Fludarabine (Fludara) is a purine analog - a chemotherapeutic drug that is used in the management of hematological malignancies.

Indications of Fludarabine (Fludara):

• Chronic lymphocytic leukemia (refractory or progressive):

  • It is indicated for the treatment of B-cell chronic lymphocytic leukemia (CLL) in adults who showed no response or progression during treatment with at least one standard regimen containing an alkylating agent.

• Off Label Use of Fludarabine in Adults:

  • Acute myeloid leukemia (newly diagnosed)
  • Acute myeloid leukemia (refractory or high/poor risk)
  • Hematopoietic stem cell transplant (allogeneic) myeloablative conditioning regimen (older adults)
  • Hematopoietic stem cell transplant (allogeneic) nonmyeloablative conditioning regimen
  • Hematopoietic stem cell transplant (allogeneic) reduced-intensity conditioning regimen
  • Non-Hodgkin lymphoma: Follicular lymphoma (relapsed/refractory)
  • Non-Hodgkin lymphoma: Mantle cell lymphoma (relapsed/refractory)
  • Waldenström macroglobulinemia

Fludarabine (Fludara) dose in adults:

Fludarabine (Fludara) Treatment dose of refractory or progressive Chronic lymphocytic leukemia (CLL), :

• IV:

  • 25 mg/m² once daily for 5 consecutive days every 28 days;
  • continue for at least 3 additional cycles after the maximal response is achieved.

• Oral (Canadian product; not available in the US):

  • 40 mg/m² once daily for 5 consecutive days every 28 days.

• CLL combination regimens (off-label dosing):

  • FC regimen:
    • 30 mg/m²/day IV for 3 days every 28 days for 6 cycles (in combination with cyclophosphamide) or
    • 20 mg/m²/day IV for 5 days every 28 days for 6 cycles (in combination with cyclophosphamide).
  • FCR regimen:
    • 25 mg/m²/day IV for 3 days every 28 days for 6 cycles (in combination with cyclophosphamide and rituximab).
  • FR regimen:
    • 25 mg/m²/day IV for 5 days every 28 days for 6 cycles (in combination with rituximab).
  • OFAR regimen:
    • 30 mg/m²/day IV for 2 days every 28 days for 6 cycles (in combination with oxaliplatin, cytarabine, and rituximab).

Fludarabine (Fludara) Treatment dose of newly diagnosed Acute myeloid leukemia (off-label):

• IV: 30 mg/m²/day for 5 days (in combination with cytarabine ± G-CSF ± idarubicin (FA, FLAG, or FLAG-IDA regimens), followed by consolidation therapy.

Fludarabine (Fludara) Treatment dose of refractory or high/poor-risk patients with Acute myeloid leukemia,  (off-label):

• IV: 30 mg/m²/day for 5 days (in combination with cytarabine and filgrastim [FLAG regimen]), may repeat once for partial remission or
• 30 mg/m²/day for 5 days for 1 or 2 cycles (in combination with cytarabine, idarubicin, and filgrastim FLAG-IDA regimen]).

Fludarabine (Fludara) Treatment dose of Hematopoietic stem cell transplant (allogeneic) myeloablative conditioning regimen (off label):

• IV: 40 mg/m²/day for 4 days (in combination with busulfan) beginning 6 days before transplantation.

Fludarabine (Fludara) Treatment dose of allogeneic hematopoietic stem cell transplant (reduced-intensity conditioning regimen) (off-label):

• IV: 30 mg/m²/day for 5 days (in combination with melphalan and alemtuzumab) prior to transplant or
• 30 mg/m²/day for 6 days beginning 10 days prior to transplant or 30 mg/m²/day for 5 days beginning 6 days prior to transplant (in combination with busulfan with or without antithymocyte globulin).

Fludarabine (Fludara) Treatment dose of allogeneic Hematopoietic stem cell transplant (nonmyeloablative conditioning regimen) (off-label):

• IV: 30 mg/m²/day for 3 doses beginning 5 days prior to transplant (in combination with cyclophosphamide and rituximab) or
• 30 mg/m²/day for 3 doses beginning 4 days prior to transplant (in combination with total body irradiation).

Fludarabine (Fludara) Treatment dose of Non-Hodgkin lymphomas (off-label): 

• Relapsed/ refractory Follicular lymphoma

  • FCR regimen:
    • 25 mg/m²/day IV  for 3 days every 21 days for 4 cycles (in combination with cyclophosphamide and rituximab)
  • FCMR regimen:
    • 25 mg/m²/day IV for 3 days every 28 days for 4 cycles (in combination with cyclophosphamide, mitoxantrone, and rituximab).
  • FNDR regimen:
    • 25 mg/m²/day IV for 3 days every 28 days for up to 8 cycles (in combination with mitoxantrone, dexamethasone, and rituximab).
  • FR regimen:
    • 25 mg/m²/day IV for 5 days every 28 days for 6 cycles (in combination with rituximab).

Fludarabine (Fludara) Treatment dose of Mantle cell lymphoma, relapsed, or refractory:

• • FC regimen:

    • 20 mg/m²/day IV for 4 to 5 days or 25 mg/m²/day for 3 to 5 days (in combination with cyclophosphamide).

Fludarabine (Fludara) Treatment dose of Waldenstrom macroglobulinemia (off-label):

• IV: 25 mg/m²/day for 5 days every 28 days or
• 25 mg/m² once daily for 5 days during weeks 5, 9, 13, 19, 23, and 27 (in combination with rituximab).

Fludarabine (Fludara) dose in children:

Fludarabine (Fludara) Treatment dose of Relapsed Acute lymphocytic leukemia (ALL) or AML:

• Children and Adolescents:

  • Continuous IV infusion:
    • 5 mg/m² bolus followed by 30.5 mg/m² /day for 48 hours in combination with cytarabine.
  • Intermittent IV dosing:
    • 25 mg/m² once daily for 5 days in combination with cytarabine and daunorubicin was used for ALL

Fludarabine (Fludara) Treatment dose of allogeneic stem cell transplant (conditioning regimen), reduced-intensity (hematologic malignancy):

• Children and Adolescents:

  • IV: 30 mg/m² once daily for 6 doses beginning 7 to 10 days prior to transplant (in combination with busulfan and thymoglobulin.

Fludarabine (Fludara) Treatment dose of allogeneic Stem cell transplant (conditioning regimen), reduced-toxicity (myeloid malignancies and non-malignant diseases [eg, sickle cell cisease]):

• Children and Adolescents:

  • IV: 30 mg/m² once daily for 6 doses days -8 to -3 (in combination with busulfan and alemtuzumab).

• Fludarabine Dosing adjustment for toxicity:

  • The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited.
  • Refer to specific protocols for management in pediatric patients if available.

  • Adult:

    • Hematologic or non-hematologic toxicity (other than neurotoxicity):
      • Dose reduction or delaying treatment should be considered.
    • Hemolysis:
      • Treatment should be withdrawn.
    • Neurotoxicity:
      • Consider treatment delay or discontinuation.

Pregnancy Risk Factor D

• Studies on animal reproduction revealed negative outcomes.
• Fludarabine administered during pregnancy can cause fetal harm.
• Effective contraception for women and men who have female partners with reproductive potential to prevent pregnancy.

Use Fludarabine while breastfeeding

• It is unknown if fludarabine secretion occurs in breast milk.
• The potential for severe adverse reactions in breastfeeding infants should be considered.

Fludarabine Dose adjustment in kidney disease:

• IV:

  • CrCl ≥80 mL/minute:
    • No dosage adjustment necessary (administer the usual dose of 25 mg/m²).
  • CrCl 50 to 79 mL/minute:
    • Reduce dose to 20 mg/m².
  • CrCl 30 to 49 mL/minute:
    • Reduce dose to 15 mg/m².
  • CrCl <30 mL/minute:
    • Use is not recommended.

• Oral (Canadian product; not available in the US):

  • CrCl 30 to 70 mL/minute:
    • 50% dose reduction.
  • CrCl <30 mL/minute:
    • Use is contraindicated.

• The following adjustments have also been used:IV:

  • CrCl 10 to 50 mL/minute:
    • Reduce dose to 75% of the usual dose.
  • CrCl <10 mL/minute:
    • 50% dose reduction.
  • Hemodialysis:
    • Reduce dose to 50% of usual dose;
    • administer after dialysis
  • Continuous ambulatory peritoneal dialysis (CAPD):
    • 50% dose reduction.
  • Continuous renal replacement therapy (CRRT):
    • Reduce dose to 75% of the usual dose.

Fludarabine (Fludara) Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling.

Common Side Effects of Fludarabine (Fludara):

• Cardiovascular:

  • Edema

• Central Nervous System:

  • Fatigue
  • Neurological Signs And Symptoms
  • Pain
  • Chills
  • Paresthesia

• Dermatologic:

  • Skin Rash
  • Diaphoresis

• Gastrointestinal:

  • Nausea And Vomiting
  • Anorexia
  • Diarrhea
  • Gastrointestinal Hemorrhage

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Anemia
  • Neutropenia
  • Thrombocytopenia
  • Bone Marrow Depression

• Infection:

  • Infection

• Neuromuscular & Skeletal:

  • Weakness
  • Myalgia

• Ophthalmic:

  • Visual Disturbance

• Respiratory:

  • Cough
  • Pneumonia
  • Dyspnea
  • Upper Respiratory Tract Infection

• Miscellaneous:

  • Fever

Rare Side Effects Of Fludarabine (Fludara):

• Cardiovascular:

  • Angina Pectoris
  • Cardiac Arrhythmia
  • Cardiac Failure
  • Cerebrovascular Accident
  • Myocardial Infarction
  • Supraventricular Tachycardia
  • Deep Vein Thrombosis
  • Phlebitis
  • Aneurysm
  • Transient Ischemic Attacks

• Central Nervous System:

  • Malaise
  • Headache
  • Sleep Disorder
  • Cerebellar Syndrome
  • Depression
  • Difficulty Thinking

• Dermatologic:

  • Alopecia
  • Pruritus
  • Seborrhea

• Endocrine & Metabolic:

  • Hyperglycemia
  • Dehydration

• Gastrointestinal:

  • Stomatitis
  • Cholelithiasis
  • Esophagitis
  • Constipation
  • Mucositis
  • Dysphagia

• Genitourinary:

  • Dysuria
  • Urinary Hesitancy
  • Hematuria
  • Proteinuria

• Hematologic & Oncologic:

  • Hemorrhage
  • Tumor Lysis Syndrome

• Hepatic:

  • Abnormal Hepatic Function Tests
  • Hepatic Failure

• Hypersensitivity:

  • Anaphylaxis

• Neuromuscular & Skeletal:

  • Osteoporosis
  • Arthralgia

• Otic:

  • Hearing Loss

• Renal:

  • Renal Failure
  • Renal Function Test Abnormality

• Respiratory:

  • Pharyngitis
  • Hypersensitivity Pneumonitis
  • Hemoptysis
  • Sinusitis
  • Bronchitis
  • Epistaxis
  • Hypoxia

Contraindications to Fludarabine (Fludara):

• The US labeling of the manufacturer does not list any contraindications.
• Canadian labeling
  • Hypersensitivity to fludarabine and any component of the formulation
  • Hemolytic anemia decompensated
  • Grave renal impairment (CrCl 30mL/minute).
  • Pentostatin combination therapy

Warnings and precautions

• Autoimmune effects: [US-Boxed Warning]

  • Fludarabine therapy can cause life-threatening autoimmune reactions, such as hemolytic anemia, autoimmune hemocytopenia/thrombocytopenicpurpura (ITP), Evans Syndrome, and acquired hemophilia.
  • This can be seen in patients with or without a history or positive Coombs test. Patients may also be in remission.
  • Corticosteroids may be used to treat hemolysis.
  • Hemolysis should prompt the discontinuation of fludarabine treatment
  • Fludarabine may cause hemolytic reactions in patients who are given it again.

• Suppression of bone marrow: [US Boxed Warning]

  • Fludarabine therapy may cause severe myelosuppression (anemia and thrombocytopenia)
  • For granulocytes, the median time to reach nadir was 13 (range: 3-25 days) and for platelets, it was 16 (range: 2–32 days).
  • Cytopenias can last from 2 to 1 year.
  • Long-term cytopenias can be treated with first-line combination therapy. Anemia lasts up to seven months, neutropenia for up to nine months, and thrombocytopenia for up to 10 years.
  • The elderly are at greater risk for prolonged cytopenia.
  • For bone marrow suppression, close monitoring is important. Doses should be reduced.

• Infection

  • Fludarabine can cause fatal opportunistic infection and reactivation of latent viral infections like Epstein-Barr and VZV (herpes simplex virus).
  • Effective prophylactic treatment should be provided to patients at higher risk for developing opportunistic infection.
  • Patients with fever, immune deficiencies, documented infections, or a history opportunistic infections should exercise caution.

• Neurotoxicity: [US Boxed Warn]

  • High doses of neurologic toxicology can cause severe symptoms such as delayed blindness, coma and death.
  • Neurotoxicity symptoms can develop between 21 and 60 days after higher doses fludarabine, but the duration of these symptoms can range from 7 days up to 225 days.
  • Fludarabine (25 mg/m/day for five days) can cause CLL in a standard dose.
  • Treatments can be administered in up to 15 sessions.
  • Long-term administration can lead to fatigue, weakness and visual disturbances.
  • It is important to warn patients about tasks that require mental alertness, such as driving or operating machinery.

• Progressive multifocal Leukoencephalopathy

  • Patients who have received combination or previous fludarabine therapy can develop progressive multifocal leukoencephalopathy (usually deadly) from the JC virus.
  • The initial symptoms may take a few weeks to appear, or they could be delayed for up to a year.
  • Any neurological changes should be assessed immediately.

• Reproductive effects

  • Damage to testicular tissue or spermatozoa may occur.

• Transfusion-associated Graft-versus-Hom Disease:

  • Fludarabine-treated patients may have non-irradiated blood transfused to them, which could lead to graft against host disease. This can prove fatal.
  • Patients receiving fludarabine should only be allowed to receive irradiated blood products due to the possibility of transfusion-related GVHD.

• Tumor lysis syndrome

  • Patients with a high tumor burden prior to treatment are at greater risk for tumor lysis syndrome.
  • Patients should receive adequate hydration as well as prophylactic antihyperuricemic treatment.

• Renal impairment

  • Patients with impaired renal function have a decreased clearance of the primary metabolite 2-fluoroara-A, so it is important to be cautious when using this compound.
  • It is not recommended for severe renal impairment (CrCl 30ml/min), while moderate impairment (CrCl 30-79ml/min), requires dosage reductions and close monitoring.

Fludarabine: Drug Interaction

Monitoring parameters:

• CBC with differential
• Platelet count
• LFTs
• serum albumin
• RFTs
• Serum uric acid
• Signs of infection
• Neurotoxicity
• Tumor lysis syndrome.

How to administer Fludarabine (Fludara)?

IV:

• For treating CLL, fludarabine should be given over half-hour.
• Continuous infusions and IV bolus over 15 minutes have been used for some off-label protocols (refer to individual studies for infusion rate details).

Oral:

• Tablet [Canadian product] It can be given orally with water as a whole with or without food without chewing, breaking or crushing

Mechanism of action of Fludarabine (Fludara):

• Fludarabine inhibits DNA polymerase, ribonucleotide reduces and DNA synthesis. 
• It also inhibited DNA primate and DNA ligase I.

Protein binding:

• 2-fluoroara-A: 19%-29%

Metabolism:

• IV: Fludarabine is quickly dephosphorylated in plasma to 2-fluoroaraA (active metabolism), which then enters tumor cells.
• It is then phosphorylated by the deoxycytidinekinase to active triphosphate derivative (2,fluoroara-ATP).

Bioavailability:

• Oral: 2-fluoro-ara-A: 50% to 65%.

Half-life elimination:

• 2-fluoro-ara-A: Adults: 20 hours.

Time to peak, plasma:

• Oral: 1 to 2 hours.

Excretion:

• Urine (primarily).

International Brands of Fludarabine:

• Fludara
• Beneflur
• Eupifluda
• Flucozol
• Fludabine
• Fludacel
• Fludamin

Fludarabine Brand Names in Pakistan: