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FLUDARABINE PHOSPHATEtablet, film coated

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use FLUDARABINE PHOSPHATEsafely and effectively. See full prescribing information for FLUDARABINE PHOSPHATE.
FLUDARABINE PHOSPHATEtablet, film coated for oraluse Initial U.S. Approval:1991
WARNING: CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY See full prescribing information for complete boxed warning. Severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m2/day for 5 days to 7 days) than the recommended intravenous dose. This toxicity was seen in ≤0.2% of patients treated at the recommended intravenous dose levels (25 mg/m2). (5.1) Life-threatening and sometimes fatal autoimmune hemolytic anemia has been reported after one or more cycles of treatment. (5.2) High incidence of fatal pulmonary toxicity was observed in a clinical investigation of the combination of fludarabine phosphate with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL). (5.3)
INDICATIONS AND USAGE
Fludarabine phosphate is a nucleotide metabolic inhibitor indicated as a single agent for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) whose disease has not responded to or has progressed during or after treatment with at least one standard alkylating-agent containing regimen. Studies demonstrating clinical benefit such as prolongation of survival or relief of symptoms have not been performed. A direct comparison of the clinical efficacy and safety of orally administered fludarabine phosphate relative to intravenously administered fludarabine phosphate has not been studied. (1)
DOSAGE AND ADMINISTRATION
Note: The oral dose is different than the intravenous dose. Chronic Lymphocytic Leukemia (CLL) (2.1): The recommended adult dose is 40 mg/m2 administered daily for five consecutive days by the oral route. Begin each 5-day course of treatment every 28 days. Renal Impairment (2.2): Reduce dose by 20% in patients with mild to moderate renal impairment (creatinine clearance 30 to 70 mL/min/1.73 m2). Reduce dose by 50% in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2)
DOSAGE FORMS AND STRENGTHS
10 milligram film-coated tablets. (see 3)
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia. Monitor blood counts before and during treatment. (5.2) Infections. Monitor for signs or symptoms of infection. (5.3) Tumor lysis syndrome. Take precautions for patients at high risk. (5.4) Transfusion-associated graft-versus-host disease. Use only irradiated blood products for transfusions. (5.6) Fludarabine phosphate dose should be adjusted in patients with mild to moderate (creatinine clearance 30 to 70 mL/min/1.73 m2) or severe (creatinine clearance < 30 mL/min/1.73 m2) renal impairment. (5.7) Fetal harm may occur when administered to a pregnant woman. Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy. (5.9)
ADVERSE REACTIONS
Most common adverse reactions (incidence > 30%) include myelosuppression (neutropenia, thrombocytopenia and anemia). Fever, weakness, infection, pain, cough and anorexia were also reported as common adverse reactions. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Antisoma Research Limited at1-866-949-7420or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
Fludarabine phosphate in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity. (5.3 and 7.1)
See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide
Revised: 02/2009

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FULL PRESCRIBING INFORMATION: CONTENTS*

*Sections or subsections omitted from the full prescribing information are not listed

WARNING: CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Chronic Lymphocytic Leukemia (CLL)

2.2 Renal Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Neurotoxicity

5.2 Bone Marrow Suppression

5.3 Pulmonary Toxicity

5.4 Infections

5.5 Tumor Lysis Syndrome

5.6 Use of Transfusions

5.7 Renal Impairment

5.8 Monitoring

5.9 Pregnancy

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post Marketing Experience

7 DRUG INTERACTIONS

7.1 Pentostatin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Bone Marrow Suppression

17.2 Infections

17.3 Pregnancy

17.4 Handling and Disposal

FULL PRESCRIBING INFORMATION

WARNING: CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY

Severe neurologic effects, including blindness, coma, and death were observed in dose-ranging studies in patients with acute leukemia when fludarabine phosphate was administered at high doses. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m2/day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m2/day). Similar severe central nervous system toxicity has been rarely (≤0.2%) reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia. [See Warnings and Precautions (5.1)] Periodic neurological assessments are recommended.

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported after one or more cycles of treatment with fludarabine phosphate. Patients undergoing treatment with fludarabine phosphate should be eva luated and closely monitored for hemolysis. [See Warnings and Precautions (5.2)]

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). Therefore, the use of fludarabine phosphate in combination with pentostatin is not recommended [See Warnings and Precautions (5.3)]

1 INDICATIONS AND USAGE

Fludarabine phosphate is indicated as a single agent for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) whose disease has not responded to or has progressed during or after treatment with at least one standard alkylating-agent containing regimen. Studies demonstrating clinical benefit such as prolongation of survival or relief of symptoms have not been performed. Studies providing a direct comparison of the clinical efficacy and safety of orally administered fludarabine phosphate relative to intravenously administered fludarabine phosphate have not been performed.