Fludarabine

Life-threatening (and sometimes fatal) autoimmune effects, including hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have occurred; evaluate and monitor closely for hemolysis. This has occurred in patients with and without a history of autoimmune hemolytic anemia or a positive Coombs test, and who may or may not be in remission from their disease. Corticosteroids may or may not effectively control the hemolytic episodes. Discontinue fludarabine if hemolysis occurs. The hemolytic effects recurred in most patients when rechallenged with fludarabine.

Severe bone marrow suppression (anemia, thrombocytopenia, and neutropenia) may occur; may be cumulative. The median time to nadir was 13 days (range: 3 to 25 days) for granulocytes and 16 days (range: 2 to 32 days) for platelets. Severe myelosuppression (trilineage bone marrow hypoplasia/aplasia) has been reported (rare) with a duration of significant cytopenias ranging from 2 months to 1 year. First-line combination therapy is associated with prolonged cytopenias, with anemia lasting up to 7 months, neutropenia up to 9 months, and thrombocytopenia up to 10 months; increased age is predictive for prolonged cytopenias (Gill 2010). Monitor patients with bone marrow impairment closely for excess toxicity; may require dosage reductions.

Serious and sometimes fatal infections, including opportunistic infections and reactivations of latent viral infections such as VZV (herpes zoster) and Epstein-Barr virus have been reported with fludarabine. Prophylactic anti-infectives should be considered for patients with an increased risk for developing opportunistic infections. Use with caution in patients with documented infection, fever, immunodeficiency, or with a history of opportunistic infection.

Higher than recommended doses (up to 96 mg/m2/day for 5 to 7 days) are associated with severe neurologic toxicity (delayed blindness, coma, death); similar neurotoxicity (agitation, coma, confusion, seizure) has been reported (rare) with standard CLL doses (25 mg/m2/day for 5 days). Symptoms of neurotoxicity due to high doses appeared from 21 to 60 days following the last fludarabine dose, although neurotoxicity has been reported as early as 7 days and up to 225 days. Although administration of up to 15 courses of treatment have been used, the possible neurotoxic effects of chronic administration are unknown. Fatigue, weakness, visual disturbances, confusion, and seizures may occur; caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).

Progressive multifocal leukoencephalopathy (PML) (usually fatal) due to JC virus has been reported; most cases were in patients who had received prior and/or other concurrent chemotherapy. Onset may be a few weeks or may be delayed up to 1 year. Evaluate any neurological change promptly.

Fludarabine may damage testicular tissue and spermatozoa.

Graft-versus-host disease (GVHD) has been observed following transfusion of non-irradiated blood in patients treated with fludarabine; fatal outcome has been observed. Patients receiving fludarabine should only receive irradiated blood products due to the potential for transfusion-related GVHD.

May cause tumor lysis syndrome; risk is increased in patients with large tumor burden prior to treatment. Hydration and prophylactic antihyperuricemic therapy should be considered in patients at risk for tumor lysis syndrome. Disease-related concerns:

Use with caution in patients with renal impairment; clearance of the primary metabolite 2-fluoro-ara-A is decreased in patients with renal impairment. Dosage reductions are recommended (monitor closely for excessive toxicity) in patients with creatinine clearance between 30 and 79 mL/minute; use is not recommended if CrCl Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

The use of fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia has resulted in an unacceptably high incidence of fatal pulmonary toxicity. The use of fludarabine in combination with pentostatin is not recommended. Special populations:

Monitor closely for excessive toxicity; may require reduced doses. Other warnings/precautions:

Should be administered under the supervision of an experienced cancer chemotherapy physician.

Avoid vaccination with live vaccines during and after fludarabine treatment.