"The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
CLL is a blood and bone ma"...
(See BOXED WARNINGS)
Dose Dependent Neurologic Toxicities
There are clear dose-dependent toxic effects seen with FLUDARA (fludarabine) 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 FLUDARA (fludarabine) 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 FLUDARA (fludarabine) FOR INJECTION on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy.
Bone Marrow Suppression
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with FLUDARA (fludarabine) 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 FLUDARA (fludarabine) 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 FLUDARA (fludarabine) 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 (fludarabine) 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 (fludarabine) FOR INJECTION should be evaluated and closely monitored for hemolysis. Discontinuation of therapy with FLUDARA (fludarabine) FOR INJECTION is recommended in case of hemolysis.
Transfusion Associated Graft-Versus-Host Disease
Transfusion-associated graft-versus-host disease has been observed after transfusion of nonirradiated blood in FLUDARA (fludarabine) 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 FLUDARA (fludarabine) FOR INJECTION should receive irradiated blood only.
In a clinical investigation using FLUDARA (fludarabine) 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 FLUDARA (fludarabine) FOR INJECTION in combination with pentostatin is not recommended.
Pregnancy Category D
Based on its mechanism of action, fludara (fludarabine) bine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of FLUDARA FOR INJECTION in pregnant women. Fludara (fludarabine) bine administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformations and decreased fetal body weights. If FLUDARA (fludarabine) 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.
Male Fertility and Reproductive Outcomes
Males with female sexual partners of childbearing potential should use contraception during and after cessation of FLUDARA FOR INJECTION therapy. Fludara (fludarabine) bine 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]
FLUDARA (fludarabine) 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.
In patients with impaired state of health, FLUDARA (fludarabine) FOR INJECTION 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.
FLUDARA (fludarabine) FOR INJECTION may reduce the ability to drive or use machines, since fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.
Tumor Cell Lysis
Tumor lysis syndrome has been associated with FLUDARA (fludarabine) FOR INJECTION treatment. This syndrome has been reported in CLL patients with large tumor burden. Since FLUDARA (fludarabine) 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.
FLUDARA (fludarabine) FOR INJECTION must be administered cautiously in patients with renal impairment. The total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with creatinine clearance 30-79 mL/min should have their FLUDARA (fludarabine) FOR INJECTION dose reduced and be monitored closely for excessive toxicity. FLUDARA (fludarabine) FOR INJECTION should not be administered to patients with creatinine clearance less than 30 mL/min. (See DOSAGE AND ADMINISTRATIONsection).
In patients aged 65 years or older, creatinine clearance should be measured before start of treatment.
During treatment, the patient's hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression.
No animal carcinogenicity studies with FLUDARA (fludarabine) FOR INJECTION have been conducted.
Fludara (fludarabine) bine 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. Fludara (fludarabine) bine 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, fludara (fludarabine) bine 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 Category D
(see WARNINGS section).
Based on its mechanism of action, fludara (fludarabine) bine phosphate can cause fetal harm when administered to a pregnant woman. There are not adequate and well-controlled studies of fludarabine phosphate in pregnant women. Fludara (fludarabine) bine phosphate was embryolethal and teratogenic in rats and rabbits. If FLUDARA (fludarabine) 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.
In rats, repeated intravenous doses of fludara (fludarabine) bine phosphate at 2.4 times and 7.2 times the recommended human IV dose (25 mg/m²) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 2.4 times the human IV dose, and was limited to slight body weight decreases at 7.2 times the human IV dose. In rabbits, repeated intravenous doses of fludara (fludarabine) bine phosphate at 3.8 times the human IV dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels ( ≥ 0.5 times the human IV dose).
It is not known whether fludara (fludarabine) bine phosphate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions including tumorigenicity 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.
Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy. FLUDARA (fludarabine) FOR INJECTION was evaluated in 62 pediatric patients (median age 10, range 1-21) with refractory acute leukemia (45 patients) or solid tumors (17 patients). The FLUDARA (fludarabine) FOR INJECTION 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 FLUDARA (fludarabine) FOR INJECTION 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.
During and after treatment with FLUDARA (fludarabine) FOR INJECTION, vaccination with live vaccines should be avoided.
Richter's syndrome has been reported in CLL patients.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 8/18/2010
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