Summary of Changes to Contraindications and Warnings

WARNINGS AND PRECAUTIONS

• Hematologic Toxicity
  • Monitor complete blood counts and platelet counts during Clolar therapy...
• Infections
  • ...Monitor patients for signs and symptoms of infection and treat promptly.
• Hyperuricemia (Tumor Lysis)
• Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome
• Hepatic Enzymes
• Hepatic and Renal Impairment
• Use in Pregnancy

ADVERSE REACTIONS

• Clinical Trials Experience
  • Initial Section
  • Table 1
  • The following less common adverse reactions have been reported in 1-4% of the 115 pediatric patients with ALL or AML...
  • Table 2
  • Hematologic Toxicity
  • Infection
  • Hepatic
  • Renal
  • Systemic Inflammatory Response Syndrome (SIRS)
  • Capillary Leak Syndrome
• Postmarketing Experience (new subsection)

USE IN SPECIFIC POPULATIONS

• Geriatric Use (new subsection)

PATIENT COUNSELING INFORMATION (new)

• Hematologic Toxicity
• Infection
• Hepatic and Renal Impairment
• Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome
• Advise male and female patients with reproductive potential to use effective contraceptive measures to prevent pregnancy...

WARNINGS AND PRECAUTIONS

Hyperuricemia (Tumor Lysis):

Administration of Clolar may result in a rapid reduction in peripheral leukemia cells. Evaluate and monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome. Provide intravenous infusion fluids throughout the five days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Administer Allopurinol if hyperuricemia (tumor lysis) is expected.

Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome:

...Re-institute Clolar when the patient is stable, generally with a 25% dose reduction. The use of prophylactic steroids may be of benefit in preventing signs and symptoms of cytokine release.

Hepatic Enzymes:

Hepato-biliary enzyme elevations were frequently observed in pediatric patients during treatment with Clolar. Some patients discontinued treatment due to hepatic enzyme abnormalities. [see ADVERSE REACTIONS (6.1)].

Hepatic and Renal Impairment:

...Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in an ongoing Phase 1/2 combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia.

Use in Pregnancy:

Clolar can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations. [See Use in Specific Populations (8.1)]