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Fludara

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

Warning(s)

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

  • Hemolysis
  • 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.)

  • 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.)

    • 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

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

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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

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

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

Actions

  • 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

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 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

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