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WARNING: FLUDARA FOR INJECTION should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. FLUDARA FOR INJECTION can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, FLUDARA FOR INJECTION 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/m 2 /day for 5-7 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 FLUDARA FOR INJECTION. Patients undergoing treatment with FLUDARA FOR INJECTION should be evaluated and closely monitored for hemolysis. In a clinical investigation using FLUDARA FOR INJECTION 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 FLUDARA FOR INJECTION in combination with pentostatin is not recommended. |
FLUDARA FOR INJECTION contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-(beta)-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each vial of sterile lyophilized solid cake contains 50 mg of the active ingredient fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2-8.2. Reconstitution with 2 mL of Sterile Water for Injection USP results in a solution containing 25 mg/mL of fludarabine phosphate intended for intravenous administration.
The chemical name for fludarabine phosphate is 9 H -Purin-6-amine, 2-fluoro-9-(5- 0 -phosphono-(beta)-D-arabinofuranosyl).
The molecular formula of fludarabine phosphate is C 10 H 13 FN 5 O 7 P (MW 365.2) and the structure is:
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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. In a study with 4 patients treated with 25 mg/m 2 /day for 5 days, the half-life of 2-fluoro-ara-A was approximately 10 hours. The mean total plasma clearance was 8.9 L/hr/m 2 and the mean volume of distribution was 98 L/m 2 . Approximately 23% of the dose was excreted in the urine as unchanged 2-fluoro-ara-A. The mean C max after the Day 1 dose was 0.57 mcg/mL and after the Day 5 dose was 0.54 mcg/mL. No information is available on pharmacokinetic parameters, other than C max , following the Day 5 dose of 25 mg/m 2 . Total body clearance of 2-fluoro-ara-A has been shown to be inversely correlated with serum creatinine, suggesting renal elimination of the compound.
A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).
Two single-arm open-label studies of FLUDARA FOR INJECTION have been conducted in patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In a study conducted by M.D. Anderson Cancer Center (MDAH), 48 patients were treated with a dose of 22-40 mg/m 2 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/m 2 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 1 and were achieved in heavily pre-treated patients. The ability of FLUDARA FOR INJECTION to induce a significant rate of response in refractory patients suggests minimal cross-resistance with commonly used anti-CLL agents.
The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks) and 21 weeks (range of 1 to 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 FLUDARA 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/mm 3 to 103,300/mm 3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline.
FLUDARA FOR INJECTION is indicated for the treatment of 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 FLUDARA FOR INJECTION in previously untreated or nonrefractory patients with CLL have not been established.
FLUDARA FOR INJECTION is contraindicated in those patients who are hypersensitive to this drug or its components.
(See boxed warning )
There are clear dose dependent toxic effects seen with FLUDARA FOR INJECTION. Dose levels approximately 4 times greater (96 mg/m 2 /day for 5 to 7 days) than that recommended for CLL (25 mg/m 2 /day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients (36%) who received FLUDARA FOR INJECTION at high doses (96 mg/m 2 /day for 5 to 7 days) developed this severe neurotoxicity. This syndrome has been reported rarely in patients treated with doses in the range of the recommended CLL dose of 25 mg/m 2 /day for 5 days every 28 days. The effect of chronic administration of FLUDARA 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 FLUDARA FOR INJECTION. In a Phase I study in 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 FLUDARA FOR INJECTION requires careful hematologic monitoring.
Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with FLUDARA 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 FLUDARA 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 FLUDARA FOR INJECTION should be evaluated and closely monitored for hemolysis.
Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of non-irradiated blood in FLUDARA FOR INJECTION treated patients. Consideration should, therefore, be given to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with FLUDARA FOR INJECTION.
In a clinical investigation using FLUDARA FOR INJECTION 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 FLUDARA FOR INJECTION in combination with pentostatin is not recommended.
Of the 133 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: FLUDARA FOR INJECTION may cause fetal harm when administered to a pregnant woman. Fludarabine phosphate was teratogenic in rats and in rabbits. Fludarabine phosphate was administered intravenously at doses of 0, 1, 10 or 30 mg/kg/day to pregnant rats on days 6 to 15 of gestation. At 10 and 30 mg/kg/day in rats, there was an increased incidence of various skeletal malformations. Fludarabine phosphate was administered intravenously at doses of 0, 1, 5 or 8 mg/kg/day to pregnant rabbits on days 6 to 15 of gestation. Dose-related teratogenic effects manifested by external deformities and skeletal malformations were observed in the rabbits at 5 and 8 mg/kg/day. Drug-related deaths or toxic effects on maternal and fetal weights were not observed. There are no adequate and well-controlled studies in pregnant women.
If FLUDARA FOR INJECTION 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.
General: FLUDARA FOR INJECTION is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed 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 FLUDARA FOR INJECTION treatment has been reported in CLL patients with large tumor burdens. Since FLUDARA FOR INJECTION 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 are inadequate data on dosing of patients with renal insufficiency. FLUDARA FOR INJECTION must be administered cautiously in patients with renal insufficiency. The total body clearance of 2-fluoro-ara-A has been shown to be inversely correlated with serum creatinine, suggesting renal elimination of the compound.
Laboratory Tests: During treatment, the patient' hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression.
Drug Interactions: The use of FLUDARA FOR INJECTION in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity (see section).
Carcinogenesis No animal carcinogenicity studies with FLUDARA FOR INJECTION have been conducted
Mutagenesis Fludarabine phosphate has been shown to be non-mutagenic to several strains of Salmonella typhimurium, including TA-98, TA-100, TA-1535 and TA-1537. In addition, fludarabine phosphate was non-mutagenic to Chinese hamster ovary (CHO) cells at the hypoxanthine-guaninephosphoribosyltransferase (HGPRT) locus under both activated and non-activated metabolic conditions. Chromosomal aberrations were observed in an in vitro assay using CHO cells under metabolically activated conditions. Fludarabine phosphate was determined to cause increased sister chromatid exchanges using an in vitro sister chromatid exchange (SCE) assay under both metabolically activated and non-activated conditions. In addition, fludarabine phosphate has also been shown to be mutagenic as indicated by an increase in the number of micronucleated erythrocyte in the in vivo mouse micronucleus test at doses up to 1000 mg/kg.
Impairment of Fertility: Studies in mice, rats and dogs have demonstrated dose-related adverse effects on the male reproductive system. Observations consisted of a decrease in mean testicular weights in mice and rats with a trend toward decreased testicular weights in dogs and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats and dogs. The possible adverse effects on fertility in humans have not been adequately evaluated.
Pregnancy Pregnancy Category D: (See section)
Nursing Mothers:
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 FLUDARA FOR INJECTION, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.Pediatric Use: The safety and effectiveness of FLUDARA FOR INJECTION in children have not been established.
The most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in CLL patients treated with FLUDARA FOR INJECTION. The most frequently reported adverse events and those reactions which are more clearly related to the drug are arranged below according to body system.
Hematopoietic Systems: Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with FLUDARA FOR INJECTION. During FLUDARA FOR INJECTION treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm 3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Myelosuppression may be severe and cumulative. Bone marrow fibrosis occurred in one CLL patient treated with FLUDARA FOR INJECTION.
Life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur in patients receiving FLUDARA FOR INJECTION (see section). The majority of patients rechallenged with FLUDARA FOR INJECTION developed a recurrence in the hemolytic process.
Metabolic: Tumor lysis syndrome has been reported in CLL patients treated with FLUDARA FOR INJECTION. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria.
Nervous System: (See section) Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in CLL patients treated with FLUDARA FOR INJECTION at the recommended dose. Peripheral neuropathy has been observed in patients treated with FLUDARA FOR INJECTION and one case of wrist-drop was reported.
Pulmonary System: Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16%, and 22% of those treated with FLUDARA FOR INJECTION in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to FLUDARA FOR INJECTION characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed.
Gastrointestinal System: Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding have been reported in patients treated with FLUDARA FOR INJECTION.
Cardiovascular: Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with FLUDARA FOR INJECTION. No other severe cardiovascular events were considered to be drug related.
Genitourinary System: Rare cases of hemorrhagic cystitis have been reported in patients treated with FLUDARA FOR INJECTION.
Skin: Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with FLUDARA FOR INJECTION.
Data in the following table are derived from the 133 patients with CLL who received FLUDARA FOR INJECTION in the MDAH and SWOG studies.
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More than 3000 patients received FLUDARA FOR INJECTION in studies of other leukemias, lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was consistent with the data presented above.
High doses of FLUDARA FOR INJECTION (see ) have been associated with an irreversible central nervous system toxicity characterized by delayed blindness, coma and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for FLUDARA FOR INJECTION overdosage. Treatment consists of drug discontinuation and supportive therapy.
The recommended dose of FLUDARA FOR INJECTION is 25 mg/m 2 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. 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 FLUDARA 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 FLUDARA FOR INJECTION be administered following the achievement of a maximal response and then the drug should be discontinued.
FLUDARA FOR INJECTION should be prepared for parenteral use by aseptically adding Sterile Water for Injection USP. When reconstituted with 2mL of Sterile Water for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2-8.2. In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection USP or 0.9% Sodium Chloride USP.
Reconstituted FLUDARA 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.
Procedures for proper handling and disposal should be considered. Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published. 2-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Caution should be exercised in the handling and preparation of FLUDARA 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.
FLUDARA FOR INJECTION is supplied as a white, lyophilized solid cake. Each vial contains 50 mg of fludarabine phosphate, 50 mg of mannitol and sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2-8.2. Store under refrigeration, between 2°-8°C (36°-46°F).
FLUDARA FOR INJECTION is supplied in a clear glass single dose vial (6mL capacity) and packaged in a single dose vial carton in a shelf pack of five.
CAUTION: Federal law prohibits dispensing without prescription.
NDC 50419-511-06
Manufactured by: Ben Venue Laboratories, Bedford, OH 44146
Manufactured for: Berlex Laboratories, Richmond, CA 94804
U. S. Patent Number: 4,357,324
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6063505 Rev. 1/96