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Ixabepilone

Pronouncation: (IX-ab-EP-i-lone)
Class: Antimitotic agent

Trade Names:
Ixempra
- Injection, lyophilized 15 mg
- Injection, lyophilized 45 mg

Pharmacology

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Blocks cells in the mitotic phase of the cell division cycle, leading to cell death.

Pharmacokinetics

Absorption

C _max occurs at end of 3 h infusion. Exhibits linear pharmacokinetics at doses of 15 to 57 mg/m ² .

Distribution

Steady-state Vd is in excess of 1,000 L at a dose of 40 mg/m ² . Serum protein binding ranges from 67% to 77%.

Metabolism

Extensively metabolized in the liver by CYP3A4.

Elimination

Eliminated primarily as metabolized drug with more than 30 metabolites excreted in urine and feces. Approximately 86% of an administered dose is eliminated within 7 days (65% feces, 21% urine). The t _½ is approximately 52 h. Accumulation in plasma not expected when administered every 3 wk.

Special Populations

Renal Function Impairment

No controlled studies conducted; however, minimally excreted via the kidney.

Age, gender, race

No meaningful effect on the pharmacokinetics.

Indications and Usage

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; 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.

Contraindications

History of severe hypersensitivity reaction to agents containing polyoxyethylated castor oil; neutrophil count less than 1,500 cells/mm ³ or platelet count less than 100,000 cells/mm ³ ; in combination with capecitabine in patients with AST or ALT more than 2.5 times ULN or bilirubin greater than 1 times ULN.

Dosage and Administration

Adults

IV 40 mg/m ² over 3 h every 3 wk. Patients with body surface area more than 2.2 m ² should be calculated based on 2.2 m ² .

Dose Adjustments During Treatment
Adults

Monotherapy or combination therapy Nonhematologic

Decrease dose by 20% in patients with grade 2 neuropathy lasting 7 days or more, grade 3 neuropathy lasting less than 7 days, or any grade 3 toxicity other than neuropathy. Discontinue treatment in patients with grade 3 neuropathy lasting 7 days or more, disabling neuropathy, or any grade 4 toxicity. No change in dose for patients with transient grade 3 arthralgia/myalgia or fatigue, and in grade 3 hand-foot syndrome.

Hematologic

Decrease dose by 20% in patients with neutrophil count less than 500 cells/mm ³ for 7 days or more, febrile neutropenia, platelets less than 25,000/mm ³ , or platelets less than 50,000/mm ³ with bleeding.

Capecitabine (when used in combination with ixabepilone) Nonhematologic

Base dosing on capecitabine labeling.

Hematologic

Hold dose for concurrent diarrhea or stomatitis until platelet count is greater than 50,000/mm ³ , then continue at same dose in patients with platelet count less than 25,000/mm ³ or less than 50,000/mm ³ with bleeding; hold dose for concurrent diarrhea or stomatitis until neutrophil count is more than 1,000 cells/mm ³ , then continue at same dose in patients with neutrophil count less than 500 cells/mm ³ for 7 days or more or febrile neutropenia.

Re-treatment criteria

Base dose adjustments at the start of a cycle on nonhematologic toxicity or blood cell counts from the preceding cycle following the previous guidelines. A new cycle should not be started unless the neutrophil count is at least 1,500 cells/mm ³ , the platelet count is 100,000 cells/mm ³ or more, and nonhematologic toxicities have resolved or improved to grade 1.

Dose Adjustments in Hepatic Function Impairment
Adults

Combination therapy

40 mg/m ² over 3 h every 3 wk in patients who have AST and ALT 2.5 times or less than the ULN and bilirubin 1 times or less than the ULN.

Monotherapy Mild hepatic function impairment

Patients with AST and ALT 2.5 times or less than the ULN and bilirubin 1 times or less than the ULN, administer 40 mg/m ² .

Mild hepatic function impairment

Patients with AST or ALT 10 times or less than the ULN and bilirubin 1.5 times or less than the ULN, administer 32 mg/m ² .

Moderate hepatic function impairment

Patients with AST and ALT 10 times or less than the ULN and bilirubin more than 1.5 times but 3 times or less than the ULN, start at 20 mg/m ² and escalate the dosage in subsequent cycles up to a max of 30 mg/m ² if tolerated. Use is not recommended in patients with AST or ALT more than 10 times the ULN or bilirubin more than 3 times the ULN.

Dosage Adjustments With Coadministration of Strong CY3A4 Inhibitors
Adults

IV If strong CYP3A4 inhibitors cannot be avoided, consider reducing the dose to 20 mg/m ² . Allow a washout period of approximately 1 wk after discontinuing the inhibitor before adjusting the dose of ixabepilone upward to the indicated dose.

Premedication

To minimize the occurrence of a hypersensitivity reaction, premedicate patients approximately 1 h before drug infusion with a histamine H ₁ antagonist (eg, diphenhydramine 50 mg orally or equivalent) and an H ₂ antagonist (eg, ranitidine 150 to 300 mg orally or equivalent). Patients who experienced a hypersensitivity reaction require premedication with corticosteroids (eg, dexamethasone 20 mg IV 30 minutes before infusion or orally 60 minutes before infusion) in addition to H ₁ and H ₂ antagonists.

General Advice

Refer to Preparation and Handling Precautions in the package labeling before preparation.

Storage/Stability

Store under refrigeration at 36° to 46°F. Protect from light. After reconstituting, the solution may be stored in the vial (not the syringe) for a maximum of 1 h at room temperature and room light. Once diluted with Ringer's lactate injection, the solution is stable at room temperature and room light for a maximum of 6 h. Administration must be completed within the 6-h period.

Drug Interactions

Grapefruit juice

Because ixabepilone concentrations may be elevated, avoid grapefruit juice.

St. John's wort

Because ixabepilone concentrations may be reduced unpredictably, avoid St. John's wort.

Strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin)

Ixabepilone concentrations may be reduced, leading to subtherapeutic levels.

Strong CYP3A4 inhibitors (eg, amprenavir, atazanavir, clarithromycin, delavirdine, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

Ixabepilone concentrations may be elevated. If a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction to ixabepilone 20 mg/m ² . Mild or moderate CYP3A4 inhibitors (eg, erythromycin, fluconazole, verapamil) have not been studied and should be used with caution.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The following adverse reactions were reported with ixabepilone monotherapy.

Cardiovascular

Hot flush (6%).

CNS

Peripheral neuropathy (63%); sensory neuropathy (62%); fatigue/asthenia (56%); headache (11%); motor neuropathy (10%); dizziness (7%); taste disorder (6%); insomnia (5%).

Dermatologic

Alopecia (48%); nail disorder, skin rash (9%); erythrodysethesia syndrome (8%); pruritus (6%); skin exfoliation, skin hyperpigmentation (2%).

EENT

Increased lacrimation (4%).

GI

Nausea (42%); stomatitis/mucositis, vomiting (29%); diarrhea (22%); anorexia (19%); constipation (16%); abdominal pain (13%); gastroesophageal reflux disease (6%).

Hematologic-Lymphatic

Leukopenia (36%); neutropenia (31%); anemia (6%); thrombocytopenia (5%); febrile neutropenia (3%).

Hypersensitivity

Hypersensitivity (5%); severe hypersensitivity, including anaphylaxis (1%).

Metabolic-Nutritional

Decreased weight (6%); dehydration (2%).

Musculoskeletal

Myalgia/arthralgia (49%); musculoskeletal pain (20%).

Respiratory

Dyspnea (9%); upper respiratory tract infection (6%); cough (2%).

Miscellaneous

Edema (9%); pain/pyrexia (8%); chest pain (5%).

Precautions

Warnings

Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT more than 2.5 times the ULN or bilirubin greater than 1 times the ULN because of increased risk of toxicity and neutropenia-related death.

Monitor

Monitor for symptoms of peripheral nephropathy; observe for hypersensitivity reactions.

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Insufficient number of subjects 65 yr of age and older to determine whether elderly patients respond differently form younger subjects.

Hepatic Function

Risk of toxicity may be increased. Use with caution and at reduced dose, depending on degree of hepatic function impairment.

Cognitive impairment

Because of dehydrated alcohol content, CNS depressant effects may occur.

Cardiotoxicity

Cardiac reactions (eg, myocardial ischemia, ventricular dysfunction) are higher with coadministration of capecitabine and ixabepilone compared with capecitabine alone.

Myelosuppression

Dose-dependent myelosuppression, primarily manifested as neutropenia, may occur.

Peripheral nephropathy

New onset or worsening of neuropathy may occur.

Overdosage

Symptoms

Fatigue, myalgia.

Patient Information

Advise patients that product contains alcohol and if they feel dizzy or drowsy to avoid activities such as driving or operating machinery.
Instruct patients to immediately contact health care provider if they experience chest tightness; feeling faint or dizzy; flushed face; heart palpitations; hives; itching; numbness, tingling, or burning in hands or feet; rash; sudden swelling of face, throat, or tongue; or trouble breathing.
Advise patients to use effective contraceptive measures to prevent pregnancy and to avoid breast-feeding during treatment.