Fludarabine Phosphate - Fludarabine Phosphate injection, Solution Prescribing Information
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a Phase I study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of fludarabine phosphate requires careful hematologic monitoring.
Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients.
Instances of life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur after one or more cycles of treatment with fludarabine phosphate 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. Steroids may or may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with fludarabine phosphate should be evaluated and closely monitored for hemolysis. Discontinuation of therapy with fludarabine phosphate is recommended in case of hemolysis.
In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine phosphate in combination with pentostatin is not recommended.
Fludarabine Phosphate Injection is a nucleotide metabolic inhibitor indicated for:
- The treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. Benefit in treatment-naïve or non-refractory CLL patients is not established. ()
1.1 IndicationFludarabine Phosphate Injection is indicated for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. The safety and effectiveness of Fludarabine Phosphate Injection in previously untreated or non-refractory patients with CLL have not been established.
- The recommended adult dose is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days. Each 5 day course of treatment should commence every 28 days. ()
2.1 Recommended DoseThe recommended adult dose of fludarabine phosphate injection is 25 mg/m2administered intravenously over a period of approximately 30 minutes daily for five consecutive days. Each 5-day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.
A number of clinical settings may predispose to increased toxicity from fludarabine phosphate injection. These include advanced age, renal impairment, and bone marrow impairment. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.
The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of fludarabine phosphate injection be administered following the achievement of a maximal response and then the drug should be discontinued.
- Reduce dose in patients with creatinine clearance 30 to 70 mL/min/l.73m2. Do not use in patients with severe renal impairment ().
2.2 Renal ImpairmentAdjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30 to 79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludarabine phosphate injection should not be administered to patients with creatinine clearance less than 30 mL/min.
Starting Dose Adjustment for Renal ImpairmentCreatinine ClearanceStarting Dose≥ 80 mL/min 25 mg/m2(full dose) 50 to 79 mL/min 20 mg/m2 30 to 49 mL/min 15 mg/m2 < 30 mL/min Do not administer Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.
Fludarabine Phosphate Injection, USP is supplied as a 50 mg per 2 mL (25 mg per mL) sterile solution.
- Renal Impairment: Fludarabine phosphate should not be used in patients with creatinine clearance < 30 mL/min/1.73m2. For patients with creatinine clearance 30 to 70 mL/min/1.73m2, reduce the dose (,
2.2 Renal ImpairmentAdjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30 to 79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludarabine phosphate injection should not be administered to patients with creatinine clearance less than 30 mL/min.
Starting Dose Adjustment for Renal ImpairmentCreatinine ClearanceStarting Dose≥ 80 mL/min 25 mg/m2(full dose) 50 to 79 mL/min 20 mg/m2 30 to 49 mL/min 15 mg/m2 < 30 mL/min Do not administer Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.
,5.9 Renal ImpairmentFludarabine phosphate must be administered cautiously in patients with renal impairment. The total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with creatinine clearance 30 to 79 mL/min should have their fludarabine phosphate dose reduced and be monitored closely for excessive toxicity. Fludarabine phosphate should not be administered to patients with creatinine clearance less than 30 mL/min
[see Dosage and Administration and Use in Specific Populations ].In patients aged 65 years or older, creatinine clearance should be measured before start of treatment.
)8.6 Patients with Renal ImpairmentThe total body clearance of the principal metabolite 2-fluoro-ara-A correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represents approximately 40% of the total body clearance. Patients with creatinine clearance 30 to 79 mL/min should have their fludarabine phosphate dose reduced and be monitored closely for excessive toxicity. Due to insufficient data, fludarabine phosphate should not be administered to patients with creatinine clearance less than 30 mL/min
[see Dosage and Administration , Warnings and Precautions ].
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