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Questions & Answers
Side Effects & Adverse Reactions
(See BOXED WARNINGS )
There are clear dose-dependent toxic effects seen with fludarabine phosphate for injection. Dose levels approximately 4 times greater (96 mg/m2/day for 5 to 7 days) than that recommended for CLL (25 mg/m2/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 fludarabine phosphate for injection at high doses (96 mg/m2/day for 5 to 7 days) developed this severe neurotoxicity. Similar severe central nervous system toxicity, including coma, seizures, agitation and confusion, has been reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.
In postmarketing experience neurotoxicity has been reported to occur either earlier or later than in clinical trials (range 7 to 225 days).
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 to 25 days) for granulocytes and 16 days (range, 2 to 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), Evans 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 non-irradiated 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 transfusion-associated 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.
Based on its mechanism of action, fludarabine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of fludarabine phosphate for injection in pregnant women. Fludarabine administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformations and decreased fetal body weights. If fludarabine phosphate 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.
Males with female sexual partners of childbearing potential should use contraception during and after cessation of fludarabine phosphate for injection therapy. Fludarabine may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain. [See PRECAUTIONS, Impairment of Fertility]
Legal Issues
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FDA Safety Alerts
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Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
Fludarabine Phosphate for Injection USP 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 for injection in previously untreated or non-refractory patients with CLL have not been established.
History
There is currently no drug history available for this drug.
Other Information
Fludarabine Phosphate for Injection USP contains fludarabine phosphate, USP, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-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, USP, 50 mg of mannitol, USP, and sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2 to 8.2. Reconstitution with 2 mL of Sterile Water for Injection, USP results in a solution containing 25 mg/mL of fludarabine phosphate, USP, intended for intravenous administration.
The chemical name for fludarabine phosphate, USP is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-β-D-arabino-furanosyl) (2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate, USP is C10H13FN5O7P (MW 365.2) and the structure is:
Sources
V-max Manufacturers
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Phibro Animal Health
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V-max | Teva Parenteral Medicines, Inc.
Usual DoseThe recommended adult dose of fludarabine phosphate for injection 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. 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 for 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 for injection be administered following the achievement of a maximal response and then the drug should be discontinued.
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 for injection should not be administered to patients with creatinine clearance less than 30 mL/min.
Starting Dose Adjustment for Renal Impairment
Creatinine Clearance
Starting 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.
Preparation of SolutionsFludarabine phosphate for injection 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, 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 to 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 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 DisposalProcedures 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. 1-4
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.
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