Fludarabine

Intravenous
B cell chronic lymphocytic leukaemia

Oral
B cell chronic lymphocytic leukaemia

CrCl (mL/min)	Dosage
<30	Contraindicated.
30-70	Reduce dose by up to 50%.

Dilute the required dose in 10 mL and 100 mL of NaCl 0.9% soln for inj or dextrose 5% to prepare a soln for bolus inj and infusion, respectively.

Decompensated haemolytic anaemia. Renal impairment (CrCl <30 mL/min). Lactation. Concomitant use w/ pentostatin.

Patient w/ severe impairment of bone marrow function, immunodeficiency, history of opportunistic infections. Renal (CrCl 30-70 mL/min) and hepatic impairment. Pregnancy.

Significant: Skin cancer (new onset or exacerbation).
Nervous: Agitation, confusion, seizure, insomnia, coma, peripheral neuropathy.
CV: Oedema, angina, CHF, arrhythmia, supraventricular tachycardia, MI, DVT, phlebitis, TIA, aneurysm, chest pain.
GI: Nausea, vomiting, diarrhoea, anorexia, stomatitis, GI bleeding, oesophagitis, constipation, mucositis, dysphagia, pancreatitis.
Resp: Cough, dyspnoea, upper resp infection, pharyngitis, allergic pneumonitis, haemoptysis, bronchitis, hypoxia, interstitial pulmonary infiltrate, sinusitis, epistaxis.
Hepatic: Abnormal LFT, cholelithiasis, hepatic failure, reversible hepatotoxicity.
Genitourinary: UTI, dysuria, haematuria, urinary hesitancy, renal failure, proteinuria.
Musculoskeletal: Arthralgia.
Ophthalmologic: Visual disturbance.
Dermatologic: Skin toxicity (e.g. maculopapular rash).
Potentially Fatal: Myelosuppression (e.g. thrombocytopenia, anaemia, neutropenia), autoimmune phenomena (e.g. haemolytic anaemia, autoimmune thrombocytopenia/thrombocytopenic purpura, Evan syndrome, acquired haemophilia), serious opportunistic infections, progressive multifocal leukoencephalopathy, tumour lysis syndrome, severe pulmonary toxicity. Rarely, neurotoxicity, transfusion-related graft-versus-host disease.

IV/Parenteral/PO: D

This drug may cause confusion, fatigue and visual disturbances, if affected, do not drive or operate machinery.

Monitor CBC w/ differential and platelet count, serum creatinine and albumin, uric acid, AST, ALT; signs of infection, neurotoxicity and tumour lysis syndrome.

Symptoms: Leukoencephalopathy (including nausea, vomiting, headache, visual disturbances, seizures), optic neuritis, papillitis, somnolence, confusion, agitation, para-/quadriparesis, incontinence, muscle spasm, irreversible CNS toxicity (characterised by delayed blindness, coma), severe thrombocytopenia, neutropenia. Management: Supportive treatment. Blood transfusion may be necessary in managing myelosuppression.

Reduced therapeutic effect w/ dipyridamole and other inhibitors of adenosine uptake. Cytarabine may reduce the metabolic activation of fludarabine. May diminish the effect of live vaccines.
Potentially Fatal: Increased risk of severe pulmonary toxicity when used in combination w/ pentostatin.

Description:
Mechanism of Action: Fludarabine, a purine antagonist metabolite, is rapidly dephosphorylated to 2-fluoro-ara-A and then converted intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP which inhibits α-DNA polymerase, ribonucleotide reductase, and DNA primase, resulting in inhibition of DNA synthesis leading to cell death.
Pharmacokinetics:
Absorption: Bioavailability: Approx 50-65% (oral). Time to peak plasma concentration: Approx 4 hr.
Distribution: Plasma protein binding: Approx 19-29%.
Metabolism: Fludarabine phosphate is rapidly dephosphorylated in the serum to fludarabine which enters the tumour cells to be rephosphorylated by deoxycytidine kinase enzyme to the active triphosphate derivative.
Excretion: Mainly via urine (40-60%). Terminal elimination half-life: Approx 20 hr.

Source: National Center for Biotechnology Information. PubChem Database. Fludarabine, CID=657237, https://pubchem.ncbi.nlm.nih.gov/compound/Fludarabine (accessed on Jan. 21, 2020)

Tab: Store between 15-30°C. IV soln: Store between 2-8°C. Protect from light.
This is a cytotoxic drug. Use appropriate personal protective equipment (e.g. gloves) for receiving, handling, admin and disposal.

Cytotoxic Chemotherapy

L01BB05 - fludarabine ; Belongs to the class of antimetabolites, purine analogues. Used in the treatment of cancer.

Anon. Fludarabine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com . Accessed 08/03/2017.

Buckingham R (ed). Fludarabine Phosphate. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/03/2017.

Fludarabine Phosphate Injection, Solution (Fresenius Kabi USA, LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 07/03/2017.

Fludarabine Phosphate Tablet, Film Coated (Antisoma Research Limited). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 07/03/2017.

Joint Formulary Committee. Fludarabine Phosphate. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/03/2017.

McEvoy GK, Snow EK, Miller J et al (eds). Fludarabine Phosphate. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 07/03/2017.