Fludarabine

Fludarabine Phosphate Injection is indicated: as a component of a combination regimen for the treatment of adults with B-cell chronic lymphocytic leukemia (CLL), for the treatment of adults with B-cell CLL who have not responded to or whose disease has progressed during treatment with at least one alkylating-agent containing regimen. Fludarabine Phosphate Injection is a nucleoside metabolic inhibitor indicated: as a component of a combination regimen for the treatment of adults with B-cell chronic lymphocytic leukemia (CLL), for the treatment of adults with B-cell CLL who have not responded to, or whose disease has progressed during treatment with at least one alkylating- agent containing regimen.

Fludarabine phosphate is rapidly converted to active 2-fluoro-ara-ATP, which appears to inhibit DNA synthesis through inhibition of DNA polymerase alpha, ribonucleotide reductase and DNA primase.

The recommended dosage is: In Combination with Cyclophosphamide and Rituximab: The recommended dosage is 25 mg/m 2 administered intravenously over 30 minutes daily for the first three days (Days 1 to 3) of each 28-day cycle for 6 cycles in combination with cyclophosphamide 250 mg/m 2 administered intravenously daily for three days (Days 1 to 3), and rituximab 375 mg/m 2 administered intravenously on Day 1 of the first cycle, followed by rituximab 500 mg/m 2 on Day 1 of subsequent cycles. Single Agent: The recommended dosage is 25 mg/m 2 administered intravenously over approximately 30 minutes daily for five consecutive days (Days 1 to 5) of each 28-day cycle. Renal impairment: Reduce the dosage for patients with creatinine clearance (CLcr) 30 to 79 mL/min. See the Full Prescribing Information for instructions for preparation and administration.

None. None.

N eurological Toxicities: Coma, seizures, agitation and confusion can occur and are dose dependent. Monitor patients for signs and symptoms of neurologic toxicity. Consider delaying or discontinuing Fludarabine Phosphate Injection if neurotoxicity occurs. M y elosuppression: Severe anemia, thrombocytopenia, neutropenia, or pancytopenia can occur and are dose dependent. Monitor blood counts before and during treatment. Consider dose delays, dose reductions, or permanent discontinuation if recovery has not occurred by the first day of the next scheduled cycle. A u t o immune Cytopenias: Life-threatening and fatal autoimmune hemolytic anemia, autoimmune thrombocytopenia/ thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia can occur. Closely monitor patients for hemolysis and manage as clinically indicated.

The following clinically significant adverse reactions are described elsewhere in the labeling: Neurologic Toxicities Myelosuppression Autoimmune Cytopenias Transfusion Associated Graft-Versus-Host Disease Tumor Lysis Syndrome The most common adverse reactions (≥ 20%) are myelosuppression (neutropenia, thrombocytopenia, or anemia), fever, infection, nausea and vomiting, weakness, and pain. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Pentostatin Avoid use of Fludarabine Phosphate Injection in combination with pentostatin due to the risk of severe and fatal pulmonary toxicity

Storage Store in a refrigerator between 2˚ and 8˚C (36˚ to 46˚F).