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fludarabine
The pyrimidine analogue, cytarabine, has been used effectively against a wide variety of acute leukemias. The success of cytarabine prompted a search for other potentially useful analogues. Fludarabine is a fluorinated analogue of adenine which is relatively resistant to deamination by adenosine deaminase. It is rapidly metabolized by deoxycytidine kinase to 2F-ara-ATP which inhibits DNA synthesis by inhibition of DNA polymerases, and prevention of elongation of DNA strands through direct incorporation into the DNA molecule. Fludarabine also inhibits RNA polymerase and protein synthesis
| Bioavailability |
oral: 50-65% bioavailable (2F-ara-A) |
Pharmacokinetics are dose dependent and linear, widely distributed, Vd suggests significant degree of tissue binding. Some accumulation occurs during a 5 day treatment cycle, but does not occur over several cycles.
| Cross blood brain barrier? | yes |
| PPB | minor |
Uptake, rapidly dephosphorylated in plasma to 2F-ara-ATP, which is necessary for cellular uptake.
| Active metabolites | 2F-ara-ATP |
| Inactive metabolites | yes |
Predominantly excreted by kidneys; clearance is inversely correlated with serum creatinine and creatinine clearance.
| Urine | 40 - 60%. |
| Half-life |
15 - 23 hours (2F-Ara-ATP). |
- Chronic lymphocytic leukemia (second-line therapy after failure of other conventional therapies) (intravenous or oral)
- Low grade non-Hodgkin’s lymphoma (second-line therapy after failure of other conventional therapies) (for intravenous only).
Other Uses:
- Acute Lymphoblastic Leukemia
- Acute Myeloid Leukemia
Emetogenic Potential:
Minimal (IV)
Extravasation Potential: None
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (rare) | E | |||
| Heart failure (rare) | E | ||||
| Pericardial effusion (rare) | E | ||||
| Dermatological | Rash (<10%; may be severe including TEN and SJS) | I | |||
| Gastrointestinal | Anorexia (1-10%) | E | |||
| Diarrhea (≥10%) | E | ||||
| GI hemorrhage (<1%) | E | ||||
| Mucositis (1-10%) | E | ||||
| Nausea (or vomiting - ≥10%, mostly mild to moderate) | I | ||||
| General | Chills | I | |||
| Edema (1-10%) | E | ||||
| Fatigue (≥10%) | E | ||||
| Fever (>10%) | I | ||||
| Hematological | Anemia (≥10%) | E | |||
| Hemolysis | E | ||||
| Myelosuppression ± infection, bleeding (≥10%) (including opportunistic infection) | E | ||||
| Other (transfusion associated GVHD) | E D | ||||
| Hepatobiliary | ↑ Amylase , lipase (may be severe) | E D | |||
| ↑ LFTs (<1%) | E | ||||
| Immune | Autoimmune disorder (hemolytic anemia, TTP, pemphigus, etc. < 1%) | D | |||
| Metabolic / Endocrine | Hyperuricemia (<1%) | I | |||
| Tumor lysis syndrome (<1%) | I | ||||
| Neoplastic | MDS , AML (1-10%) | D | |||
| Other (flare in skin cancer lesions) | E | ||||
| Nervous System | Agitation (rare) | E | |||
| Confusion (<1%) | E | ||||
| Encephalopathy (36% with high doses) | E D L | ||||
| Peripheral neuropathy (1-10%) | D | ||||
| Seizure (rare) | E | ||||
| Ophthalmic | Blurred vision (visual changes - common) | E | |||
| Optic nerve disorder (optic neuritis - rare) | E | ||||
| Renal | Renal failure (rare) | E | |||
| Respiratory | Cough , dyspnea (>10%) | E | |||
| Pneumonitis (rare) | D | ||||
| Pulmonary fibrosis (rare) | D | ||||
| Urinary | Hemorrhagic Cystitis (rare) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
Myelosuppression may be cumulative, is often reversible but may persist for up to a year.
Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g., some leukemias and lymphomas), can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.
In a dose-finding study, severe irreversible central nervous system effects, including blindness, demyelination, coma and death, were seen in 36% of patients receiving four times the recommended dose for chronic lymphocytic leukemia (i.e., ≥96 mg/m2/day x 5-7 days). Symptoms appeared from 21 to 60 days post dosing. These effects are rare (0.2%) at the recommended dose
Risk of leukoencephalopathy (including PRES/RPLS) increases when fludarabine is given at high doses or following, or in combination with, medications known to be associated with encephalopathy, in patients with cranial or total body irradiation, Graft versus Host Disease, renal impairment, or following Hematopoietic Stem Cell Transplantation. Late onset encephalopathy has been reported up to 4.8 years after fludarabine treatment.
Life-threatening and sometimes fatal autoimmune hemolytic anemia has been reported to occur during or after treatment with fludarabine in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs’ test. Steroids may be beneficial. Re-challenge with fludarabine should be avoided. It is recommended that patients receive irradiated blood (or white cell-depleted red cells using a leuco-filter) to minimize the chances of hemolytic anemia and transfusion-induced graft-versus-host disease. Other autoimmune phenomena have been reported including ITP, TTP, Evans syndrome and pemphigus.
Fludarabine in combination with pentostatin (deoxycoformycin) results in an unacceptably high incidence of fatal pulmonary toxicity, and concomitant use is contraindicated.
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy. In general, fludarabine should be discontinued when the maximal response has been obtained.
Single Agent:
Intravenous:
- q4w: 25 mg/m2/day over 30 minutes x 5 days, q28d
Oral:
- q4w: 40mg/m2/day x 5 days, q28d
Continue until maximal response (complete or partial remission, usually 6 cycles), and then discontinue the drug.
In combination with other chemotherapeutic agents:
Intravenous: 25 – 30 mg/m2/day over 30 minutes x 3 days, q28d. Refer to individual regimen for details.
Some centres use the guidelines below:
|
Toxicity / Grade |
Action |
Dose next cycle |
|
Platelet < 100 x 109/L and/or ANC < 1.5 x 109/L |
Hold until recovery |
reduce by 25% |
|
Febrile neutropenia, thrombocytopenic bleeding |
Hold until recovery |
reduce by 25% |
|
Grade 3 non-hematologic toxicity |
Hold until recovery |
reduce by 25% |
| Suspected encephalopathy | Hold and investigate (preferablly with MRI) | Discontinue if confirmed |
|
Grade 4 non-hematologic toxicity OR Any grade neurotoxicity, hemolysis OR Suspected/proven pneumonitis/fibrosis |
Discontinue |
Discontinue |
No data available; use with caution.
|
Creatinine clearance (mL/min) |
Dose |
|
30-70 |
50% |
|
< 30 |
CONTRAINDICATED |
Limited data available. Exercise caution and assess creatinine clearance.
Safety and efficacy not established.
- Oral: Self-administration; drug available by outpatient prescription. Tablets should be swallowed whole with water, and should not be broken, crushed or chewed.
- In clinical investigation, pharmacokinetic parameters after oral administration were not significantly affected by concomitant food intake.
- Intravenous: Mix in 50mL minibag (Normal Saline or Dextrose 5%); Give over 30 minutes. Do not admix with other drugs.
- Patients who are hypersensitive to this drug or its components
- Patients who have severe renal impairment (< 30 mL/min)
- Patients who have decompensated hemolytic anemia
- The use of fludarabine in combination with pentostatin (deoxycoformycin) is contraindicated due to unacceptably high incidence of fatal pulmonary toxicity.
- Patients with GI toxicity should be monitored carefully as volume depletion may reduce clearance and increase toxicity.
- Usage in high dose is not recommended (see "Adverse Effects" section) because of the risk of severe toxicity.
- Fludarabine is associated with myelosuppression, irreversible CNS effects, and auto-immune anemia, including some fatal cases.
- Use with caution in patients with poor performance status, infections, immunosuppression or myelosuppression.
- Irradiated blood products should be used to minimize the risk of transfusion related Graft versus Host disease.
- Consider prophylaxis in patients at increased risk of developing opportunistic infections.
- Avoid the use of live vaccines.
Pregnancy and Lactation:
- Fludarabine is clastogenic, teratogenic and embryotoxic; it crosses the placenta and inhibits spermatogenesis. It is contraindicated in pregnancy.
- Adequate contraception must be used by both sexes, during treatment and for at least 6 months after fludarabine cessation.
- Since fludarabine is secreted into breast milk in animals, breast feeding is contraindicated.
- Effects on fertility are unknown.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Cytarabine | ↓ metabolism of fludarabine, increases intracellular concentration and exposure of cytarabine active metabolite | Competes for deoxycytidine kinase needed to convert both drugs to their active form | Clinical importance is yet unknown |
| Pentostatin (deoxycoformycin) | This combination may be associated with severe and/or fatal pulmonary toxicity | Unknown | Concurrent therapy is CONTRAINDICATED; avoid. |
| Dipyridamole and other inhibitors of adenosine uptake | ↓ effect of fludarabine | ↓ adenosine uptake | Avoid concomitant therapy |
| Live virus vaccines | May result in severe systemic infection | Immunosuppression | Avoid concourrent use |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recomendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and before each cycle |
Renal function tests |
Baseline and before each cycle |
Clinical toxicity assessment of fever, infection, hemolysis, dehydration, pulmonary, GI, CNS |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| Liver function tests | Baseline and regular |
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)
Coiffier B, Neidhardt-Berard EM, Tilly H, et al. Fludarabine alone compared to CHVP plus interferon in elderly patients with follicular lymphoma and adverse prognostic parameters: a GELA study. Annals of Oncology 1999; 10: 1191-7.
Foran JM, Rohatiner AZS, Coiffier B, et al. Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, waldenstrom’s macroglobulinemia, and mantle cell lymphoma. JCO 1999; 17: 546-53.
Product Monograph: Fludara® (fludarabine). Sanofi-Aventis Canada, September 18, 2014.
Product Monograph: Fludarabine Phosphate. Novopharm Limited, July 19, 2006.
Product Monograph: Fludarabine Phosphate: Hospira Healthcare Corp., June 18, 2007.
April 2023 Removed NDFP forms
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