Skip to Content


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
Brands: Fludara

Medically reviewed by Last updated on Jul 22, 2020.


  • Risk of severe bone marrow suppression.1 2 3 4 5 6 22 23 39 95 (See Hematologic Effects under Cautions.)

  • Possible life-threatening and sometimes fatal autoimmune hemolytic anemia after one or more courses of fludarabine therapy.1 Evaluate and monitor patients closely for hemolysis.1 95 (See Hematologic Effects under Cautions.)

  • 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.)

      Pulmonary Toxicity
    • Possible fatal pulmonary toxicity associated with concomitant use of fludarabine and pentostatin.1 8 87 Do not use fludarabine concomitantly with pentostatin.1 8 87 95 (See Specific Drugs under Interactions.)

      Experience of Supervising Clinician
    • Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.1 9 95


Antimetabolite antineoplastic agent; synthetic purine antagonist.1 2 3 4 5 6 7 9 21 95

Uses for Fludarabine

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

Fludarabine Dosage and Administration


  • 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


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


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


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


Available as fludarabine phosphate; dosage expressed in terms of the salt.1 9 95

Pediatric Patients

Other Neoplasms†
Acute Lymphocytic Leukemia (ALL)†

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

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


Chronic Lymphocytic Leukemia (CLL)

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†

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†

Maximum 7 mg/m2 (as a loading dose) followed by 20 mg/m2 once daily for 5 days.1


Chronic Lymphocytic Leukemia (CLL)

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 Fludarabine


  • Known hypersensitivity to fludarabine and/or any ingredient in the formulation.1 95




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


Category D.


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 Fludarabine

Specific Drugs




Corticosteroids (prednisone)

Increased incidence of opportunistic infections 44

Prednisone should be omitted from regimens containing fludarabine or other purine antagonists44


Cytarabine substantially decreases fludarabine metabolism7 67 74 and may inhibit the antineoplastic effect of fludarabine 67


Possible severe and/or fatal pulmonary toxicity (e.g., pneumonitis)1 8 87

Concomitant therapy is not recommended1 8 87

Fludarabine Pharmacokinetics

Pharmacokinetic parameters generally are expressed in terms of fludarabine (2-fluoro-ara-A) and fludarabine triphosphate (2-fluoro-ara-ATP).80 81



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



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


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




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



Discard unused solution within 8 hours after initial entry into vial.95 80


For information on systemic interactions resulting from concomitant use, see Interactions.

Drug Compatibility

Y-Site CompatibilityHID


Allopurinol sodium


Amikacin sulfate


Ampicillin sodium

Ampicillin sodium–sulbactam sodium



Bleomycin sulfate

Butorphanol tartrate



Cefazolin sodium

Cefepime HCl

Cefotaxime sodium


Ceftizoxime sodium

Ceftriaxone sodium

Cefuroxime sodium

Cimetidine HCl


Clindamycin phosphate






Dexamethasone sodium phosphate

Diphenhydramine HCl

Doxorubicin HCl

Doxycycline hyclate



Etoposide phosphate







Gemcitabine HCl

Gentamicin sulfate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium phosphate

Hydrocortisone sodium succinate

Hydromorphone HCl


Imipenem–cilastatin sodium


Magnesium sulfate


Melphalan HCl

Meperidine HCl


Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Minocycline HCl

Mitoxantrone HCl

Morphine sulfate


Nalbuphine HCl

Ondansetron HCl


Piperacillin sodium–tazobactam sodium

Potassium chloride

Promethazine HCl

Ranitidine HCl

Sodium bicarbonate



Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate



Acyclovir sodium

Amphotericin B

Chlorpromazine HCl

Daunorubicin HCl

Ganciclovir sodium

Hydroxyzine HCl

Prochlorperazine edisylate


  • 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.)


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fludarabine Phosphate


Dosage Forms


Brand Names



For injection, for IV use only

50 mg

Fludara (with mannitol 50 mg)


Injection, for IV use only

25 mg/mL*

Fludarabine Phosphate Injection (preservative-free; with mannitol 25 mg/mL)


AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.


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.

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.

5. Von Hoff DD. Phase I clinical trials with fludarabine phosphate. Semin Oncol. 1990; 17(Suppl 8):33-8.

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.

7. Plunkett W, Huang P, Gandhi V. Metabolism and action of fludarabine phosphate. Semin Oncol. 1990; 17(Suppl 8):3-17.

8. Parke-Davis. Nipent (pentostatin) for injection prescribing information. Morris Plains, NJ: 1991 Oct.

9. Berlex Laboratories. Fludara (fludarabine phosphate) for injection product monograph. Alameda, CA: 1991 Nov.

10. Trissel LA, Parks PT, Santiago NM. Visual compatibility of fludarabine phosphate with antineoplastic drugs, anti-infectives, and other selected drugs during simulated Y-site injection. Am J Hosp Pharm. 1991; 48:2186-9.

11. National Cancer Institute. Fludarabine. In: NCI investigational drugs pharmaceutical data 1990. 1990:72-4.

12. Cheson BD, Bennett JM, Grever M et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996; 87:4990-7.

13. Catovsky D, Fooks J, Richards S. Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survival. A report from the MRC CLL 1 trial. MRC Working Party on Leukaemia in Adults. Br J Haematol. 1989; 72:141-9.

14. Cheson BD. Current approaches to the chemotherapy of B-cell chronic lymphocytic leukemia: a review. Am J Hematol. 1989; 32:72-7.

15. Cheson BD. Recent advances in the treatment of B-cell chronic lymphocytic leukemia. Oncology (Williston Park). 1990; 4:71-8,83-4,87-8,90.

16. The French Cooperative Group on Chronic Lymphocytic Leukemia. A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. Blood. 1990; 75:1422-5.

17. The French Cooperative Group on Chronic Lymphocytic Leukemia. Effects of chlorambucil and therapeutic decision in initial forms of chronic lymphocytic leukemia (stage A): results of a randomized clinical trial on 612 patients. Blood. 1990; 75:1414-21.

18. French Cooperative Group on Chronic Lymphocytic Leukaemia. Natural history of stage A chronic lymphocytic leukaemia untreated patients. Br J Haematol. 1990; 76:45-57.

19. Keller JW, Knospe WH, Raney M et al. Treatment of chronic lymphocytic leukemia using chlorambucil and prednisone with or without cycle-active consolidation chemotherapy: a Southeastern Cancer Study Group Trial. Cancer. 1986; 1185-92.

20. Keating MJ, Kantarjian H, Talpaz M et al. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989; 74:19-25.

21. Kantarjian HM, Alexanian R, Koller CA et al. Fludarabine therapy in macroglobulinemic lymphoma. Blood. 1990; 75:1928-31.

22. Kantarjian HM, Redman JR, Keating MJ. Fludarabine phosphate therapy in other lymphoid malignancies. Semin Oncol. 1990; 17(Suppl 8):66-70.

23. Hochster H, Cassileth P. Fludarabine phosphate therapy of non-Hodgkin’s lymphoma. Semin Oncol. 1990; 17(Suppl 8):63-5.

24. Chronic lymphocytic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jun.

25. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food Drug and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

26. Food and Drug Administration. Specific requirements on content and format of labeling for human prescription drugs; proposed addition of “geriatric use” subsection in the labeling (Docket No. 89N-0474). Fed Regist. 1990; 55:46134-7.

27. Budavari S, ed. The Merck Index. 11th ed. Rahway, NJ: Merck & Co, Inc. 1989:645.

28. Hairy cell leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

29. Spriggs DR, Stopa E, Mayer RJ et al. Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study. Cancer Res. 1986; 46:5953-8.

30. Chun HG, Leyland-Jones BR, Caryk SM et al. Central nervous system toxicity of fludarabine phosphate. Cancer Treat Rep. 1986; 70:1225-8.

31. Warrell RP Jr, Berman E. Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol. 1986; 4:74-9.

32. Kantarjian HM, Schachner J, Keating MJ. Fludarabine therapy in hairy cell leukemia. Cancer. 1991; 67: 1291-3.

33. Kraut EH, Chun HG. Fludarabine phosphate in refractory hairy cell leukemia. Am J Hematol. 1991; 37:59-60.

34. Smith OP, Mehta AB. Fludarabine monophosphate for prolymphocytic leukaemia. Lancet. 1990; 336:820.

35. Cervantes F, Salgado C, Montserrat E et al. Fludarabine for prolymphocytic leukaemia and risk of interstitial pneumonitis. Lancet. 1990; 336:1130.

36. Kantarjian HM, Childs C, O’Brien S et al. Efficacy of fludarabine, a new adenine nucleoside analogue, in patients with prolymphocytic leukemia and the prolymphocytoid variant of chronic lymphocytic leukemia. Am J Med. 1991; 90:223-8.

37. Sporn JR. Sustained response of refractory prolymphocytic leukemia to fludarabine. Acta Haematol. 1991; 85: 209-11.

38. Whelan JS, Davis CL, Rule S et al. Fludarabine phosphate for the treatment of low grade lymphoid malignancy. Br J Cancer. 1991; 64:120-3.

39. Hochster HS, Kim KM, Green MD et al. Activity of fludarabine in previously treated non-Hodgkin’s low-grade lyphoma: results of an Eastern Cooperative Oncology Group study. J Clin Oncol. 1992; 10:28-32.

40. Cheson BD. New chemotherapeutic agents for non-Hodgkin’s lymphomas. Hematol Oncol Clin North Am. 1991; 5: 1027-51.

41. Grever M, Leiby J, Kraut E et al. A comprehensive phase I and II clinical investigation of fludarabine phosphate. Semin Oncol. 1990; 17(Suppl 8):39-48.

42. Bouroncle BA, Neff JC, Grever MR. Effectiveness of fludarabine monophosphate in prolymphocytic leukemia (PLL). Proc Am Soc Clin Oncol. 1990; 9:214.

43. Avramis VI, Champagne J, Sato J et al. Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients. Cancer Res. 1990; 50:7226-31.

44. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995; 333:1052-7.

45. Merkel DE, Griffin NL, Kagan-Hallet K et al. Central nervous system toxicity with fludarabine. Cancer Treat Rep. 1986; 70:1449-50.

46. Rai KR, Peterson BL, Appelbaum FR et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000; 343:1750-7.

47. Dighiero G, Binet J-L. When and how to treat chronic lymphocytic leukemia. N Engl J Med. 2000; 343:1799-801.

48. Morrison VA, Rai KR, Peterson BL et al. Impact of therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011. J Clin Oncol. 2001; 19:3611-21.

49. Harvey WH, Fleming TR, Beltran G et al. Phase II study of fludarabine phosphate in previously untreated patients with hepatoma: a Southwest Oncology Group study. Cancer Treat Rep. 1987; 71:1111-2.

50. Hurst PG, Habib MP, Garewal H et al. Pulmonary toxicity associated with fludarabine monophosphate. Invest New Drugs. 1987; 5:207-10.

51. Schilling PJ, Vadhan-Raj S. Concurrent cytomegalovirus and pneumocystis pneumonia after fludarabine therapy for chronic lymphocytic leukemia. N Engl J Med. 1991; 323:833-4.

52. Von Hoff DD, Dahlberg S, Hartstock RJ et al. Activity of fludarabine monophosphate in patients with advanced mycosis fungoides: a Southwest Oncology Group Study. J Natl Cancer Inst. 1990; 82:1353-5.

53. List AF, Kummet TD, Adams JD et al. Tumor lysis syndrome complicating treatment of chronic lymphocytic leukemia with fludarabine phosphate. Am J Med. 1990; 89:388-90.

54. Weeks JC, Tierney MR, Weinstein MC. Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. N Engl J Med. 1991; 325:81-6.

55. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia: a randomized, controlled clinical trial. N Engl J Med. 1988; 319:902-7.

56. Griffiths H, Brennan V, Lea J et al. Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood. 1989; 73:366-8.

57. ASHP Commission on Therapeutics. ASHP therapeutic guidelines for intravenous immune globulin. Clin Pharm. 1992; 11:117-36.

58. Foon KA, Rai KR, Gale RP. Chronic lymphocytic leukemia: new insights into biology and therapy. Ann Intern Med. 1990; 113:525-9.

59. Keating MJ, Kantarjian H, O’Brien S et al. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol. 1991; 9:44-9.

60. Weiss GR, Bayne J, Kuhn JG et al. A clinical-pharmacological study of the intraperitoneal administration of fludarabine phosphate. Region Cancer Treat. 1990; 3:158-62.

61. In: Wilson JD, Braunwald E, Isselbacher KJ et al, eds. Harrison’s principles of internal medicine. l2th ed. New York: McGraw-Hill Company; 1991:1559-61.

62. Leiby JM, Snider KM, Kraut EH et al. Phase II trial of 9-β-D-arabinosyl-2-fluoradenine 5′-monophosphate in non-Hodgkin’s lymphoma: prospective comparison of response with deoxycytidine kinase activity. Cancer Res. 1987; 47:2719-22.

63. Adult non-Hodgkin’s lymphoma. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

64. Saven A, Piro L. Newer purine analogues for the treatment of hairy-cell leukemia. N Engl J Med. 1994; 330:691-7.

65. National Cancer Institute Cancer Therapy Evaluation Program. Group C treatment protocol: Fludarabine phosphate in patients with refractory chronic lymphocytic leukemia. NCI protocol No. I89-0018. Bethesda, MD: National Cancer Institute; 1989.

66. Hersh MR, Kuhn JG, Phillips JL et al. Pharmacokinetic study of fludarabine phosphate (NSC 312887). Cancer Chemother Pharmacol. 1986; 17:277-80.

67. Danhauser L, Plunkett W, Liliemark J et al. Comparison between the plasma and intracellular pharmacology of 1-β-d-arabinofuranosylcytosine and 9-β-d-arabinofuranosyl-2-fluoroadenine 5′-monophosphate in patients with relapsed leukemia. Leukemia. 1987; 1:638-43.

68. Danhauser L, Plunkett W, Keating M et al. 9-β-d-arabinofuranosyl-2-fluoroadenine 5′-monophosphate pharmacokinetics in plasma and tumor cells of patients with relapsed leukemia and lymphoma. Cancer Chemother Pharmacol. 1986; 18:145-52.

69. Malspeis L, Grever MR, Staubus AE et al. Pharmacokinetics of 2-F-ara-A (9-β-d-arabinofuranosyl-2-fluoroadenine) in cancer patients during phase I clinical investigation of fludarabine phosphate. Semin Oncol. 1990; 17(Suppl 8):18-32.

70. Noker PE, Duncan GF, El Dareer SM et al. Disposition of 9-β-d-arabinofuranosyl-2-fluoroadenine 5′-phosphate in mice and dogs. Cancer Treat Rep. 1983; 67:445-56.

71. Tseng WC, Derse D, Cheng YC et al. In vitro biological activity of 9-β-d-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol Pharmacol. 1982; 21:474-7.

72. Brockman RW, Cheng YC, Schabel FM Jr et al. Metabolism and chemotherapeutic activity of 9-β-d-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase. Cancer Res. 1980; 40:3610-5.

73. Brockman RW, Schabel FM Jr, Montgomery JA. Biologic activity of 9-β-d-arabinofuranosyl-2-fluoroadenine, a metabolically stable analog of 9-β-d-arabinofuranosyladenine. Biochem Pharmacol. 1977; 26:2193-6.

74. Gandhi V, Plunkett W. Modulation of arabinosylnucleoside metabolism by arabinosylnucleotides in human leukemia cells. Cancer Res. 1988; 48:329-34.

75. Avramis VI. Pharmacodynamics and proposed mechanism of therapeutic action and host toxicity of 9-β-d-arabinofuranosyl-2-fluoroadenine monophosphate (F-araAMP) in P338 murine leukemia-bearing mice. Cancer Invest. 1989; 7:129-37.

76. Barreuco JR, Jacobsen DM, Chang CH et al. Proposed mechanism of therapeutic selectivity for 9-β-d-arabinofuranosyl-2-fluoroadenine against murine leukemia based upon lower capacities for transport and phosphorylation in proliferative intestinal epithelium compared to tumor cells. Cancer Res. 1987; 47:700-6.

77. Sirotnak FM, Chello PL, Dorick DM et al. Specificity of systems mediating transport of adenosine, 9-β-d-arabinofuranosyl-2-fluoroadenine, and other purine nucleoside analogues in L1210 cells. Cancer Res. 1983; 43:104-9.

78. Avramis VI, Plunkett W. Metabolism of 9-β-d-arabinosyl-2-fluoroadenine-5′-phosphate by mice bearing P338 leukemia. Cancer Drug Deliv. 1983; 1:1-10.

79. Dow LW, Bell DE, Poulakos L et al. Differences in metabolism and cytotoxicity between 9-β-d-arabinofuranosyladenine and 9-β-d-arabinofuranosyl-2-fluoroadenine in human leukemic lymphoblasts. Cancer Res. 1980; 40:1405-10.

80. Berlex Laboratories, Alameda, CA: Personal communication.

81. Avramis VI, Plunkett W. 2-fluoro-ATP: a toxic metabolite of 9-β-d-arabinosyl-2-fluoroadenine. Biochem Biophys Res Commun. 1983; 113:35-43.

82. Jensen KF, Nygaard P. Purine nucleoside phosphorylase from Escherichia coli and Salmonella typhimurium: purification and some properties. Eur J Biochem. 1975; 51:253-65.

83. Huang P, Plunkett W. Phosphorylytic cleavage of 2-fluoroadenine from 9-β-d-arabinofuranosyl -2-fluoroadenine by Escherichia coli: a pathway for 2-fluoro-ATP production. Biochem Pharmacol. 1987; 36:2945-50.

84. Avramis VI, Plunkett W. Metabolism and therapeutic efficacy of 9-β-d-arabinofuranosyl-2-fluoroadenine against murine leukemia P388. Cancer Res. 1982; 42:2587-91.

85. El Dareer SM, Struck RF, Tillery KF et al. Disposition of 9-β-d-arabinofuranosyl-2-fluoroadenine in mice, dogs, and monkeys. Drug Metab Dispos. 1980; 8:60-3.

86. Struck RF, Shortnacy AT, Kirk MC et al. Identification of metabolites of 9-β-d-arabinofuranosyl-2-fluoroadenine, an antitumor and antiviral agent. Biochem Pharmacol. 1982; 31:1975-8.

87. Reviewers’ comments (personal observations).

88. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet. 1993; 340:952-6.

89. Jaiyesimi IA, Kantarjian HM, Estey EH. Advances in therapy for hairy cell leukemia. A review. Cancer. 1993; 72:5-16.

90. Spielberger RT, Golomb HM. Hairy cell leukemia 1992. Leukemia. 1992; 6(Suppl 4):142-6.

91. Golomb HM, Ratain MJ, Mick R et al. The treatment of hairy cell leukemia: an update. Leukemia. 1992; 6(Suppl 2):24-7.

92. Anon. Drugs of choice for cancer . Treat Guidel Med Lett.. 2005; 1:41-52.

93. Saven A, Piro LD. Treatment of hairy cell leukemia. Blood. 1992; 79:1111-20.

94. Bryson HM, Sorkin EM. Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies. Drugs. 1993; 46:872-94.

95. Sicor. Fludarabine phosphate injection (for intravenous use only) prescribing information. Irvine, CA; 2005 Nov.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:730-4.