Usual Adult Dose for Breast Cancer

Recommended dosage: 40 mg/m2 IV over 3 hours every 3 weeks
The dosage for patients with a body surface area (BSA) exceeding 2.2 m2 should be calculated based on a 2.2 m2 BSA.

Comments:

• All patients should be premedicated approximately 1 hour before the infusion (see Administration Advice).

• 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.
• 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.

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

• Monitor hepatic function before treatment initiation and periodically during treatment.
• Dose reduction is recommended when administering this drug as a single agent.
• The alcohol content of this drug should be taken into account when administering to patients with hepatic impairment.
• Dosage recommendations below are for the first course of therapy. Further decrease in additional courses should be based on individual tolerance.

• AST and ALT 2.5 x ULN or less and bilirubin 1 x ULN or less: No modification (40 mg/m2)
• AST and ALT 10 x ULN or less and bilirubin 1.5 x ULN or less: 32 mg/m2
• AST and ALT 10 x ULN or less and bilirubin greater than 1.5 x ULN to 3 x ULN or less: 20 to 30 mg/m2 (consider increasing dose to 30 mg/m2 in subsequent cycles if a dose of 20 mg/m2 is tolerated).
• AST and ALT greater than 10 x ULN or bilirubin greater than 3 x ULN: Avoid use

• AST or ALT 2.5 times the upper limit of normal (ULN) or less or bilirubin 1 x ULN or less: 40 mg/m2
• AST or ALT greater than 2.5 x ULN or bilirubin greater than 1 x ULN: Contraindicated

Dose Adjustments

DUE TO ADVERSE REACTIONS:

• Patients should be evaluated during therapy by observation and laboratory tests including complete blood cell counts. If toxicities are present therapy should be delayed until recovery.
• If adverse reactions recur, dose can be reduced by an additional 20%.

• Grade 2 neuropathy (moderate) lasting 7 days or more: Decrease dose by 20%
• Grade 3 neuropathy (severe) lasting less than 7 days: Decrease dose by 20%
• Grade 3 neuropathy (severe) lasting 7 days or more or disabling neuropathy: Discontinue therapy
• Any Grade 3 toxicity (severe) other than neuropathy: Decrease dose by 20%
• Transient grade 3 arthralgia/myalgia/fatigue/Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia): No change in dose
• Any grade 4 toxicity (disabling): Discontinue therapy

• Neutrophil less than 500 cells/mm3 for 7 days or more: Decrease dose by 20%
• Febrile neutropenia: Decrease dose by 20%
• Platelets less than 25,000/mm3 or platelets less than 50,000/mm3 with bleeding: Decrease dose by 20%

• Follow capecitabine label.

• Platelets less than 25,000/mm3 or platelets less than 50,000/mm3 with bleeding: Hold for concurrent diarrhea or stomatitis until platelet count is greater than 50,000/mm3 then continue at same dose
• Neutrophil less than 500 cells/mm3 for 7 days or more or febrile neutropenia: Hold for concurrent diarrhea or stomatitis until neutrophil count is greater than 1000 cells/mm3, then continue the same dose.

• Dosage adjustments at the beginning of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle.
• 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 the nonhematologic toxicities have improved to Grade 1 or have resolved.

• Use of concomitant strong CYP450 3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, voriconazole).
• Grapefruit juice may increase plasma concentrations of this drug and should be avoided.
• If a strong CYP450 3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is suggested. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the dose is adjusted upward.

• Use of concomitant strong CYP450 3A4 inducers should be avoided.
• If coadministration with a strong CYP450 3A4 inducer cannot be avoided, gradually increase the dose from 40 mg/m2 to 60 mg/m2 depending on tolerance. Administer as a 4-hour IV infusion and monitor adverse reactions.
• If the strong inducer is discontinued, the dose of this drug should be returned to the dose used prior to initiation of the strong CYP450 3A4 inducer.

Precautions

US BOXED WARNINGS:
Toxicity in patients with hepatic impairment:

• This drug in combination with capecitabine is contraindicated in patients with AST or ALT greater than 2.5 x upper limit of normal (ULN) or bilirubin greater than 1 x ULN due to increased risk of toxicity and neutropenia-related death.

• In patients who have a neutrophil count less than 1500 cells/mm3 or a platelet count less than 100,000 cells/mm3
• In patients with a history of a severe hypersensitivity to agents containing Cremophor EL or its derivatives (e.g., polyoxyethylated castor oil)
• This drug in combination with capecitabine is contraindicated in patients with AST or ALT greater than 2.5 x ULN or bilirubin greater than 1 x ULN

Dialysis

Data not available

Other Comments

Administration advice:
Premedication:

• To minimize the chance of a hypersensitivity reaction, all patients should be premedicated approximately 1 hour prior to administration of this drug with an H1 antagonist (e.g., diphenhydramine 50 mg orally or equivalent) and an H2 antagonist (e.g., ranitidine 150 to 300 mg orally or equivalent).
• If a patient experiences a hypersensitivity reaction in one cycle, premedicate in subsequent cycles with a corticosteroid (e.g., dexamethasone 20 mg IV 30 minutes prior to infusing this drug or orally 60 minutes prior to infusion) in addition to the H1 and H2 antagonists. Extension of the infusion time should also be considered.

• This is a hazardous drug and special handling, and disposal procedures should be followed. See manufacturer's product information for specific instructions.
• Once prepared and diluted, IV administration should be completed within 6 hours.

• Store in a refrigerator at 2C to 8C (36F to 46F) in the original package
• Protect from light
• After reconstitution, and further dilution, this drug 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.

• Prior to constituting this drug, the drug 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.
• The drug kit contains 2 vials, a vial labeled ixabepilone for injection which contains ixabepilone powder and a vial containing diluent.
• Only the supplied diluent may be used for reconstituting this drug.
• See the manufacturer product information for further instructions.

• Lactated Ringer's Injection
• Sodium Chloride 0.9% Injection (pH adjusted with Sodium Bicarbonate Injection, USP)
• Plasmalyte A Injection pH 7.4

• Hepatic function
• Peripheral neuropathy symptoms

• Read the FDA-approved patient label (Patient Information) before you start receiving treatment.
• This drug contains alcohol. If you are dizzy or drowsy, avoid activities that may be dangerous, such as driving or operating machinery.
• Do not drink grapefruit juice while taking this drug because it may cause you to have too much of this drug in your blood and lead to side effects.
• Do not take this drug if you are pregnant. This drug can harm an unborn baby.
• Contact your healthcare provider immediately if you experience:
• chest pain, difficulty breathing, feel your heart beating (palpitations), or unusual weight gain,
• urticaria, pruritus, rash, flushing, swelling, difficulty breathing, chest tightness, or other hypersensitivity related symptoms
• if you have a fever of 100 F or higher and any symptoms of infection (chills, cough, burning or pain on urination)
• or if you have numbness or tingling of your hands or feet