Usage
- Fludarabine is primarily indicated for the treatment of B-cell chronic lymphocytic leukemia (CLL) in adult patients who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent-containing regimen.
- Pharmacological classification: Fludarabine is an antineoplastic antimetabolite, specifically a purine nucleoside analogue.
- Mechanism of Action: Fludarabine interferes with DNA synthesis and repair, ultimately leading to cell death. It is incorporated into DNA and RNA, inhibiting several enzymes involved in nucleic acid synthesis, including DNA polymerase, ribonucleotide reductase, and DNA primase.
Alternate Names
- Fludarabine phosphate
- Brand Names: Fludara, Oforta
How It Works
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Pharmacodynamics: Fludarabine’s primary effect is cytotoxicity against actively proliferating lymphocytes, particularly B-cells. This leads to a reduction in the number of malignant cells.
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Pharmacokinetics:
- Absorption: Following IV administration, fludarabine is rapidly and completely absorbed. Oral bioavailability is approximately 50-60%. Food does not significantly affect absorption.
- Metabolism: Fludarabine is rapidly dephosphorylated to 2F-ara-A, which is then taken up by cells and phosphorylated intracellularly to the active triphosphate form (2F-ara-ATP).
- Elimination: Fludarabine is primarily excreted by the kidneys, with a small amount excreted in the bile. Renal impairment significantly affects elimination. It is partially metabolized by the liver.
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Mode of Action: Fludarabine’s active metabolite (2F-ara-ATP) inhibits DNA synthesis by interfering with DNA polymerase and ribonucleotide reductase, leading to cell death. It incorporates into DNA and RNA strands, further disrupting nucleic acid function and repair mechanisms.
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Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults (CLL):
- IV: 25 mg/m² administered intravenously over approximately 30 minutes daily for 5 consecutive days, repeated every 28 days.
- Oral: 40 mg/m² administered orally once daily for 5 consecutive days, repeated every 28 days.
Children:
- Dosage must be determined by a physician based on the child’s body surface area and specific condition. Pediatric safety and efficacy have not been fully established for all indications.
Special Cases:
- Elderly Patients: Close monitoring for toxicity is recommended, and dosage may need to be reduced.
- Patients with Renal Impairment: Dose reduction is necessary. Creatinine Clearance (CrCl) 30-70 mL/min: Reduce dose up to 50%. CrCl <30 mL/min: Contraindicated.
- Patients with Hepatic Dysfunction: No specific dosage adjustments are available; however, caution is advised due to potential for increased toxicity.
- Patients with Comorbid Conditions: Monitor closely for toxicity, and consider dose adjustments as needed.
Clinical Use Cases
Fludarabine’s primary clinical use is in the management of B-cell chronic lymphocytic leukemia (CLL) in adults. It is not typically used in settings like intubation, surgical procedures, mechanical ventilation, the intensive care unit (ICU), or emergency situations. Other uses may include certain lymphomas and some cases of acute leukemia.
Dosage Adjustments
- Dose adjustments are based on renal function, age, and the presence of other comorbid conditions.
Side Effects
Common Side Effects:
- Myelosuppression (neutropenia, thrombocytopenia, anemia)
- Nausea
- Vomiting
- Diarrhea
- Fatigue
- Fever
- Edema
Rare but Serious Side Effects:
- Severe neurologic effects (blindness, coma, seizures, agitation, confusion)
- Autoimmune hemolytic anemia
- Tumor lysis syndrome
- Severe infections
- Pulmonary toxicity
Long-Term Effects:
Adverse Drug Reactions (ADR):
- Tumor lysis syndrome
- Severe myelosuppression
- Autoimmune phenomena
- Neurotoxicity
Contraindications
- Decompensated hemolytic anemia
- Severe renal impairment (CrCl <30 mL/min)
- Lactation
Drug Interactions
- Pentostatin (increased risk of pulmonary toxicity)
- Dipyridamole (decreases renal clearance of fludarabine)
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D
- Fludarabine is contraindicated during pregnancy due to the risk of fetal harm.
- Fludarabine is contraindicated during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Purine nucleoside analogue that inhibits DNA synthesis.
- Side Effects: Myelosuppression, nausea, vomiting, diarrhea, fatigue, fever. Serious side effects include neurotoxicity, autoimmune hemolytic anemia.
- Contraindications: Decompensated hemolytic anemia, severe renal impairment, lactation.
- Drug Interactions: Pentostatin, dipyridamole.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: IV: 25 mg/m² daily for 5 days every 28 days; Oral: 40 mg/m² daily for 5 days every 28 days.
- Monitoring Parameters: Complete blood counts, renal function tests, neurological assessment.
Popular Combinations
- Fludarabine is sometimes combined with other chemotherapeutic agents in the treatment of certain lymphomas; however, caution must be exercised due to potential additive toxicities.
Precautions
- General Precautions: Monitor closely for myelosuppression, infections, and neurotoxicity.
- Specific Populations: See dosage adjustments for renal impairment and elderly patients.
- Lifestyle Considerations: Patients should avoid activities that increase the risk of bleeding or infection.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Fludarabine?
A: The standard adult dose for CLL is 25 mg/m² IV daily for 5 days every 28 days or 40 mg/m² orally daily for 5 days every 28 days. Dosage adjustments are necessary for renal impairment and elderly patients.
Q2: What are the most common side effects?
A: Myelosuppression (low blood counts), nausea, vomiting, diarrhea, fatigue, and fever.
Q3: What are the serious side effects to watch for?
A: Severe neurologic effects (blindness, coma, seizures), autoimmune hemolytic anemia, tumor lysis syndrome, and severe infections.
Q4: Is Fludarabine safe during pregnancy or breastfeeding?
A: No, Fludarabine is contraindicated during pregnancy and breastfeeding.
Q5: How does Fludarabine work?
A: It interferes with DNA synthesis and repair, leading to the death of cancer cells.
Q6: What should be monitored during treatment with Fludarabine?
A: Complete blood counts, renal function, and neurological status should be closely monitored.
Q7: Are there any drug interactions I should be aware of?
A: Concomitant use of pentostatin should be avoided due to the increased risk of pulmonary toxicity. Dipyridamole can decrease the renal clearance of fludarabine.
Q8: What if my patient has renal impairment?
A: Dose reduction is necessary based on creatinine clearance. If CrCl is less than 30 mL/min, fludarabine is contraindicated.
Q9: Can Fludarabine be given orally?
A: Yes, an oral formulation exists and is typically dosed at 40 mg/m² daily for 5 days every 28 days. Bioavailability is lower than IV administration, necessitating a higher dose.
