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Oforta

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Oforta

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Neurotoxicity

Dose-dependent neurotoxicity has been observed with fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m /day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m2/day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 days to 60 days following the last dose. Thirteen of 36 patients (36.1%) who received fludarabine phosphate intravenously at high doses ( ≥ 96 mg/m2/day for 5 days to 7 days per course) developed severe neurotoxicity, while only one of 443 patients (0.2%) who received the drug intravenously at low doses ( ≤ 40 mg/m2/day for 5 days per course) developed toxicity. In the pivotal clinical study conducted with Oforta™ (fludarabine phosphate tablets) administered at 40 mg/m2, severe impairment of consciousness was reported in one patient. The effect of chronic administration of fludarabine phosphate on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

Bone Marrow Suppression

Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3 days to 25 days) for granulocytes and 16 days (range, 2 days 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 Oforta™ (fludarabine phosphate tablets) 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. One case of pancytopenia was reported in the pivotal clinical study conducted with Oforta™ (fludarabine phosphate tablets) .

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine phosphate 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 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 Oforta™ (fludarabine phosphate tablets) should be evaluated and closely monitored for hemolysis.

Pulmonary Toxicity

A high incidence of fatal pulmonary toxicity was observed in a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults. Therefore, the use of Oforta™ (fludarabine phosphate tablets) in combination with pentostatin is not recommended.

Infections

Of 133 adult patients with CLL who received intravenous fludarabine phosphate in two clinical trials, there were 29 fatalities during study. Approximately 50% of the fatalities were due to infection and 25% due to progressive disease. Of 183 adult patients with CLL that received Oforta™ (fludarabine phosphate tablets) in two clinical trials, there were 13 deaths. Approximately 50% of the deaths were due to progressive disease, while two patient deaths (15%) were attributed to infection. Monitor for signs and symptoms of infection.

Tumor Lysis Syndrome

Tumor lysis syndrome associated with fludarabine phosphate treatment has been reported in patients with CLL with large tumor burdens. Since Oforta™ (fludarabine phosphate tablets) 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.

Use of Transfusions

Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of non-irradiated blood in fludarabine phosphate treated patients. Consideration should, therefore, be given to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with Oforta™ (fludarabine phosphate tablets) .

Renal Impairment

Oforta™ (fludarabine phosphate tablets) must be administered cautiously in patients with renal impairment. Following dosing of the intravenous product, the total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with mild to moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have their Oforta™ (fludarabine phosphate tablets) dose reduced by 20% and be monitored closely. Patients with severe impairment of renal function (creatinine clearance < 30 mL/min/1.73 m2) should have their Oforta™ (fludarabine phosphate tablets) dose reduced by 50% and be monitored closely.

Monitoring

  • Hematologic and Nonhematologic Toxicity

Oforta™ (fludarabine phosphate tablets) is an 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.

  • Hematopoietic Suppression

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

  • Infections

Patients treated with Oforta™ (fludarabine phosphate tablets) appear to be at an increased risk of infection. Monitor for signs and symptoms of infection.

Pregnancy

Based on its mechanism of action, Oforta™ (fludarabine phosphate tablets) can cause fetal harm when administered to a pregnant woman. Fludarabine phosphate administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformation, and decreased fetal body weights. If Oforta™ (fludarabine phosphate tablets) 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 6 months after the cessation of therapy. [see Use in Specific Populations].

Patient Counseling Information

Bone Marrow Suppression

Inform patients that Oforta™ (fludarabine phosphate tablets) decreases blood cell counts such as white blood cells, platelets, and red blood cells. Thus, it is important that periodic assessment of their blood count be performed to detect the development of neutropenia, thrombocytopenia and anemia. [See WARNINGS AND PRECAUTIONS]

Infections

Instruct patients to notify their physician promptly if fever or other signs of infection such as chills, cough, or burning pain on urination occurs while on therapy. [See WARNINGS AND PRECAUTIONS]

Pregnancy

Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy. Oforta™ (fludarabine phosphate tablets) may cause fetal harm when administered to a pregnant woman. [See WARNINGS AND PRECAUTIONS]

Handling and Disposal

Instruct patients that caution should be exercised in the handling of Oforta™ (fludarabine phosphate tablets) . Do not crush tablets. Avoid exposure by direct contact of the skin or mucous membranes or by inhalation. If contact occurs, wash thoroughly with soap and water or wash the eyes immediately with gently flowing water for at least 15 minutes. Consult healthcare provider in case of a skin reaction or if the drug gets in the eyes. Ask your healthcare provider or pharmacist for directions about how to safely dispose of Oforta™ (fludarabine phosphate tablets) .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal carcinogenicity studies with Oforta™ (fludarabine phosphate tablets) have been conducted.

Oforta™ is a clastogen.

Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberration assay) in the presence of metabolic activation and induced sister chromatid exchanges both in the presence and absence of 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). Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells either in the presence or absence of metabolic activation.

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.

Use In Specific Populations

Pregnancy

"Pregnancy Category D. See WARNINGS AND PRECAUTIONS section." Based on its mechanism of action, Oforta™ (fludarabine phosphate tablets) 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 Oforta™ (fludarabine phosphate tablets) 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 6 months after the cessation of therapy.

In rats, repeated intravenous doses of fludarabine phosphate at 1.5 times and 4.5 times the recommended human oral dose (40 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 1.5 times the human oral dose, and was limited to slight body weight decreases at 4.5 times the human oral dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 2.4 times the human oral 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 ( ≥ 0.3 times the human oral dose).

Nursing Mothers

It is not known whether Oforta™ (fludarabine phosphate tablets) 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of 78 previously treated patients with B-CLL treated with Oforta™ (fludarabine phosphate tablets) 50% were ≥ age 65 and 3% were ≥ age 75. The response rate was generally lower among patients age 65 and older. Among previously treated patients (Study 1) age 65 and older, the overall objective response, according to standardized response criteria developed by the National Cancer Institute CLL Working Group (NCI criteria), was 41%. The safety profile among younger and older patients on study was similar. Other reported clinical experience has not identified differences in responses or safety between older and younger patients.

Patients with Renal Impairment

In patients receiving intravenous fludarabine phosphate, the total body clearance of the metabolite 2-fluoro-ara-adenine (2F-ara-A) correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represented approximately 40% of the total body clearance. Patients with mild to moderate renal impairment (30 to 70 mL/min/1.73 m2) receiving 20% reduced fludarabine phosphate dose had a similar exposure compared to patients with normal renal function receiving the recommended dose (AUC; 21 nM»h/mL versus 20 nM»h/mL). Two patients with severe renal impairment ( < 30 mL/min/1.73 m ) receiving 40% reduced fludarabine phosphate dose had a 40% increase in exposure compared to patients with normal renal function receiving the recommended dose. The mean total body clearance was 172 mL/min for patients with normal renal function, 124 mL/min for patients with mild to moderately impaired renal function, and 71 mL/min for the two patients with severe renal impairment.

Last reviewed on RxList: 8/5/2009
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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