Generic Name: Fludarabine Phosphate
Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 2-Fluoro-9-(5-O-phosphono-β-D-arabinofuranosyl)9H -purin-6-amine
Molecular Formula: C10H13FN5O7P
CAS Number: 75607-67-9
- Neurotoxicity
Possible severe neurologic effects (e.g., blindness, coma, death) following administration of high dosages (96 mg/m2; approximately 4 times the currently recommended dosage for chronic lymphocytic leukemia [CLL]) to patients with acute leukemia.1 2 3 5 6 9 29 30 31 45 95 Risk of CNS effects in patients receiving relatively low dosages (e.g., equivalent to those currently recommended for CLL).1 3 5 6 9 30 39 45 52 95 (See Neurotoxicity under Cautions.)
Introduction
Antimetabolite antineoplastic agent; synthetic purine antagonist.1 2 3 4 5 6 7 9 21 95
Uses for Fludara
Chronic Lymphocytic Leukemia (CLL)
Treatment of B-cell CLL (B-CLL) in patients refractory to at least one standard alkylating agent-containing regimen (e.g., chlorambucil with or without prednisone) or whose disease has progressed during treatment;1 2 3 4 6 14 15 20 21 44 58 64 considered a drug of choice.92 95 Has been designated an orphan drug by FDA for this use.25
Used in the management of previously untreated† CLL2 3 4 6 14 46 58 59 (has been designated an orphan drug by FDA for this use)25 or in leukemia that was contemporaneously responsive to standard therapy†.1 2 4 6 14 24 46 58 59
Non-Hodgkin’s Lymphoma
Treatment of low-grade, advanced (stage III or IV) adult non-Hodgkin’s lymphoma† that failed or relapsed after previous therapy†;2 6 15 23 39 40 41 62 63 92 has been designated an orphan drug by FDA for use in this condition.25
Acute Leukemias
Treatment of either acute myeloid (myelogenous, nonlymphocytic) leukemia† (AML, ANLL) or acute lymphocytic leukemia† (ALL) refractory to conventional therapy or which has relapsed following remission.2 5 29 30 31 45 92
Severe toxicity, associated with the relatively high dosages that appear to be necessary for adequate response in these leukemias, may preclude use of the drug as monotherapy for remission induction of these cancers.2 5 29 30 31 45 80 87 92
Prolymphocytic Leukemia and Prolymphocytoid Variant
Palliative treatment of prolymphocytic leukemia† (PLL) or prolymphocytoid chronic lymphocytic leukemia† (CLL-Pro) refractory to standard chemotherapy (e.g., chlorambucil and prednisone).34 35 36 37 38 42
Hairy Cell Leukemia
Treatment of hairy cell leukemia† (leukemic reticuloendotheliosis); other drugs (e.g., cladribine, pentostatin) considered the initial therapies of choice.28 64 88 89 90 91 92 93 94
Waldenstrom’s Macroglobulinemia
Treatment of refractory macroglobulinemia†.6 21
Mycosis Fungoides
Treatment of mycosis fungoides, a form of cutaneous T-cell lymphoma†.52 92
Fludara Dosage and Administration
General
Risk of certain toxic effects (e.g., neurotoxicity) is increased with increasing dosage.1 2 3 4 5 6 9 29 30 31 45
Consult specialized references for procedures for proper handling and disposal of antineoplastics.1 95
Administration
IV Administration
Administer by IV infusion.1 2 4 5 6 9 15 20 21 22 23 29 31 33 36 59 65 95
Has been administered by rapid IV injection† and by continuous† IV infusion (e.g., over 48 hours).2 4 5 6 15 30 41 43 62 65
Handle with caution (by trained nonpregnant personnel); use protective equipment (e.g., latex gloves, protective eyewear).1 Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.1 95 If powder or solution of the drug comes in contact with the skin or mucosa, immediately wash affected area thoroughly with soap and water; flush affected eye(s) thoroughly with water1 or saline.80
Reconstitution
Reconstitute vial containing 50 mg of fludarabine phosphate powder by adding 2 mL of sterile water for injection to provide a solution containing 25 mg/mL.1
Agitate the solution for complete dissolution of the drug in ≤15 seconds.80
Dilution
Using the commercially available (25 mg/mL) or reconstituted solution, withdraw the appropriate dose and add to a compatible IV fluid (e.g., 100 or 125 mL of 5% dextrose or 0.9% sodium chloride injection).1 95
Rate of Administration
Administer by IV infusion over 30 minutes.1 9 80 95
It is not known whether the rate of IV administration affects the risk of toxicity; neurotoxicity has occurred with rapid IV injection or slow IV infusion.30 80 87
Dosage
Available as fludarabine phosphate; dosage expressed in terms of the salt.1 9 95
Pediatric Patients
Other Neoplasms†
Acute Lymphocytic Leukemia (ALL)†
IV
10.5 mg/m2 as a loading dose followed by 30.5 mg/m2 as a continuous infusion daily for 5 days tested in pediatric patients.1 95
Solid Tumors
IV
Maximum tolerated dose was 7 mg/m2 as a loading dose followed by 20 mg/m2 as a continuous infusion daily for 5 days.1 95
Adults
Chronic Lymphocytic Leukemia (CLL)
IV
Initially, 25 mg/m2 administered as a single daily dose for 5 consecutive days;1 3 6 68 80 87 dosages up to 30 mg/m2 have been administered as a single daily dose for 5 consecutive days.3 4 6 58 87 95
Administer each 5-day course of therapy at 28-day intervals.1 3 6 Initially may administer for at least 2 or 3 courses to determine patient response, unless unacceptable toxicity or disease progression occurs.3 80 87 Continue therapy until a maximal response achieved or dose-limiting toxicity develops; if maximal response achieved without such toxicity, administer 3 additional courses of therapy and then discontinue the drug.1 3 95
Decrease dosage or temporarily withhold therapy if evidence of hematologic or nonhematologic toxicity occurs;1 delay or permanently discontinue drug if neurologic toxicity develops.1 (See Neurotoxicity under Cautions.)
Some patients have received up to 15 courses of therapy.1 3 95
Adjust dosage in patients who may be predisposed to fludarabine-induced toxicity (e.g., those with advanced age and/or impaired renal or bone marrow function).1 41
Other Neoplasms†
IV
Administer 18–30 mg/m2 daily for 5 consecutive days at 28-day intervals.2 6 21 22 23 32 33 36 38 41 52
Prescribing Limits
Pediatric Patients
Other Neoplasms†
Solid Tumors†
IV
Maximum 7 mg/m2 (as a loading dose) followed by 20 mg/m2 once daily for 5 days.1
Adults
Chronic Lymphocytic Leukemia (CLL)
IV
Maximum 40 mg/m2 daily for 5 days may be well tolerated,29 but the relative risk to benefit of dosages exceeding those currently recommended remains to be established; such dosages currently are not recommended except under controlled clinical conditions (e.g., in investigational protocols).80 87
Special Populations
Renal Impairment
Decrease dosage by 20% in patients with moderate renal impairment (Clcr 30–70 mL/minute); not recommended in patients with severe renal impairment (Clcr <30 mL/minute).1 95
Geriatric Patients
Possible age-related decreases in renal function; adjust dosage accordingly.1 95
Consider substantial dosage reduction in patients with advanced Rai stage CLL.4
Cautions for Fludara
Contraindications
Warnings/Precautions
Warnings
Neurotoxicity
Severe, potentially irreversible or fatal neurologic effects (e.g., delayed, progressive encephalopathy and blindness, coma) reported;1 2 3 5 6 9 29 30 31 45 95 manifestations usually appear 21–60 days after completion of a course of therapy.1 2 29 30 31 95
Neurotoxicity appears to be dose related:1 2 3 6 9 29 30 31 45 95 usually occurring with dosages higher than those currently recommended for CLL.1 2 3 5 6 9 29 30 31 41 45 However, such toxicity may occur rarely at relatively low dosages.1 3 5 9 30 45 52 95
Monitoring for visual changes as evidence of neurotoxicity has been suggested.30
Hematologic Effects
Risk of severe, cumulative, often reversible, myelosuppression (e.g., anemia, thrombocytopenia, neutropenia).1 2 3 4 5 6 9 22 23 39 95 95
Dosage adjustment and interruption of therapy and/or transfusions may be needed depending on severity of myelosuppression.9 Recovery of neutrophil and platelet count usually is complete within 5–7 weeks after discontinuance of therapy, but occasionally may require longer periods.87
Risk of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes fatal.1 95 Clinically significant cytopenia may last 2–12 months.1 95
Risk of life-threatening and sometimes fatal autoimmune hemolytic anemia, may recur upon rechallenge; close monitoring for hemolysis recommended.1 95 Not known whether corticosteroids are beneficial for management of these hemolytic episodes.1 95
Transfusion-associated Graft-versus-host Disease
Possible transfusion-associated graft-versus-host disease following transfusion of nonirradiated blood products.1 95 Consider use of irradiated blood products in patients requiring blood transfusions.1 95
Pulmonary Toxicity
Risk of severe and/or fatal pulmonary toxicity (e.g., pneumonitis) when administered concomitantly with pentostatin; do not use fludarabine with pentostatin.1 8 87 95 (See Specific Drugs under Interactions.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm (skeletal malformations, external deformities); avoid pregnancy during therapy.1 95
Use during pregnancy only in life-threatening situations or severe disease when safer drugs cannot be used or are ineffective.80 87
If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 95
Sensitivity Reactions
Pulmonary Hypersensitivity
Possible pulmonary hypersensitivity (diffuse interstitial pneumonitis characterized by dyspnea, hypoxia, cough, and pulmonary infiltrates).1 3 5 6 9 35 60 51 95
Interstitial pneumonitis usually delayed, occurring 3–28 days after administration of the third or later course of therapy.2 5 6 35 50
General Precautions
Toxicity and Adequate Patient Monitoring
Highly toxic, very low therapeutic index; therapeutic response is unlikely without some evidence of toxicity.1 3 4 5 6 9 29 30 31 41 45 (See Boxed Warning.) Severe toxicity most likely in poor risk patients (e.g., geriatric patients, those with impaired renal or bone marrow function), but fatality may occur in those in relatively good condition.
Administer only under supervision of a qualified clinician experienced in the use of cytotoxic therapy.1 9 95
Closely observe for signs of hematologic and nonhematologic toxicity during therapy.1 30 65 95
If severe adverse effects occur, discontinue therapy or reduce dosage and institute appropriate measures as necessary.1 9 65 87 95
Tumor Lysis Syndrome
May occur as a result of CLL treatment.1 3 6 9 53 65 95
Increased risk in patients with large initial tumor burden.1 95
Closely monitor such patients and take appropriate precautions.1 95 Consider potential benefit of prophylactic allopurinol, adequate hydration, and/or urinary alkalinization.53 65 80 87
Specific Populations
Pregnancy
Category D.
Lactation
Not known whether fludarabine is distributed into milk.1 95 Discontinue nursing or the drug.1 95
Pediatric Use
Safety and efficacy not established.1 80 87 95
In clinical studies in a limited number of pediatric patients with certain cancers (e.g., acute leukemia, solid tumors),2 5 43 adverse effect profile generally was similar to that in adults.5 43 87
Bone marrow suppression (particularly thrombocytopenia), fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection were reported.1 95 Pulmonary hypersensitivity and peripheral neuropathy not reported.1 95
Geriatric Use
Safety and efficacy in geriatric patients have not been studied specifically to date; however, CLL, for which safety and efficacy have been established,1 2 3 4 6 9 14 15 20 21 58 occurs principally in patients >50 years of age.24 58 61
Possible increased risk of fludarabine-induced toxicity due to age-related decrease in renal function.1 26 95 Closely monitor such patients (especially those with advanced Rai stage CLL)4 and adjust dosage accordingly.1 95
Renal Impairment
Clearance of fludarabine directly correlates with creatinine clearance.1 41 80 87 95
Possible increased risk of fludarabine-induced toxicity;1 2 3 95 monitor closely for excessive toxicity.1 95
Adjust dosage carefully in patients with impaired renal function;1 41 80 87 95 reduce dosage in those with moderate renal impairment.1 95 Do not use fludarabine in patients with severe renal impairment.1 95 (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Nausea and/or vomiting,1 2 3 4 6 9 22 23 95 anorexia,1 9 95 diarrhea,1 3 4 6 22 95 GI bleeding,1 9 95 fever,1 3 4 22 95 chills,1 95 rash,1 2 3 4 6 9 22 95 urinary tract infection,1 9 95 edema,1 3 9 95 cough,1 4 95 dyspnea,1 4 95 upper respiratory infection,1 9 95 infection,1 3 4 22 38 95 weakness,1 3 9 95 pain,1 9 95 malaise,1 9 22 95 fatigue,1 9 22 95 paresthesia,1 3 9 95 visual disturbances.19 23 39
Interactions for Fludara
Specific Drugs
Drug
|
Interaction
|
Comments
|
|---|
Corticosteroids (prednisone)
|
Increased incidence of opportunistic infections 44
|
Prednisone should be omitted from regimens containing fludarabine or other purine antagonists44
|
Cytarabine
|
Cytarabine substantially decreases fludarabine metabolism7 67 74 and may inhibit the antineoplastic effect of fludarabine 67
|
|
Pentostatin
|
Possible severe and/or fatal pulmonary toxicity (e.g., pneumonitis)1 8 87
|
Concomitant therapy is not recommended1 8 87
|
Fludara Pharmacokinetics
Pharmacokinetic parameters generally are expressed in terms of fludarabine (2-fluoro-ara-A) and fludarabine triphosphate (2-fluoro-ara-ATP).80 81
Distribution
Extent
Widely distributed,2 9 69 80 with highest concentrations in the liver, kidneys, and spleen.2 9 70 85
Extent of distribution into CNS in humans is not known.2 3 5 6 9 29 30 31 45
Apparently crosses the placenta.1 95 Not known whether fludarabine is distributed into human milk.1 95
Plasma Protein Binding
Approximately 19–29%.1 95
Special Populations
AUC is similar in patients with moderate renal impairment (Clcr 17–41 mL/minute per 1.73 m2) to those with normal renal function.1 95
Elimination
Metabolism
Fludarabine monophosphate is rapidly and completely dephosphorylated to fludarabine (2-fluoro-ara-A; an active metabolite) and then phosphorylated intracellularly via deoxycytidine kinase to fludarabine triphosphate (2-fluoro-ara-ATP; an active metabolite).1 2 3 4 5 6 7 62 66 67 68 69 70 75 76 77 78 79 95
Elimination Route
Excreted principally in urine as fludarabine (2-fluoro-ara-A).1 41 95
Half-life
Terminal half-life is about 20 hours.1 95
Special Populations
Total body clearance is 124 and 172 mL/minute in patients with moderate renal impairment (Clcr 17–41 mL/minute per 1.73 m2) and in those with normal renal function, respectively.1 95
Stability
Storage
Parenteral
Powder for Injection
2–8°C.1 Do not store at room temperature.80
Use reconstituted and diluted solutions within 8 hours after preparation.1 11 80
Injection
2–8°C.95
Discard unused solution within 8 hours after initial entry into vial.95 80
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Drug Compatibility
Y-Site CompatibilityHID
Compatible
|
|---|
Allopurinol sodium
|
Amifostine
|
Amikacin sulfate
|
Aminophylline
|
Ampicillin sodium
|
Ampicillin sodium–sulbactam sodium
|
Amsacrine
|
Aztreonam
|
Bleomycin sulfate
|
Butorphanol tartrate
|
Carboplatin
|
Carmustine
|
Cefazolin sodium
|
Cefepime HCl
|
Cefotaxime sodium
|
Ceftazidime
|
Ceftizoxime sodium
|
Ceftriaxone sodium
|
Cefuroxime sodium
|
Cimetidine HCl
|
Cisplatin
|
Clindamycin phosphate
|
Co-trimoxazole
|
Cyclophosphamide
|
Cytarabine
|
Dacarbazine
|
Dactinomycin
|
Dexamethasone sodium phosphate
|
Diphenhydramine HCl
|
Doxorubicin HCl
|
Doxycycline hyclate
|
Droperidol
|
Etoposide
|
Etoposide phosphate
|
Famotidine
|
Filgrastim
|
Floxuridine
|
Fluconazole
|
Fluorouracil
|
Furosemide
|
Gemcitabine HCl
|
Gentamicin sulfate
|
Granisetron HCl
|
Haloperidol lactate
|
Heparin sodium
|
Hydrocortisone sodium phosphate
|
Hydrocortisone sodium succinate
|
Hydromorphone HCl
|
Ifosfamide
|
Imipenem–cilastatin sodium
|
Lorazepam
|
Magnesium sulfate
|
Mannitol
|
Melphalan HCl
|
Meperidine HCl
|
Mesna
|
Methotrexate sodium
|
Methylprednisolone sodium succinate
|
Metoclopramide HCl
|
Minocycline HCl
|
Mitoxantrone HCl
|
Morphine sulfate
|
Multivitamins
|
Nalbuphine HCl
|
Ondansetron HCl
|
Pentostatin
|
Piperacillin sodium–tazobactam sodium
|
Potassium chloride
|
Promethazine HCl
|
Ranitidine HCl
|
Sodium bicarbonate
|
Teniposide
|
Thiotepa
|
Ticarcillin disodium–clavulanate potassium
|
Tobramycin sulfate
|
Vancomycin HCl
|
Vinblastine sulfate
|
Vincristine sulfate
|
Vinorelbine tartrate
|
Zidovudine
|
Incompatible
|
|---|
Acyclovir sodium
|
Amphotericin B
|
Chlorpromazine HCl
|
Daunorubicin HCl
|
Ganciclovir sodium
|
Hydroxyzine HCl
|
Prochlorperazine edisylate
|
ActionsActions
Exact mechanism(s) not fully elucidated, but appears to involve inhibition of α-DNA polymerase, ribonucleotide reductase, and DNA primase through competition with the physiologic substrate, deoxyadenosine triphosphate, resulting in inhibition of DNA synthesis.1 2 3 4 5 6 7 95
T cells are more sensitive than B cells to fludarabine's cytotoxic effects;2 4 drug is highly active against B-cell lymphoproliferative disorders, including CLL.1 2 3 4 6 9 14 15 20 21 58 64 Cytolytic effect appears to be relatively rapid even in neoplasms that are characterized by a slow proliferative rate.9 53
Advice to Patients
Importance of immediately informing clinician if fever, sore throat, or unusual bleeding or bruising occurs.80 87
Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy, advise pregnant women of risk to the fetus.1 95 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1 95
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Fludarabine Phosphate
Routes
|
Dosage Forms
|
Strengths
|
Brand Names
|
Manufacturer
|
|---|
Parenteral
|
For injection, for IV use only
|
50 mg
|
Fludara (with mannitol 50 mg)
|
Berlex
|
|
Injection, for IV use only
|
25 mg/mL*
|
Fludarabine Phosphate Injection (preservative-free; with mannitol 25 mg/mL)
|
Sicor
|
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
1. Berlex Laboratories. Fludara (fludarabine phosphate) for injection prescribing information. Montville, NJ: 2003 Oct.
2. Hood MA, Finley RS. Fludarabine: a review. DICP. 1991; 25:518-24. [IDIS 280755] [PubMed 2068837]
3. Anon. Fludarabine. Med Lett Drugs Ther. 1991; 33:89-90. (IDIS 285668)
4. Keating MJ. Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol. 1990; 17(Suppl 8):49-62. [PubMed 1699283]
5. Von Hoff DD. Phase I clinical trials with fludarabine phosphate. Semin Oncol. 1990; 17(Suppl 8):33-8. [PubMed 1699281]
6. Chun HG, Leyland-Jones B, Cheson BD. Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. J Clin Oncol. 1991; 9:175-88. [PubMed 1702143]
