Fludarabine Phosphate (Page 4 of 5)

7 DRUG INTREACTIONS

7.1 Pentostatin

The use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended due to the risk of fatal pulmonary toxicity [see Warnings and Precautions (5.5)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

[See Warnings and Precautions (5.6)].

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 Injection in pregnant women. In rats, repeated intravenous doses of fludarabine phosphate at 2.4 times and 7.2 times the recommended human intravenous dose (25 mg/m 2) 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 intravenous dose, and was limited to slight body weight decreases at 7.2 times the human intravenous dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 3.8 times the human intravenous 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 intravenous dose). If this drug 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.

8.3 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 tumorigenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric Use

Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy.

Fludarabine phosphate was evaluated in 62 pediatric patients (median age 10, range 1 to 21) with refractory acute leukemia (45 patients) or solid tumors (17 patients). Limited pharmacokinetic data for fludarabine phosphate are available in children (ages 1 to 21 years). When fludarabine phosphate was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.

The fludarabine phosphate regimen tested for pediatric lymphocytic leukemia (ALL) patients was a loading bolus of 10.5 mg/m 2 /day followed by a continuous infusion of 30.5 mg/m 2 /day for 5 days. In 12 pediatric patients with solid tumors, dose-limiting myelosuppression was observed with a loading dose of 8 mg/m 2 /day followed by a continuous infusion of 23.5 mg/m 2 /day for 5 days. The maximum tolerated dose was a loading dose of 7 mg/m 2 /day followed by a continuous infusion of 20 mg/m 2 /day for 5 days. Treatment toxicity included bone marrow suppression. Platelet counts appeared to be more sensitive to the effects of fludarabine phosphate 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.

8.6 Patients with Renal Impairment

The total body clearance of the principal metabolite 2-fluoro-ara-A correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represents approximately 40% of the total body clearance. Patients with creatinine clearance 30 to 79 mL/min should have their fludarabine phosphate dose reduced and be monitored closely for excessive toxicity. Due to insufficient data, fludarabine phosphate should not be administered to patients with creatinine clearance less than 30 mL/min [see Dosage and Administration (2.2), Warnings and Precautions (5.9)].

10 OVERDOSAGE

High doses of fludarabine phosphate [see Warnings and Precautions (5)] have been associated with an irreversible central nervous system toxicity characterized by delayed blindness, coma and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for fludarabine phosphate overdosage. Treatment consists of drug discontinuation and supportive therapy.

11 DESCRIPTION

Fludarabine Phosphate Injection contains fludarabine phosphate, a nucleotide metabolic inhibitor. Fludarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9- ß -D-arabinofuranosyladenine (ara-A), that is relatively resistant to deamination by adenosine deaminase.

The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0- phosphono- ß -D-arabinofuranosyl)(2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is C 10 H 13 FN 5 O 7 P (MW 365.2) and the structure is provided in Figure 1.

Figure 1: Chemical Structure of Fludarabine Phosphate

Chemical Structure

Each mL contains 25 mg of the active ingredient fludarabine phosphate, 25 mg of mannitol, water for injection, q.s.; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0 to 7.1. Fludarabine Phosphate Injection is a sterile solution intended for intravenous administration.

12 CLINICAL PHARMACOLOGY

12 Mechanism of Action

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

12.3 Pharmacokinetics

Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoroara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro , plasma protein binding of fludarabine ranged between 19% and 29%. A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal carcinogenicity studies with fludarabine have been conducted.

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). 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.

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 [see Warnings and Precautions (5.7)].

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