Fludarabine Phosphate

Approved Indications:

• Treatment of chronic lymphocytic leukemia (CLL), particularly in patients who have received at least one prior therapy.
• Treatment of low-grade non-Hodgkin lymphoma (NHL) including follicular lymphoma and small lymphocytic lymphoma.
• Off-label use in other hematologic malignancies such as hairy cell leukemia and prolymphocytic leukemia.

Disease Stages:

• Used in both initial and relapsed/refractory CLL.
• Indicated for patients with symptomatic or progressive disease requiring therapy.

• Adults (CLL):
• Standard dose: 25 mg/m² IV daily for 5 consecutive days, repeated every 28 days.
• Typical treatment duration: 4 to 6 cycles; may be extended based on response and tolerability.
• Elderly:
• Dose adjustments may be necessary based on renal function and performance status.
• Pediatrics:
• Limited data; dosing usually weight- or surface area-based and individualized.
• Renal Impairment:
• Dose reduction recommended for creatinine clearance <70 mL/min.
• Severe impairment (CrCl <30 mL/min): use with caution or consider alternative therapy.
• Hepatic Impairment:
• No specific dose adjustments, but monitor closely.
• Administration:
• Administered as intravenous infusion over 30 minutes.
• Ensure adequate hydration before and after infusion to reduce nephrotoxicity risk.
• Monitoring:
• Regular blood counts before each cycle.
• Monitor for signs of infection and neurotoxicity.

Fludarabine phosphate is a purine nucleoside analog prodrug converted intracellularly to 2-fluoro-ara-ATP, its active triphosphate form. This metabolite inhibits DNA synthesis by interfering with DNA polymerase alpha and ribonucleotide reductase, resulting in inhibition of DNA chain elongation and repair. It also inhibits RNA synthesis and induces apoptosis of malignant lymphocytes, leading to decreased proliferation of cancerous cells.

• Absorption:
  Not applicable (IV administration only).
• Distribution:
  Widely distributed in body tissues; crosses blood-brain barrier in small amounts.
• Metabolism:
  Rapid intracellular conversion to active triphosphate metabolites.
• Elimination:
  Renal excretion of unchanged drug and metabolites; approximately 60% eliminated via kidneys.
• Half-life:
  Terminal plasma half-life about 20 hours for fludarabine; intracellular triphosphate metabolites have longer persistence.

• Pregnancy:
  FDA Category D. Contraindicated in pregnancy due to teratogenicity and fetal toxicity. Women of childbearing potential must use effective contraception.
• Lactation:
  Unknown if excreted in human milk. Breastfeeding not recommended during therapy and for 1 month after last dose.

• Primary class: Antineoplastic agent
• Subclass: Purine nucleoside analog

• Known hypersensitivity to fludarabine or its components.
• Severe immunosuppression or uncontrolled infections.
• Significant bone marrow suppression unrelated to malignancy.
• Pregnancy and breastfeeding.

• Myelosuppression: Severe neutropenia, anemia, and thrombocytopenia; monitor blood counts closely.
• Infections: High risk of opportunistic infections, including Pneumocystis jirovecii pneumonia; prophylaxis recommended.
• Neurotoxicity: Risk of progressive multifocal leukoencephalopathy (PML) and other CNS toxicities; discontinue if severe symptoms develop.
• Tumor lysis syndrome: Monitor electrolytes during initial treatment cycles.
• Immunosuppression: Risk of autoimmune hemolytic anemia and other immune-mediated effects.
• Use with caution in patients with renal impairment.

Common Adverse Effects:

• Hematologic: Neutropenia, anemia, thrombocytopenia
• Fatigue
• Nausea, vomiting
• Fever and infections

Serious/Rare Side Effects:

• Neurotoxicity: Confusion, seizures, PML
• Autoimmune hemolytic anemia
• Opportunistic infections (including fungal, viral)
• Tumor lysis syndrome
• Severe bone marrow suppression

• Increased immunosuppression and infection risk with other myelosuppressive agents or immunosuppressants.
• Avoid live vaccines during and after therapy due to immunosuppression.
• Caution with nephrotoxic drugs; monitor renal function.
• Potential interactions with drugs that affect renal clearance.

• Recommendations emphasize infection prophylaxis (e.g., Pneumocystis jirovecii pneumonia prophylaxis).
• Updated warnings on neurotoxicity and monitoring.
• Guidelines suggest dose modifications in renal impairment and close monitoring in elderly.
• No recent changes in standard dosing; clinical trials exploring combination therapies continue.

• Store at controlled room temperature 20°C to 25°C (68°F to 77°F).
• Protect from light and moisture.
• Do not freeze.
• Keep in original packaging until use.
• Use immediately after reconstitution or as directed.