FLUDARABINE - fludarabine phosphate injection, solution
APP Pharmaceuticals, LLC
Fludarabine Phosphate Injection
FOR INTRAVENOUS USE ONLY
Rx only
WARNING
Fludarabine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Fludarabine can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, fludarabine was associated with severe neurologic effects, including blindness, coma, and death. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m2/day for 5 to 7 days) than the recommended dose. Similar severe central nervous system toxicity has been rarely (0.2%) reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.
Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine. Patients undergoing treatment with fludarabine should be eva luated and closely monitored for hemolysis.
In a clinical investigation using fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended.
DESCRIPTION
Fludarabine Phosphate Injection contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-ß-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each mL contains 25 mg of the active ingredient fludarabine phosphate, 25 mg of mannitol, water for injection, qs; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0–7.1. Fludarabine Phosphate Injection is a sterile solution intended for intravenous administration.
The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-ß-D-arabinofuranosyl) (2-fluoro-ara-AMP). The structure is:
CLINICAL PHARMACOLOGY
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.
Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara- A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoroara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro, plasma protein binding of fludarabine ranged between 19% and 29%.
A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).
Special Populations
Pediatric Patients
Limited pharmacokinetic data for fludarabine phosphate for injection are available from a published study of children (ages 1 to 21 years) with refractory acute leukemias or solid tumors (Children’s Cancer Group Study 097). When fludarabine phosphate for injection was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.
Patients with Renal Impairment
The 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 moderate renal impairment (17 to 41 mL/min/m2) receiving 20% reduced fludarabine dose had a similar exposure (AUC; 21 versus 20 nM•h/mL) compared to patients with normal renal function receiving the recommended dose. The mean total body clearance was 172 mL/min for normal and 124 mL/min for patients with moderately impaired renal function.
Clinical Studies
Two single-arm open-label studies of fludarabine have been conducted in adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In
