if the patient becomes pregnant while receiving ixabepilone, inform the patient of the potential hazard to the fetus. It is not known if ixabepilone is excreted into human milk.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) No teratogenic effects were observed in fetuses of 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 (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ixabepilone is classified as FDA pregnancy category D. It may cause fetal harm when given to pregnant women (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    2) There are no adequate and well-controlled studies with ixabepilone in pregnant women. However, as ixabepilone may cause fetal harm in pregnant women, advise women to not become pregnant while receiving ixabepilone. If ixabepilone is initiated during pregnancy or if the patient becomes pregnant while receiving ixabepilone, inform the patient of the potential hazard to the fetus (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) ANIMAL STUDIES
    1) In rats, a maternally toxic dose of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC) produced an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    2) In rabbits, ixabepilone doses of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC) caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREASTFEEDING
    1) It is not known if ixabepilone is excreted into human milk (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    2) Due to the potential for serious adverse events in the infant, a decision should be made whether to discontinue nursing or to discontinue ixabepilone. The importance of the drug to the mother should be taken into consideration (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) ANIMAL STUDIES
    1) In lactating rats, following intravenous administration of radiolabeled ixabepilone on postpartum days 7 to 9, milk radioactivity concentrations were similar to those in plasma and declined in parallel with the plasma concentrations (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) The effects of ixabepilone on human fertility are unknown. In rats, no effects on mating or fertility at doses up to 0.2 mg/kg/day (approximately one-fifteenth the human clinical exposure based on AUC) were observed in males or females (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor for symptoms of burning sensation, paresthesia, discomfort or neuropathic pain. Nerve conduction studies may be useful.
    D) Obtain an ECG and institute continuous cardiac monitoring.
    E) Monitor serial CBC with differential and platelet count.
    F) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract. Monitor serum electrolytes in patients with prolonged vomiting and/or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor for symptoms of burning sensation, paresthesia, discomfort or neuropathic pain. Nerve conduction studies may be useful.
    D) Obtain an ECG and institute continuous cardiac monitoring.
    E) Monitor serial CBC with differential and platelet count.
    F) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract. Monitor serum electrolytes in patients with prolonged vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; ixabepilone is only available parenterally.

Range Of Toxicity

Summary

    A) TOXICITY: Limited overdose data exists. An adult inadvertently received a total dose of 185 mg and developed myalgia (grade 1) and fatigue (grade 1). Recovery was uneventful. Peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (eg, nausea, anorexia, diarrhea, abdominal pain, and stomatitis) have been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone.
    B) THERAPEUTIC DOSE: ADULT: 40 mg/m(2) administered intravenously over 3 hours every 3 weeks. For patients with a body surface area greater than 2.2 m(2) the dose should be calculated based on 2.2 m(2). Dose adjustments may be necessary based on clinical and laboratory monitoring. CHILD: Safety and efficacy of ixabepilone use has not been determined in pediatric patients. The safety profile of ixabepilone in children was consistent with that seen in adults and the maximum tolerated dose was 8 mg/m(2) IV daily for 5 days every 21 days in a phase 1 trial evaluating the safety of ixabepilone in 21 pediatric patients 2 to 18 years of age.

Therapeutic Dose

    7.2.1) ADULT
    A) BREAST CANCER
    1) MONO- OR COMBINATION THERAPY: Recommended dose is 40 mg/m(2) IV infused over 3 hours every 3 weeks (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    2) DOSE ADJUSTMENTS: For patients with a body surface area greater than 2.2 m(2), the dose should be calculated based on 2.2 m(2) (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    7.2.2) PEDIATRIC
    A) The efficacy of ixabepilone has not been determined in pediatric patients (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) The safety profile of ixabepilone was consistent with that seen in adults and the maximum tolerated dose was 8 mg/m(2) IV daily for 5 days every 21 days in a phase 1 trial evaluating the safety of ixabepilone in 21 pediatric patients 2 to 18 years of age (median, 12 years; 19 with advanced or refractory solid tumors and 2 with acute leukemias). Five dosing levels ranging from 3 to 10 mg/m(2) were administered as 1-hour daily infusions for the first 5 days of a 21-day cycle and no significant anti-tumor activity was observed. In a phase 2 trial, 47 pediatric patients (3 to 18 years of age) and 12 adults with advanced or refractory solid tumors were treated with of ixabepilone 8 mg/m(2) IV daily for 5 days every 21 days and, due to lack of efficacy, this trial was terminated early (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Minimum Lethal Exposure

    A) ANIMAL DATA
    1) In a rat study, single intravenous doses of ixabepilone of 60 to 180 mg/m(2) resulted in mortality between 5 and 14 days after dosing. Toxic effects included gastrointestinal, hematopoietic, lymphatic, peripheral-nervous, and male-reproductive events (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    2) Severe toxicity including gastrointestinal toxicity and death 3 days after dosing occurred. Fatalities were reported 3 days after dosing in dogs that received a single intravenous dose of 100 mg/m(2) (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Maximum Tolerated Exposure

    A) Peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (eg, nausea, anorexia, diarrhea, abdominal pain, and stomatitis) have been reported after the inadvertent administration of up to 100 mg/m(2) of ixabepilone (Prod Info IXEMPRA(R)Kit IV injection, 2011).
    B) CASE REPORT
    1) An adult inadvertently received a total dose of ixabepilone 185 mg and developed myalgia (grade 1) and fatigue (grade 1). Recovery was uneventful (Prod Info IXEMPRA(TM) IV injection, 2007).
    C) CLINICAL TRIALS
    1) In phase I studies, the maximum tolerated dose was 6 mg/m(2) per day. In a follow-up study, escalating dose levels of ixabepilone at 7.4 mg/m(2) to 59.2 mg/m(2) as an hourly infusion every 21 days were studied. Neutropenia was the dose-limiting toxicity at 50 mg/m(2). Other symptoms included grade 3 or 4 fatigue and weakness (Fornier, 2007).
    2) The safety profile of ixabepilone in children was consistent with that seen in adults and the maximum tolerated dose was 8 mg/m(2) IV daily for 5 days every 21 days in a phase 1 trial evaluating the safety of ixabepilone in 21 pediatric patients 2 to 18 years of age (median, 12 years; 19 with advanced or refractory solid tumors and 2 with acute leukemias). Five dosing levels ranging from 3 to 10 mg/m(2) were administered as 1-hour daily infusions for the first 5 days of a 21-day cycle and no significant anti-tumor activity was observed. In a phase 2 trial, 47 pediatric patients (3 to 18 years of age) and 12 adults with advanced or refractory solid tumors were treated with ixabepilone 8 mg/m(2) IV daily for 5 days every 21 days and, due to lack of efficacy, this trial was terminated early (Prod Info IXEMPRA(R)Kit IV injection, 2011).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) The mean AUC was 2143 ng x hr/mL (coefficient of variation (CV), 48%) after a single intravenous dose of ixabepilone 40 mg/m(2) (Prod Info IXEMPRA(TM) IV injection, 2007).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ixabepilone, an epothilone B analog, is an antimicrotubule agent (Prod Info IXEMPRA(TM) IV injection, 2007). It has a mechanism of action similar to the taxanes. However, ixabepilone is structurally different and has demonstrated cytotoxic activity in taxane-sensitive and taxane-resistant tumor cell lines. Ixabepilone inhibits microtubules, halting cell division in the mitotic phase and resulting in subsequent cell death (Prod Info IXEMPRA(TM) IV injection, 2007; Chowdhury et al, 2007). Ixabepilone stabilizes the microtubules by directly binding to the beta-tubulin subunits (alpha-beta-II and alpha-beta-III). Epothilones are isolated from the myxobacterium, Sorangium cellulosum (Prod Info IXEMPRA(TM) IV injection, 2007).

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