No

Antineoplastic Agent, Antimetabolite

Treatment of chronic lymphocytic leukemia (B-cell) in patients who have not responded to other alkylating agent regimen

D

Hypersensitivity of fludarabine; patients with severe infections

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Use with caution with renal insufficiency, patients with a fever, documented infection, or pre-existing hematological disorders (particularly granulocytopenia) or in patients with pre-existing central nervous system disorder (epilepsy), spasticity, or peripheral neuropathy. Use with caution in patients with pre-existing renal insufficiency. Life-threatening and sometimes fatal autoimmune hemolytic anemia have occurred.

>10%:

Cardiovascular: Edema

Central nervous system: Fever, chills, fatigue, pain

Dermatologic: Rash

Gastrointestinal: Mild nausea, vomiting, diarrhea, stomatitis, GI bleeding

Genitourinary: Urinary infection

Hematologic: Myelosuppression: Dose-limiting toxicity; myelosuppression may not be related to cumulative dose

Granulocyte nadir: 13 days (3-25)

Platelet nadir: 16 days (2-32)

WBC nadir: 8 days

Recovery: 5-7 weeks

Neuromuscular & skeletal: Paresthesia, myalgia, weakness

Respiratory: Manifested as dyspnea and a nonproductive cough; lung biopsy has shown pneumonitis in some patients, pneumonia

Miscellaneous: Infection

1% to 10%:

Cardiovascular: Congestive heart failure

Central nervous system: Malaise, headache

Dermatologic: Alopecia

Endocrine & metabolic: Hyperglycemia

Gastrointestinal: Anorexia

Otic: Hearing loss

<1%: Reported with higher dose levels; most patients shown to have CNS demyelination; somnolence, blindness, coma, and death also occurred; severe neurotoxicity; skin rash, metabolic acidosis, metallic taste, life-threatening and sometimes fatal autoimmune hemolytic anemia; often recurs on rechallenge; steroid treatment may or may not be beneficial; reversible hepatotoxicity, renal failure, hematuria, increased serum creatinine, interstitial pneumonitis, tumor lysis syndrome

There are clear dose-dependent toxic neurologic effects associated with fludarabine. Doses of 96 mg/m²/day for 5-7 days are associated with a syndrome characterized by delayed blindness, coma, and death. Symptoms appeared from 21-60 days following the last dose. The central nervous system toxicity has distinctive features of delayed onset and progressive encephalopathy resulting in fatal outcomes. It is reported at an incidence rate of 36% at high doses ( greater than or equal to 96 mg/m²/day for 5-7 days) and <0.2% for low doses ( less than or equal to 125 mg/m²/course).

Increased toxicity: Cytarabine when administered with or prior to a fludarabine dose competes for deoxycytidine kinase decreasing the metabolism of F-ara-A to the active F-ara-ATP (inhibits the antineoplastic effect of fludarabine); however, administering fludarabine prior to cytarabine may stimulate activation of cytarabine

Store intact vials under refrigeration (2°C to 8°C); stable for 48 hours at room temperature

Reconstitute vials with 2 mL SWI to result in a concentration of 25 mg/mL; solution is stable for 16 days at room temperature (22°C to 25°C) and under refrigeration (2°C to 8°C)

Further dilution in 100 mL D₅W or NS is stable for 48 hours at room temperature or refrigeration

Standard I.V. dilution:

Dose/100 mL D₅W or NS

Stable for 48 hours at 4°C to 25°C

Fludarabine is analogous to that of Ara-C and Ara-A. Following systemic administration, FAMP is rapidly dephosphorylated to 2-fluoro-Ara-A. 2-Fluoro-Ara-A enters the cell by a carrier-mediated transport process, then is phosphorylated intracellularly by deoxycytidine kinase to form the active metabolite 2-fluoro-Ara-ATP. 2-Fluoro-Ara-ATP inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase.

Absorption: Oral preparation is under study

Bioavailability: 75%

Distribution: V_d: 38-96 L/m²; widely distributed with extensive tissue binding

Metabolism: I.V.: Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-vidarabine, which subsequently enters tumor cells and is phosphorylated to the active triphosphate derivative; rapidly dephosphorylated in the serum

Half-life, elimination: 2-fluoro-vidarabine: 9 hours

Elimination: 23% of a dose of fludarabine is recovered in urine as 2-fluoro-vidarabine

I.V.:

Acute leukemia: 10 mg/m² bolus over 15 minutes followed by continuous infusion of 30.5 mg/m²/day over 5 days or

10.5 mg/m² bolus over 15 minutes followed by 30.5 mg/m²/day over 48 hours followed by cytarabine has been used in clinical trials

Solid tumors: 9 mg/m² bolus followed by 27 mg/m²/day continuous infusion over 5 days

Adults:

Chronic lymphocytic leukemia: 25 mg/m²/day over a 30-minute period for 5 days; 5-day courses are repeated every 28 days days

Non-Hodgkin's lymphoma: Loading dose: 20 mg/m² followed by 30 mg/m²/day for 48 hours

Dosing in renal impairment: Cl_cr <50 mL/minute: Monitor closely for toxicity; dose reduction is indicated in patients with renal failure. However, no specific guidelines are available

CBC with differential, platelet count, AST, ALT, creatinine, serum albumin, uric acid

Peak plasma levels: 0.3-0.9 mg/mL following a short infusion of 25 mg/m²

Sedation is common

Myelosuppression is common; use caution with clozapine and carbamazepine; concurrent use with low potency antipsychotics and TCAs may produce additive sedation

No information available to require special precautions

No effects or complications reported

This drug can only be administered by infusion. During therapy, do not use alcohol, aspirin-containing products, and OTC medications without consulting prescriber. It is important to maintain adequate nutrition and hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) during therapy; frequent small meals may help. You may experience mild nausea or vomiting (frequent small meals, frequent mouth care, sucking lozenges, or chewing gum may help). You may experience loss of hair (reversible); you will be more susceptible to infection (avoid crowds and exposure to infection as much as possible). Yogurt or buttermilk may help reduce diarrhea. Frequent mouth care and use of a soft toothbrush or cotton swabs may help prevent mouth sores. Report extreme fatigue, pain or numbness in extremities, severe GI upset or diarrhea, bleeding or bruising, fever, chills, sore throat, vaginal discharge, difficulty or pain on urination, muscle pain or weakness, unusual cough or difficulty breathing, or other unusual side effects. Pregnancy/breast-feeding precautions: Do not get pregnant; use appropriate contraceptive measures. Do not breast-feed while on this drug and for several weeks after last dose. Male: Use barrier contraceptive measures when having intercourse with women of childbearing age. Do not breast-feed.

Parenteral: Fludarabine phosphate has been administered by intermittent I.V. infusion over 15-30 minutes and by continuous infusion; in clinical trials the loading dose has been diluted in 20 mL D₅W and administered over 15 minutes and the continuous infusion diluted to 240 mL in D₅W and administered at a constant rate of 10 mL/hour; in other clinical studies fludarabine has been diluted to a concentration of 0.25 to 1 mg/mL in D₅W or sodium chloride 0.9%

Powder for injection, as phosphate, lyophilized: 50 mg (6 mL)

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Avramis VI, Champagne J, Sato J, et al, "Pharmacology of Fludarabine Phosphate After a Phase I/II Trial by a Loading Bolus and Continuous Infusion in Pediatric Patients," Cancer Res, 1990, 50(22):7226-31.

Hood MA and Finley RS, "Fludarabine: A Review," DICP, 1991, 25(5):518-24.

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Plunkett W, Gandhi V, Huang P, et al, "Fludarabine: Pharmacokinetics, Mechanisms of Action, and Rationales for Combination Therapies," Semin Oncol, 1993, 20(5 Suppl 7):2-12.

Ross SR, McTavish D, and Faulds D, "Fludarabine. A Review of Its Pharmacological Properties and Therapeutic Potential in Malignancy," Drugs, 1993, 45(5):737-59.

Von Hoff DD, "Phase I Clinical Trials With Fludarabine Phosphate," Semin Oncol, 1990, 17(5 Suppl 8):33-8.

Wright SJ, Robertson LE, O'Brien S, et al, "The Role of Fludarabine in Hematological Malignancies," Blood Rev, 1994, 8(3):125-34.