Fludarabine Phosphate (Page 3 of 5)

6.2 Post Marketing Experience

The following adverse reactions have been identified during post approval use of oral fludarabine phosphate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possibly to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematopoietic Systems

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in post-marketing surveillance. 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.

Nervous System

In post-marketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or concurrent chemotherapy. The median time to onset was approximately one year.

Pulmonary System

In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate use which resulted in acute respiratory distress syndrome, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure. After exclusion of an infectious origin, some patients experienced symptom improvement with corticosteroids.

7 DRUG INTERACTIONS

7.1 Pentostatin

The use of fludarabine phosphate in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity. [See Warnings and Precautions (5.6)]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

“Pregnancy Category D. See Warnings and Precautions section.”

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 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).

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 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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of 78 previously treated patients with B-CLL treated with oral fludarabine phosphate 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.

8.6 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 m2) 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.

10 OVERDOSAGE

High doses of fludarabine phosphate [See Indications and Usage (1.1) and Warnings and Precautions (5.1)] 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. In Study 2, two patients ingested an overdose of 20% to 33% of oral fludarabine phosphate. No serious side effects were reported.

11 DESCRIPTION

The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-ß-D-arabinofuranosyl)(2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is C10 H13 FN5 O7 P (MW 365.2) and the structure is provided in Figure 1

Image from Drug Label Content
(click image for full-size original)

Fludarabine phosphate film-coated tablets for oral administration contain fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-beta -D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each tablet contains 10 mg of the active ingredient fludarabine phosphate. The tablet core consists of microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, croscarmellose sodium and magnesium stearate. The film-coat contains hypromellose, talc, titanium dioxide (E171) and ferric oxide pigment (red/E172, yellow/E172).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fludarabine phosphate (2F-ara-AMP) is a synthetic purine nucleotide antimetabolite agent. Upon administration, 2F-ara-AMP is rapidly dephosphorylated in the plasma to 2F-ara-A, which then enters into the cell. Intracellularly, 2F-ara-A is converted to the 5′-triphosphate, 2-fluoro-ara-ATP (2F-ara-ATP). 2F-ara-ATP competes with deoxyadenosine triphosphate for incorporation into DNA. Once incorporated into DNA, 2F-ara-ATP functions as a DNA chain terminator, inhibits DNA polymerase alpha, gamma, and delta, and inhibits ribonucleoside diphosphate reductase. 2F-ara-A also inhibits DNA primase and DNA ligase I. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a randomized, uncontrolled, open-label, parallel study, patients with B-cell CLL were administered a single dose of oral fludarabine phosphate 40 mg/m2 (n = 42) or intravenous fludarabine phosphate 25 mg/m2 (n=14). The maximum increase in the baseline-corrected mean change in QTcI (individual-corrected QT interval) following treatment with oral fludarabine phosphate was less than 10 milliseconds.

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