Fludarabine Generic Name & Formulations
Store refrigerated between 2° and 8° C (36° and 46° F).
Fludarabine Dosage and Administration
Fludarabine Boxed Warnings
Dose-dependent toxic effects were seen with fludarabine. Dose levels ~4 times greater than that recommended for CLL were associated with a syndrome characterized by delayed blindness, coma and death. Thirteen of 36 patients (36%) who received fludarabine at high doses (96 mg/m2/day for 5 to 7 days) developed this severe neurotoxicity.
Severe bone marrow suppression (eg, anemia, thrombocytopenia, and neutropenia), has been reported in patients treated with fludarabine. While chemotherapy induced myelosuppression is reversible, administration of fludarabine requires careful hematologic monitoring.
Cases of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported. Clinically significant cytopenia in the reported cases has ranged from ~2 months to ~1 year; these episodes have occurred both in previously treated or untreated patients.
Cases of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs’ test and who may or may not be in remission from their disease. Patients undergoing treatment with fludarabine should be evaluated and closely monitored for hemolysis.
Transfusion-associated graft-versus-host disease has been seen rarely after transfusion of non-irradiated blood in fludarabine-treated patients. Should give consideration to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with fludarabine.
Patients undergoing therapy should be closely monitored for signs of hematologic and nonhematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of anemia, neutropenia and thrombocytopenia.
Tumor lysis syndrome associated with fludarabine treatment has been reported in CLL patients with large tumor burdens. Since fludarabine can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.
There is inadequate data on dosing of patients with renal insufficiency. In patients with renal insufficiency, use caution with fludarabine administration. Patients with moderate impairment of renal function (CrCl 30-70 mL/min/1.73m2) should have their fludarabine dose reduced by 20% and monitored closely. Fludarabine is not recommended for those with severely impaired renal function (CrCl <30 mL/min/1.73m2).
Fludarabine may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women.
If fludarabine is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Nursing Mother Considerations
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fludarabine, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy.
In vitro, plasma protein binding of fludarabine ranged between 19% and 29%.
The terminal half-life of 2-fluoro-ara-A was ~20 hours.
Fludarabine Adverse Reactions
Fludarabine Clinical Trials
Two single-arm open-label studies of fludarabine phosphate for injection have been conducted in adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen.
In a study conducted by MD Anderson Cancer Center (MDAH), 48 patients were treated with a dose of 22-40 mg/m2 daily for 5 days every 28 days. Another study conducted by the Southwest Oncology Group (SWOG) involved 31 patients treated with a dose of 15-25 mg/m2 daily for 5 days every 28 days.
The overall objective response rates were 48% and 32% in the MDAH and SWOG studies, respectively. The complete response rate in both studies was 13%; the partial response rate was 35% in the MDAH study and 19% in the SWOG study. These response rates were obtained using standardized response criteria developed by the National Cancer Institute CLL Working Group 3 and were achieved in heavily pretreated patients.
The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1-68 weeks) and 21 weeks (range of 1-53 weeks) respectively. The median duration of disease control was 91 weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with fludarabine phosphate for injection was 43 weeks and 52 weeks in the MDAH and SWOG studies, respectively.
Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of anemic patients. Similarly, average platelet count improved from 63,500/mm3 to 103,300/mm3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline.
Fludarabine Patient Counseling