Introduction

Antimetabolite antineoplastic agent; synthetic purine antagonist.

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; considered a drug of choice. Has been designated an orphan drug by FDA for this use.

Used in the management of previously untreated^{† [off-label]} CLL (has been designated an orphan drug by FDA for this use) or in leukemia that was contemporaneously responsive to standard therapy^{† [off-label]}.

Non-Hodgkin’s Lymphoma

Treatment of low-grade, advanced (stage III or IV) adult non-Hodgkin’s lymphoma^{† [off-label]} that failed or relapsed after previous therapy^{† [off-label]}; has been designated an orphan drug by FDA for use in this condition.

Acute Leukemias

Treatment of either acute myeloid (myelogenous, nonlymphocytic) leukemia^{† [off-label]} (AML, ANLL) or acute lymphocytic leukemia^† (ALL) refractory to conventional therapy or which has relapsed following remission.

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.

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).

Hairy Cell Leukemia

Treatment of hairy cell leukemia^† (leukemic reticuloendotheliosis); other drugs (e.g., cladribine, pentostatin) considered the initial therapies of choice.

Waldenstrom’s Macroglobulinemia

Treatment of refractory macroglobulinemia^†.

Mycosis Fungoides

Treatment of mycosis fungoides, a form of cutaneous T-cell lymphoma^†.

Fludarabine Dosage and Administration

General

• Risk of certain toxic effects (e.g., neurotoxicity) is increased with increasing dosage.

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Administration

IV Administration

Administer by IV infusion.

Has been administered by rapid IV injection^† and by continuous^† IV infusion (e.g., over 48 hours).

Handle with caution (by trained nonpregnant personnel); use protective equipment (e.g., latex gloves, protective eyewear). Avoid exposure by inhalation or by direct contact of the skin or mucous membranes. 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 water or saline.

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.

Agitate the solution for complete dissolution of the drug in ≤15 seconds.

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).

Rate of Administration

Administer by IV infusion over 30 minutes.

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.

Dosage

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

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.

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.

Adults

Chronic Lymphocytic Leukemia (CLL)

IV

Initially, 25 mg/m² administered as a single daily dose for 5 consecutive days; dosages up to 30 mg/m² have been administered as a single daily dose for 5 consecutive days.

Administer each 5-day course of therapy at 28-day intervals. Initially may administer for at least 2 or 3 courses to determine patient response, unless unacceptable toxicity or disease progression occurs. 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.

Decrease dosage or temporarily withhold therapy if evidence of hematologic or nonhematologic toxicity occurs; delay or permanently discontinue drug if neurologic toxicity develops. (See Neurotoxicity under Cautions.)

Some patients have received up to 15 courses of therapy.

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).

Other Neoplasms†

IV

Administer 18–30 mg/m² daily for 5 consecutive days at 28-day intervals.

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.

Adults

Chronic Lymphocytic Leukemia (CLL)

IV

Maximum 40 mg/m² daily for 5 days may be well tolerated, 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).

Special Populations

Renal Impairment

Decrease dosage by 20% in patients with moderate renal impairment (Cl_cr 30–70 mL/minute); not recommended in patients with severe renal impairment (Cl_cr <30 mL/minute).

Geriatric Patients

Possible age-related decreases in renal function; adjust dosage accordingly.

Consider substantial dosage reduction in patients with advanced Rai stage CLL.

Contraindications

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

Warnings/Precautions

Warnings

Neurotoxicity

Severe, potentially irreversible or fatal neurologic effects (e.g., delayed, progressive encephalopathy and blindness, coma) reported; manifestations usually appear 21–60 days after completion of a course of therapy.

Neurotoxicity appears to be dose related: usually occurring with dosages higher than those currently recommended for CLL. However, such toxicity may occur rarely at relatively low dosages.

Monitoring for visual changes as evidence of neurotoxicity has been suggested.

Hematologic Effects

Risk of severe, cumulative, often reversible, myelosuppression (e.g., anemia, thrombocytopenia, neutropenia).

Dosage adjustment and interruption of therapy and/or transfusions may be needed depending on severity of myelosuppression. Recovery of neutrophil and platelet count usually is complete within 5–7 weeks after discontinuance of therapy, but occasionally may require longer periods.

Risk of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes fatal. Clinically significant cytopenia may last 2–12 months.

Risk of life-threatening and sometimes fatal autoimmune hemolytic anemia, may recur upon rechallenge; close monitoring for hemolysis recommended. Not known whether corticosteroids are beneficial for management of these hemolytic episodes.

Transfusion-associated Graft-versus-host Disease

Possible transfusion-associated graft-versus-host disease following transfusion of nonirradiated blood products. Consider use of irradiated blood products in patients requiring blood transfusions.

Pulmonary Toxicity

Risk of severe and/or fatal pulmonary toxicity (e.g., pneumonitis) when administered concomitantly with pentostatin; do not use fludarabine with pentostatin. (See Specific Drugs under Interactions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm (skeletal malformations, external deformities); avoid pregnancy during therapy.

Use during pregnancy only in life-threatening situations or severe disease when safer drugs cannot be used or are ineffective.

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Sensitivity Reactions

Pulmonary Hypersensitivity

Possible pulmonary hypersensitivity (diffuse interstitial pneumonitis characterized by dyspnea, hypoxia, cough, and pulmonary infiltrates).

Interstitial pneumonitis usually delayed, occurring 3–28 days after administration of the third or later course of therapy.

General Precautions

Toxicity and Adequate Patient Monitoring

Highly toxic, very low therapeutic index; therapeutic response is unlikely without some evidence of toxicity. (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.

Closely observe for signs of hematologic and nonhematologic toxicity during therapy.

If severe adverse effects occur, discontinue therapy or reduce dosage and institute appropriate measures as necessary.

Tumor Lysis Syndrome

May occur as a result of CLL treatment.

Increased risk in patients with large initial tumor burden.

Closely monitor such patients and take appropriate precautions. Consider potential benefit of prophylactic allopurinol, adequate hydration, and/or urinary alkalinization.

Specific Populations

Pregnancy

Category D.

Lactation

Not known whether fludarabine is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

In clinical studies in a limited number of pediatric patients with certain cancers (e.g., acute leukemia, solid tumors), adverse effect profile generally was similar to that in adults.

Bone marrow suppression (particularly thrombocytopenia), fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection were reported. Pulmonary hypersensitivity and peripheral neuropathy not reported.

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, occurs principally in patients >50 years of age.

Possible increased risk of fludarabine-induced toxicity due to age-related decrease in renal function. Closely monitor such patients (especially those with advanced Rai stage CLL) and adjust dosage accordingly.

Renal Impairment

Clearance of fludarabine directly correlates with creatinine clearance.

Possible increased risk of fludarabine-induced toxicity; monitor closely for excessive toxicity.

Adjust dosage carefully in patients with impaired renal function; reduce dosage in those with moderate renal impairment. Do not use fludarabine in patients with severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea and/or vomiting, anorexia, diarrhea, GI bleeding, fever, chills, rash, urinary tract infection, edema, cough, dyspnea, upper respiratory infection, infection, weakness, pain, malaise, fatigue, paresthesia, visual disturbances.

General

• Risk of certain toxic effects (e.g., neurotoxicity) is increased with increasing dosage.

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Administration

IV Administration

Administer by IV infusion.

Has been administered by rapid IV injection^† and by continuous^† IV infusion (e.g., over 48 hours).

Handle with caution (by trained nonpregnant personnel); use protective equipment (e.g., latex gloves, protective eyewear). Avoid exposure by inhalation or by direct contact of the skin or mucous membranes. 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 water or saline.

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.

Agitate the solution for complete dissolution of the drug in ≤15 seconds.

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).

Rate of Administration

Administer by IV infusion over 30 minutes.

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.

Dosage

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

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.

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.

Adults

Chronic Lymphocytic Leukemia (CLL)

IV

Initially, 25 mg/m² administered as a single daily dose for 5 consecutive days; dosages up to 30 mg/m² have been administered as a single daily dose for 5 consecutive days.

Administer each 5-day course of therapy at 28-day intervals. Initially may administer for at least 2 or 3 courses to determine patient response, unless unacceptable toxicity or disease progression occurs. 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.

Decrease dosage or temporarily withhold therapy if evidence of hematologic or nonhematologic toxicity occurs; delay or permanently discontinue drug if neurologic toxicity develops. (See Neurotoxicity under Cautions.)

Some patients have received up to 15 courses of therapy.

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).

Other Neoplasms†

IV

Administer 18–30 mg/m² daily for 5 consecutive days at 28-day intervals.

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.

Adults

Chronic Lymphocytic Leukemia (CLL)

IV

Maximum 40 mg/m² daily for 5 days may be well tolerated, 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).

Special Populations

Renal Impairment

Decrease dosage by 20% in patients with moderate renal impairment (Cl_cr 30–70 mL/minute); not recommended in patients with severe renal impairment (Cl_cr <30 mL/minute).

Geriatric Patients

Possible age-related decreases in renal function; adjust dosage accordingly.

Consider substantial dosage reduction in patients with advanced Rai stage CLL.

Specific Drugs