Usual Adult Dose for Soft Tissue Sarcoma

• Normal Bilirubin and AST or ALT 2.5 Times the Upper Limit of Normal (ULN) or Less:

1.5 mg/m2 via IV infusion every 21 days (3 weeks)

• Serum Bilirubin Levels Above Institutional ULN:

No recommended dose.

Duration of Therapy: Until disease progression or unacceptable toxicity

Comments:

• Administer this drug over 24 hours through a central venous line using an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter.
• Complete infusion within 30 hours of drug reconstitution.
• Administer dexamethasone 20 mg IV 30 minutes prior to each dose.

Use: Treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.

Renal Dose Adjustments

• Mild (CrCl 60 to 89 mL/min) or Moderate (CrCl 30 to 59 mL/min) Renal Impairment: No adjustment recommended.
• Severe (CrCl less than 30 mL/min) Renal Impairment or End Stage Renal Disease: Data not available.

Liver Dose Adjustments

SEVERE LIVER DYSFUNCTION (Bilirubin 2 x ULN and AST or ALT 3 x ULN with Alkaline Phosphatase Less than 2 x ULN) in the prior treatment cycle: Permanently discontinue treatment.

FOR ELEVATED ALT, AST, ALKALINE PHOSPHATASE, or TOTAL BILIRUBIN:

• First Dose Reduction: 1.2 mg/m2 every 3 weeks
• Second Dose Reduction: 1.0 mg/m2 every 3 weeks
• Once reduced, the dose should not be increased in subsequent treatment cycles.

ALT or AST:

• More than 2.5 x ULN: Delay next dose for up to 3 weeks.
• More than 5 x ULN: Reduce next dose by one dose level.

Alkaline Phosphatase:

• More than 2.5 x ULN: Delay next dose for up to 3 weeks and reduce next dose by one dose level.

Total Bilirubin:

• Greater than the ULN: Delay next dose for up to 3 weeks and reduce next dose by one dose level.

PERMANENTLY DISCONTINUE TREATMENT FOR:

• Persistent adverse reactions requiring a dosing delay of more than 3 weeks.
• Adverse reactions requiring dose reduction following administration of this drug at 1.0 mg/m2.

Dose Adjustments

Strong CYP450 3A Inhibitors (including grapefruit products):

• Avoid concomitant use.
• If necessary to use strong CYP450 3A inhibitor for less than 14 days, administer the CYP450 inhibitor 1 week after infusion of this drug and discontinue the inhibitor the day prior to the next infusion of this drug.

Strong CYP450 3A Inducers (including St. John's Wort):

• Avoid concomitant use.

FOR THE FOLLOWING ADVERSE REACTIONS:

• First Dose Reduction: 1.2 mg/m2 every 3 weeks
• Second Dose Reduction: 1.0 mg/m2 every 3 weeks
• Once reduced, the dose should not be increased in subsequent treatment cycles.

PLATELETS:

• Less than 100,000 platelets/microliter: Delay next dose for up to 3 weeks.
• Less than 25,000 platelets/microliter: Reduce next dose by one dose level.

ABSOLUTE NEUTROPHIL COUNT:

• Less than 1,500 neutrophils/microliter: Delay next dose for up to 3 weeks
• Less than 1,000 neutrophils/microliter with fever/infection: Reduce next dose by one dose level.
• Less than 500 neutrophils/microliter lasting more than 5 days: Reduce next dose by one dose level.

CREATINE PHOSPHOKINASE:

• More than 2.5 x ULN: Delay next dose for up to 3 weeks.
• More than 5 x ULN: Reduce next dose by one dose level.

DECREASED LEFT VENTRICULAR EJECTION FRACTION:

• Less than lower limit of normal (LLN) OR Clinical evidence of cardiomyopathy: Delay next dose for up to 3 weeks.
• Absolute decrease of 10% or more from baseline and less than LLN OR Clinical evidence of cardiomyopathy: Reduce next dose by one dose level.

OTHER NON-HEMATOLOGIC ADVERSE REACTIONS:

• Grade 3 or 4: Delay next dose for up to 3 weeks and reduce next dose by one dose level.

PERMANENTLY DISCONTINUE TREATMENT FOR:

• Persistent adverse reactions requiring a dosing delay of more than 3 weeks
• Adverse reactions requiring dose reduction following drug administration at 1.0 mg/m2

Precautions

CONTRAINDICATIONS:

• Patients with known severe hypersensitivity, including anaphylaxis, to this drug.

Safety and efficacy have not been established in pediatric patients.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Storage Requirements:

• Drug vials should be stored in a refrigerator at 2 to 8 degrees Celsius (36 to 46 Fahrenheit).
• Any unused portion of the reconstituted product or of the infusion solution should be discarded 30 hours after administration.
• Drug vials with particles or discoloration should be discarded.

Reconstitution/Preparation Techniques:

• Preparation, handling, and disposal of this drug should be performed in a manner consistent with safe procedures for cytotoxic agents.
• Pregnant healthcare providers should not handle, prepare, or administer this drug.
• Areas (e.g., skin, eyes, mucous membranes) accidentally exposed to this drug should be flushed with clean water for at least 15 minutes.
• This drug should not be mixed with other drugs.
• The manufacturer product information should be consulted for reconstitution and dilution instructions.

General:

• This drug has shown in vitro and in vivo antiproliferative activity against a range of human tumor cell lines and experimental tumors, including malignancies such as sarcoma, breast, non-small cell lung, ovarian, and melanoma.
• There is no specific antidote for this drug; supportive measures should be instituted as required if overdose occurs.
• This drug is hydrophobic and has a low solubility in water.
• Diluted solution of this drug is compatible with Type 1 colorless glass vials; polyvinylchloride (PVC) and polyethylene (PE) bags and tubing; PE and polypropylene (PP) mixture bags; polyethersulfone (PES) in-line filters; titanium, platinum or plastic ports; silicone and polyurethane catheters; and pumps having contact surfaces made of PVC, PE, or PE/PP.

Monitoring:

• Cardiovascular: Left ventricular ejection fraction (before treatment initiation and at 2- to 3-month intervals during treatment)
• Hematologic: Neutrophil count (prior to each dose and periodically throughout treatment cycle); full blood cell count including differential and platelet count (baseline, weekly for the first 2 cycles, and then once between cycles)
• Hepatic: Liver function tests (prior to each dose); additional monitoring of bilirubin, alkaline phosphatase, and aminotransferases (weekly during first 2 therapy cycles and at least once between treatments in subsequent cycles)
• Musculoskeletal: Creatine phosphokinase levels (prior to each dose; weekly during first 2 therapy cycles; at least once between treatments in subsequent cycles; and when a patient is experiencing musculoskeletal toxicity, muscle weakness, or muscle pain)
• Renal: CrCl (prior to and during treatment)

Patient Advice:

• Avoid grapefruit, grapefruit juice, St. John's Wort, and alcohol during treatment.
• Use effective contraception during treatment and for at least 2 months after the last dose if you are a female patient with childbearing potential; use effective contraception for at least 5 months after the last dose if you are a male patient with a female partner of childbearing potential.
• This drug may cause side effects such as fatigue and weakness that can affect your ability to perform certain activities; avoid potentially dangerous activities such as driving and operating machinery until you know how this drug affects you.
• Tell your healthcare provider right away if you notice any of this drug leaking out of your vein or around the catheter during your infusion, or if you notice any redness, swelling, itching, or discomfort at the infusion site.