Fludarabine

Uses

Fludarabine Phosphate is used for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. The safety and effectiveness of Fludarabine Phosphate in previously untreated or non-refractory patients with CLL have not been established.

Fludarabine is also used to associated treatment for these conditions: B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma refractory, Refractory Non-Hodgkin's lymphoma

How Fludarabine works

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.

Dosage

Fludarabine dosage

Intravenous (Adult):

Chronic lymphocytic leukaemia:25 mg/m2BSA daily given by bolus inj or by IV infusion over 30 minutes for 5 consecutive days. Courses may be repeated every 28 days, usually for up to 6 cycles.Oral (Adult):

Chronic lymphocytic leukaemia:40 mg/m2BSA daily for 5 consecutive days. Courses may be repeated every 28 days, usually for up to 6 cycles.

Side Effects

Fever, chills, cough, dyspnoea, pneumonia; GI disturbances, stomatitis; oedema; tumour lysis syndrome; skin rashes; haemolytic anaemia, haemorrhagic cystitis; neurological disturbances including peripheral neuropathy, agitation, confusion, visual disturbances and coma. Progressive encephalopathy and blindness (high doses).

Precaution

Routine monitoring of blood counts and Hb conc. Monitor for signs of autoimmune haemolytic anaemia; elderly. Avoid contact with skin and eyes; avoid inhalation. Myelosuppression may be cumulative and severe increasing risk of opportunistic infections. Increased risk of tumour lysis syndrome in patients with high tumour burden.

Interaction

Co-administration with pentostatin may lead to pulmonary toxicity. Reduced metabolic activation of fludarabine with cytarabine. Reduced therapeutic efficacy with dipyridamole and other adenosine uptake inhibitors.

Food Interaction

• Take with or without food. Administration with food delays absorption, but not to a clinically significant extent.

Fludarabine Drug Interaction

Minor: levofloxacin, levofloxacinUnknown: lorazepam, lorazepam, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, meperidine, meperidine, heparin, heparin, furosemide, furosemide, vitamin a topical, vitamin a topical, bioflavonoids, bioflavonoids, sotalol, sotalol

Fludarabine Disease Interaction

Major: infections, hemolytic anemia, myelosuppressionModerate: peripheral neuropathy, renal dysfunction, transfusion/graft-vs-host disease

Elimination Route

Bioavailability is 55% following oral administration.

Half Life

20 hours

Clearance

• 117-145 mL/min [patients with B-cell CLL receiving IV administration of a single dose of 40 mg/m^2.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Renal impairment (CrCl <30 mL/min); decompensated haemolytic anaemia. Pregnancy and lactation. Concomitant use of live vaccines.

Special Warning

Renal Impairment:

• CrCl 30-70: May reduce the doses by up to 50%
• Severe impairment: Avoid

Storage Condition

Refrigerate at 2-8° C

Innovators Monograph

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