FLUDARA

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 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.

Injection is a sterile solution intended for intravenous administration.

Treatment of

B-cell chronic lymphoid leukaemia (CLL) in adult patients with sufficient bone marrow reserves.

Front-line treatment with

Fludara 50 mg should only be initiated in adult patients with advanced disease, Ill/Intravenous Rai (Step C Binet) or Stage I/II Rai (Step A/B Binet) when the patient has symptoms associated with disease or a progressive disease.

A second group of patients with a history of renal failure is a group of patients with a history of renal failure.

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/m 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).

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Summary of the Safety Profile After experience with Fludara, the most common adverse events are myelosuppression (neutropenia, thrombocytopenia and anaemia), infections including pneumonia, cough, fever, fatigue, weakness, nausea, vomiting and diarrhoea.

Other commonly reported adverse events include chills, oedema, malaise, peripheral neuropathy, visual disorders, anorexia, mucitis, stomatitis and rashes.

Severe opportunistic infections occurred in patients treated with Fludara.

Deaths resulting from serious adverse reactions were reported.

Tabulated list of adverse reactions

The table below lists the undesirable events, agglomerated by the class of the mydremium-debate virus, mydremium-debate virus, mydremium-debate virus, mydremium-debate virus, mydremium-debate virus, mydremium-debate virus, mydremium-debate virus, mydremium-debate virus, mydremium-debate virus, mydremium-debate virus.

High doses of fludarabine phosphate 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.

The recommended adult dose is 25 mg/m 2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days.

Each 5 day course of treatment should commence every 28 days.

Reduce dose in patients with creatinine clearance to 70 mL/min/l.73 m 2.

Do not use in patients with severe renal impairment. 2.1 Recommended Dose The recommended adult dose of fludarabine phosphate injection is 25 mg/m 2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days.

Each 5-day course of treatment should commence every 28 days.

Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity.

Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

A number of clinical settings may predispose to increased toxicity from Fludarabine Phosphate Injection.

These include advanced age, renal impairment, and bone marrow impairment.

Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

The optimal duration of treatment has not been clearly established.

It is recommended that three additional cycles of Fludarabine Phosphate Injection be administered following the achievement of a maximal response and then the drug should be discontinued. 2.2 Renal Impairment Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance to 79 mL/min, as estimated by the Cockroft-Gault equations.

These adjustments are based on a pharmacokinetic study in patients with renal impairment.

Injection should not be administered to patients with creatinine clearance less than 30 mL/min. Starting Dose Adjustment for Renal Impairment Creatinine Clearance Starting Dose ≥ 80 mL/min 25 mg/m 2 (full dose) 50 to 79 mL/min 20 mg/m 2 30 to 49 mL/min 15 mg/m 2 < 30 mL/min Do not administer Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly. 2.3 Use of Infusion Solutions Fludarabine Phosphate Injection contains no antimicrobial preservative and should be used within 8 hours of opening.

Care must be taken to assure sterility of infusion solutions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Injection should not be mixed with other drugs.

Injection, USP is supplied as a sterile solution containing 50 mg/2 mL (25 mg/mL) of fludarabine phosphate in a 2 mL single use vial.

NDC 0527-1242-02 one carton containing 1 vial of Fludarabine Phosphate Injection. 16.2 Storage Store refrigerated between 2° and 8°C (36° and 46°F). 16.3 Handling and Disposal Procedures for proper handling and disposal should be considered.

Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs.

Several guidelines on this subject have been published. 1-4 Caution should be exercised in the handling and preparation of Fludarabine Phosphate Injection solution.

The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage.

If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.

Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.

Store refrigerated between 2° and 8°C (36° and 46°F).

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.

Fludarabine phosphate was embryolethal and teratogenic in rats and rabbits.

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.

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.

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 to 21) with refractory acute leukemia (45 patients) or solid tumors (17 patients).

Limited pharmacokinetic data for fludarabine phosphate are available in children (ages 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.