Fludara (Fludarabine)

FLUDARA®

Berlex Canada

Fludarabine Phosphate

Antineoplastic

Action And Clinical Pharmacology: Fludarabine is a fluorinated analog of adenine that is relatively resistant to deamination by adenosine deaminase.

Fludarabine (2F-ara-AMP) is rapidly dephosphorylated to 2-fluoro-ara-A (2F-ara-A) and then phosphorylated intracellularly by deoxycytidine kinase to the active 2-fluoro-ara-ATP (2F-ara-ATP). The antitumor activity of this metabolite is the result of inhibition of DNA synthesis via inhibition of ribonucleotide reductase and DNA polymerase a. Maximum 2F-ara-ATP levels in leukemic lymphocytes of chronic lymphocytic leukemia (CLL) patients were observed at a median of 4 hours and exhibited a considerable variation. 2F-ara-ATP levels in leukemic cells were always considerably higher than maximum 2F-ara-A levels in the plasma, indicating an accumulation at the target sites. 2F-ara-ATP elimination from CLL target cells likewise showed a considerable scattering with a median half-life of approximately 23 hours.

Clinical pharmacology studies have focused on 2F-ara-A pharmacokinetics in plasma. After doses of fludarabine phosphate of 80 to 260 mg/m and with sampling continuing for 30 hours, elimination of 2F-ara-A was characterized as triphasic with calculations of an initial half-life (t1/2) of 5.4 minutes, an intermediate half-life (t1/2) of 1.4 hours and a terminal half-life (t1/2) of 10.2 hours. Other studies, in which sampling was performed for up to 72 hours, gave comparable initial and intermediate half-lives, but revealed a 2F-ara-A terminal half-life of up to 31 hours.

In patients receiving 20 to 125 mg/mof fludarabine as an i.v. infusion the area under the concentration-time curve for 2F-ara-A was directly related to the dose of fludarabine given. In addition, the terminal half-life was approximately the same (8 hours) for all dose levels, indicating dose-independent elimination in this dose range.

The mean steady-state volume of distribution (Vdss) of 2F-ara-A in one study was 96 L/msuggesting a significant degree of tissue binding. Another study, in which Vdss for patients was determined to be 44 L/m supports the suggestion of tissue binding.

Based upon compartmental analysis of pharmacokinetic data, the rate-limiting step for excretion of 2F-ara-A from the body appears to be release from tissue binding sites. Total body clearance of 2F-ara-A has been shown to be inversely correlated with serum creatinine, suggesting renal elimination of the compound.

Two open-label studies of fludarabine have been conducted in patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. Overall objective response rates were 32% in one study, and 48% in the other, with median time to response at 21 and 7 weeks respectively.

Indications And Clinical Uses: The use of fludarabine should be restricted to second line therapy in patients with CLL who have failed other conventional therapies. Such patients should be treated by well-trained oncologists skilled in the use of chemotherapeutic agents.

Contra-Indications: In those patients who are hypersensitive to this drug or its components.

Manufacturers’ Warnings In Clinical States: 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 irreversible neurologic effects, including blindness, coma and death.

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur during or after treatment with fludarabine. The causality of the development of this complication has not been identified. Patients undergoing treatment with fludarabine should be evaluated and closely monitored for signs of autoimmune hemolytic anemia (decline in hemoglobin linked with hemolysis and a positive Coombs’ test). Discontinuation of therapy with fludarabine is recommended in the event of hemolysis. The transfusion of irradiated blood and the administration of adrenocorticoid preparations are the most common treatment measures for autoimmune hemolytic anemia.

In a clinical investigation using fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory CLL, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended.

When high doses of fludarabine were administered in dose-ranging studies in acute leukemia patients, a syndrome with delayed onset, characterized by blindness, coma, and death was identified. Symptoms appeared from 21 to 60 days post dosing. Demyelination, especially of the occipital cortex of the brain was noted. The majority of these cases occurred in patients treated with doses approximately four times greater (96 mg/mday for 5 to 7 days) than the recommended dose. Thirteen of 36 patients (36.1%) who received fludarabine at high doses (96 mg/mday for 5 to 7 days/course) developed severe neurotoxicity, while only one of 443 patients (0.2%) who received the drug at low doses (40 mg/mday for 5 days/course) developed the toxicity. The effect of chronic administration of fludarabine on the central nervous system is unknown. Periodic neurological assessments are recommended.

Bone marrow suppression, notably thrombocytopenia, anemia, leukopenia and neutropenia, may occur with administration of fludarabine and requires careful hematologic monitoring. In a Phase I study in 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 requires careful hematologic monitoring.

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur during or after 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. Steroids may or may not be effective in controlling these hemolytic episodes. One study was performed with 31 patients with hemolytic anemia related to the administration of fludarabine. Since the majority (90%) of these patients rechallenged with fludarabine developed a recurrence in the hemolytic process, rechallenge with fludarabine should be avoided. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with fludarabine should be evaluated and closely monitored for signs of autoimmune hemolytic anemia (decline in hemoglobin linked with hemolysis and a positive Coombs’ test). Discontinuation of therapy with fludarabine is recommended in the event of hemolysis. The transfusion of irradiated blood and the administration of adrenocorticoid preparations are the most common treatment measures for autoimmune hemolytic anemia.

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.

Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with fludarabine. Fatal outcome as a consequence of this disease has been reported with a high frequency. Therefore, patients who require blood transfusion and who are undergoing, or who have received treatment with fludarabine should receive irradiated blood only.

There are inadequate data on dosing of patients with renal insufficiency. Fludarabine must be administered cautiously in patients with renal insufficiency. It is recommended that the fludarabine dose should be reduced by up to 50% for patients with a creatinine clearance between 30 and 70 mL/min, and close hematologic monitoring should be used to assess toxicity.

Pregnancy: Safe use of fludarabine in pregnancy has not been established. Fludarabine has been shown to be teratogenic in rats and in rabbits. A study in rats demonstrated a transfer of fludarabine and/or metabolites across the placental barrier. Therefore, the benefits to the pregnant patient should be carefully weighed against the potential toxicity to the fetus.

Precautions: General: Fludarabine 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 neutropenia, thrombocytopenia, anemia and leukopenia.

Laboratory Tests: During treatment, the patient’s hematologic (particularly neutrophils and platelets) and serum chemistry profiles should be monitored regularly.

Drug Interactions: In a clinical investigation using fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory CLL, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended.

Impairment of Fertility: Preclinical toxicology 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 dogs and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats and dogs. The possible adverse effects on fertility in males and females in humans have not been adequately evaluated. Therefore, it is recommended that females of child-bearing potential and males take contraceptive measures during fludarabine therapy, and for at least 6 months after the cessation of fludarabine therapy.

Lactation: It is not known whether fludarabine is excreted in human milk. However, there is evidence from animal data that fludarabine and/or metabolites transfer from maternal blood to milk. Therefore, breast-feeding is not recommended during fludarabine therapy.

Children: The safety and effectiveness of fludarabine in children have not been established.

Geriatrics: Since there are limited data for the use of fludarabine in elderly persons (>75 years), caution should be exercised with the administration of fludarabine in these patients. The total body clearance of the principal plasma metabolite 2F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced kidney function demonstrated an increased total body exposure (AUC of 2F-ara-A). Limited clinical data are available in patients with impairment of renal function (creatinine clearance below 70 mL/min). Since renal impairment is frequently present in patients over the age of 70 years, creatinine clearance should be measured. If creatinine clearance is between 30 and 70 mL/min, the dose should be reduced by up to 50%, and close hematologic monitoring should be used to assess toxicity (see Warnings and Dosage).

Adverse Reactions: The most common adverse events occurring with fludarabine use include myelosuppression (anemia, leukopenia, neutropenia and thrombocytopenia), fever and chills, decreased resistance to infection, and nausea and vomiting. Other events reported include malaise, fatigue, anorexia, weakness and edema.

Hematopoietic: Myelosuppression and anemia have been reported in patients treated with fludarabine. Myelosuppression may be severe and cumulative. Life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur in patients receiving fludarabine. The majority of patients rechallenged with fludarabine developed a recurrence in the hemolytic process. (See Warnings for information on autoimmune hemolytic anemia associated with fludarabine).

Nervous System: Following administration of fludarabine at doses of 20 to 30 mg/mday in 133 patients with CLL, reported events included weakness, visual disturbances, loss of hearing, numbness, agitation, confusion and coma. There was one case of peripheral neuropathy and one case of wrist drop. (See Warnings for the information on neurotoxicity associated with high doses of fludarabine).

Pulmonary: Pneumonia, cough and shortness of breath have all been reported. Pneumonia, a frequent manifestation of infection in CLL patients occurred in 16 and 22% of those treated with fludarabine in the MDACC and SWOG studies, respectively. Pulmonary hypersensitivity reactions to fludarabine characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed.

Gastrointestinal: Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding have been reported in patients treated with fludarabine.

Skin: Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with fludarabine. Additionally, in rare cases, a toxic epidermal necrolysis (Lyell’s disease) may develop.

Cardiovascular: Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine. No other severe cardiovascular events were considered to be drug related.

Genitourinary: Rare cases of hemorrhagic cystitis.

Metabolic: Tumor lysis syndrome has been reported in CLL patients treated with fludarabine. This complication may include hyperuricaemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria. Changes of hepatic and pancreatic enzymes are possible.

The spectrum of adverse reactions reported in patients (n=3 000) receiving fludarabine in studies of lymphomas and other leukemias and solid tumors is consistent with the above data.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: High doses of fludarabine have been associated with an irreversible CNS toxicity characterized by delayed blindness, coma and death. High doses are also associated with bone marrow suppression manifested by thrombocytopenia and neutropenia. There is no known specific antidote for fludarabine overdosage. Treatment consists of drug discontinuation and supportive therapy.

Dosage And Administration: Usual Dose: The usual starting dose is 25 mg/madministered i.v. over a period of approximately 30 minutes, daily for 5 days every 28 days. Dosage may be decreased based on evidence of hematologic or nonhematologic toxicity.

Fludarabine should be prepared for parenteral use by aseptically adding Sterile Water for Injection USP. When reconstituted with 2 mL of Sterile Water for Injection USP, each mL of the resulting solution will contain 25 mg of fludarabine phosphate. The product may be further diluted for i.v. administration to a concentration of 1 mg/mL in 5% Dextrose Injection USP, or in 0.9% Sodium Chloride Injection USP.

Note that in patients with decreased renal function (creatinine clearance between 30 and 70 mL/min), the dose should be reduced by up to 50% (see Warnings).

The optimal duration of treatment has not been clearly established. It is recommended that 3 additional cycles of fludarabine be administered following the achievement of a maximal response and then the drug should be discontinued.

Stability and Storage: Store under refrigeration at 2 to 8°C. Fludara contains no antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. It is recommended to discard unused solutions 8 hours after reconstitution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Fludarabine should be prepared for parenteral use by aseptically adding Sterile Water for Injection USP. When reconstituted with 2 mL of Sterile Water for Injection USP, each mL of the resulting solution will contain 25 mg of fludarabine, 25 mg of mannitol and 3 mg of sodium. The pH range of the final solution is 7.2 to 8.2.

The product may be further diluted for i.v. administration to a concentration of 1 mg/mL in 5% Dextrose Injection USP, or in 0.9% Sodium Chloride Injection USP.

Incompatibilities: There are no known incompatibilities.

Handling and Disposal: Fludarabine should not be handled by pregnant staff. Proper handling and disposal procedures should be observed, with consideration given to the guidelines used for cytotoxic drugs. Any spillage or waste material may be disposed of by incineration.

Caution should be exercised in the preparation of the fludarabine 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 comes into contact with the skin or mucous membranes, the area should be washed thoroughly with soap and water. In the event of contact with the eyes, rinse them thoroughly with copious amounts of water. Exposure by inhalation should be avoided.

Availability And Storage: Each 6 mL vial of sterile lyophilized solid cake or powder contains: fludarabine phosphate sodium equivalent to fludarabine phosphate 50 mg. Nonmedicinal ingredients: mannitol and sodium. For i.v. administration. Single vial carton, packs of 5.

FLUDARA® Berlex Canada Fludarabine Phosphate Antineoplastic

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