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Fludarabine Injection (Fludarabine Phosphate Injection) - Warnings and Precautions

 
 



WARNING

Fludarabine Phosphate for Injection, USP should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Fludarabine Phosphate for Injection, USP can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, Fludarabine Phosphate for Injection, USP 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, 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.

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, USP. Patients undergoing treatment with Fludarabine Phosphate for Injection, USP should be evaluated and closely monitored for hemolysis.

In a clinical investigation using Fludarabine Phosphate for Injection, USP 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 Phosphate for Injection, USP in combination with pentostatin is not recommended.

 

WARNINGS

(See  BOXED WARNINGS)

There are clear dose dependent toxic effects seen with Fludarabine Phosphate for Injection, USP. 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, USP 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.

The effect of chronic administration of Fludarabine Phosphate for Injection, USP 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, USP. 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, USP 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, USP 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, USP 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, USP 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, USP 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, USP should receive irradiated blood only.

In a clinical investigation using Fludarabine Phosphate for Injection, USP 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, USP 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

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 in pregnant women. Fludarabine phosphate was embryolethal and teratogenic in both rats and rabbits. If Fludarabine Phosphate for Injection, USP 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. Women of childbearing potential and fertile males must take contraceptive measures during and at least for six months after cessation of treatment with Fludarabine Phosphate for Injection, USP.

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.

PRECAUTIONS

General

Fludarabine Phosphate for Injection, USP 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 Fludarabine Phosphate for Injection, USP treatment has been reported in CLL patients with large tumor burdens. Since Fludarabine Phosphate for Injection, USP 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.

In patients with impaired state of health, Fludarabine Phosphate for Injection, USP should be given with caution and after careful risk/benefit consideration. This applies especially for patients with severe impairment of bone marrow function (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency or with a history of opportunistic infection. Prophylactic treatment should be considered in patients at increased risk of developing opportunistic infections.

There are inadequate data on dosing of patients with renal insufficiency. Fludarabine Phosphate for Injection, USP must be administered cautiously in patients with renal insufficiency. The total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have their fludarabine phosphate dose reduced by 20% and be monitored closely. Fludarabine Phosphate for Injection, USP is not recommended for patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).

Fludarabine phosphate may reduce the ability to drive or use machines, since fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.

Laboratory Tests

During treatment, the patient's hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression.

Drug Interactions

The use of Fludarabine Phosphate for Injection, USP in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity (see WARNINGS section).

Carcinogenesis

No animal carcinogenicity studies with Fludarabine Phosphate for Injection, USP have been conducted.

Mutagenesis

Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells (HGRPT assay in Chinese hamster ovary cells) either in the presence or absence of metabolic activation. Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberrations in the presence of metabolic activation) and induced sister chromatid exchanges both with and without metabolic activation. In addition, fludarabine phosphate was clastogenic in vivo (mouse micronucleus assay) but was not mutagenic to germ cells (dominant lethal test in male mice).

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 WARNINGS section).

Nursing Mothers

It is not known whether fludarabine phosphate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions including tumorgenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy. Fludarabine was evaluated in 62 pediatric patients (median age 10, range 1 to 21) with refractory acute leukemia (45 patients) or solid tumors (17 patients). The fludarabine regimen tested for pediatric acute lymphocytic leukemia (ALL) patients was a loading bolus of 10.5 mg/m2/day followed by a continuous infusion of 30.5 mg/m2/day for 5 days. In 12 pediatric patients with solid tumors, dose-limiting myelosuppression was observed with a loading dose of 8 mg/m2/day followed by a continuous infusion of 23.5 mg/m2/day for 5 days. The maximum tolerated dose was a loading dose of 7 mg/m2/day followed by a continuous infusion of 20 mg/m2/day for 5 days. Treatment toxicity included bone marrow suppression. Platelet counts appeared to be more sensitive to the effects of fludarabine than hemoglobin and white blood cell counts. Other adverse events included fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection. There were no reported occurrences of peripheral neuropathy or pulmonary hypersensitivity reaction.

Vaccination

During and after treatment with Fludarabine Phosphate for Injection, USP, vaccination with live vaccines should be avoided.

Disease Progression

Disease progression and transformation (e.g. Richter's syndrome) have been reported in CLL patients.

Page last updated: 2009-02-01

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