Fludarabine - Fludara®
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Preparation of Solutions1
Reconstituted fludarabine phosphate for injection contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared solutions.1
|Stability / Miscellaneous
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-fluoro-ara-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).
Patients with Renal Impairment
INDICATIONS AND USAGE
The effect of chronic administration of fludarabine phosphate for injection on the central nervous system is unknown, however, patients have received the recommended dose for up to 15 courses of therapy.
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate for injection. In a Phase I study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3-25 days) for granulocytes and 16 days (range, 2-32) 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 for injection 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), Evan's syndrome, and acquired hemophilia have been reported to occur after one or more cycles of treatment with fludarabine phosphate for injection 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 for injection 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 for injection should be evaluated and closely monitored for hemolysis. Discontinuation of therapy with fludarabine is recommended in case of hemolysis.
Transfusion-associated graft-versus-host disease has been observed after transfusion of nonirradiated blood in fludarabine phosphate for injection treated patients. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusionassociated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with fludarabine phosphate for injection should receive irradiated blood only.
In a clinical investigation using fludarabine phosphate for injection 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 for injection in combination with pentostatin is not recommended.
Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study. Approximately 50% of the fatalities were due to infection and 25% due to progressive disease.
Pregnancy Category D
Fludarabine phosphate was embryolethal and teratogenic in rats and rabbits. Fludarabine phosphate was administered at doses of 0, 1, 10 or 30 mg/kg/day (0.24, 2.4 times and 7.2 times the recommended human dose on a mg/m2 basis, respectively) to pregnant rats on days 6 to 15 of gestation. At 10 and 30 mg/kg/day administered during organogenesis, there was a dose-related increase in various skeletal variations and a decrease in mean fetal body weights. Maternal toxicity was not apparent at 10 mg/kg/day, and was limited to slight body weight decreases at 30 mg/kg/day. In a dose finding study malformations, such as limb and tail defects, were induced at 40 mg/kg/day (9.6 times the recommended human dose on a mg/m2 basis). In a reproduction toxicity study on rabbits Fludarabine phosphate was administered intravenously at doses of 0, 1, 5 or 8 mg/kg/day (approximately 0.5, 2.4, and 3.8 times the recommended human dose on a mg/m2 basis) on days 6 to 18 of gestation. A dose of 8 mg/kg/day administered during organogenesis increased embryo and fetal lethality as indicated by a higher number of resorptions and a decrease in live fetuses. Compound-related teratogenic effects manifested by external deformities and skeletal malformations were observed at 8 mg/kg/day. The most frequent external malformations observed in rabbits were cleft palate, adactyly, brachydactyly and syndactyly along with skeletal malformations such as fused metatarsals, phalanges, sternebrae and limb bones and some soft tissue malformations (diaphragmatic herniae). Fetal body weights were decreased in rabbits given 8 mg/kg/day.
A number of clinical settings may predispose to increased toxicity from fludarabine phosphate for injection. These include advanced age, renal insufficiency, 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 for injection be administered following the achievement of a maximal response and then the drug should be discontinued.
Reconstituted fludarabine phosphate for injection contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Fludarabine phosphate for injection should not be mixed with other drugs.
Handling and Disposal
Caution should be exercised in the handling and preparation of fludarabine phosphate for injection solution. The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.
Fludarabine phosphate for injection, USP is supplied in a clear glass single dose vial (6 mL capacity) and packaged individually.
NDC Dosage Package
1) [PACKAGE INSERT DATA] : Fludarabine phosphate (Fludarabine Phosphate) injection. [Teva Parenteral Medicines, Inc.] Irvine, CA 92618. Revised: 07/2007.
2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.
Procedures for proper handling and disposal: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165. OSHA Technical Manual, TED 1-0. 15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. https://www.osha.gov/dts/osta/otm/otm_vi_2.html American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006: 63 1172-1193. Polvich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.). Pittsburgh, PA: Oncology Nursing Society