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Fludarabine: Drug information

Fludarabine: Drug information
(For additional information see "Fludarabine: Patient drug information" and see "Fludarabine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Bone marrow suppression:

Fludarabine can severely suppress bone marrow function.

Autoimmune effects:

Instances of life-threatening and sometimes fatal autoimmune phenomena, such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura, Evans syndrome, and acquired hemophilia, have been reported to occur after 1 or more cycles of treatment with fludarabine. Patients undergoing treatment with fludarabine should be evaluated and closely monitored for hemolysis.

Neurotoxicity:

When used at high doses in dose-ranging studies in patients with acute leukemia, fludarabine was associated with severe neurologic effects, including blindness, coma, and death. This severe CNS toxicity occurred in 36% of patients treated with dosages approximately 4 times greater (96 mg/m2/day for 5 to 7 days) than the recommended dosage. Similar severe CNS toxicity, including agitation, coma, confusion, and seizures, has been reported (0.2% or less) in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.

Combination with pentostatin:

In a clinical investigation using fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended.

Experienced physician:

Fludarabine injection should be administered under the supervision of a qualified health care provider experienced in the use of antineoplastic therapy.

Brand Names: Canada
  • Fludara
Pharmacologic Category
  • Antineoplastic Agent, Antimetabolite;
  • Antineoplastic Agent, Antimetabolite (Purine Analog)
Dosing: Adult

Note: Prophylactic anti-infectives should be considered for patients with an increased risk for developing opportunistic infections. Consider hydration and prophylactic antihyperuricemic therapy in patients at risk for tumor lysis syndrome.

Acute myeloid leukemia, newly diagnosed

Acute myeloid leukemia, newly diagnosed (off-label use): IV: 30 mg/m2/day for 5 days (in combination with cytarabine ± G-CSF ± idarubicin (FA, FLAG, or FLAG-IDA regimens), followed by consolidation therapy (Borthakur 2008; Burnett 2013).

Acute myeloid leukemia, refractory or high/poor-risk patients

Acute myeloid leukemia, refractory or high/poor-risk patients (off-label use): IV: 30 mg/m2/day for 5 days (in combination with cytarabine and filgrastim [FLAG regimen]), may repeat once for partial remission (Montillo 1998) or 30 mg/m2/day for 5 days for 1 or 2 cycles (in combination with cytarabine, idarubicin, and filgrastim [FLAG-IDA regimen]) (Virchis 2004).

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (off-label dosing/combinations):

FC regimen: IV: 30 mg/m2/day for 3 days every 28 days for 6 cycles (in combination with cyclophosphamide) (Eichhorst 2006) or 20 mg/m2/day for 5 days every 28 days for 6 cycles (in combination with cyclophosphamide) (Flinn 2007).

FCR regimen: IV: 25 mg/m2/day for 3 days every 28 days for 6 cycles (in combination with cyclophosphamide and rituximab) (Fischer 2016; Keating 2005; Robak 2010; Wierda 2005).

FR regimen: IV: 25 mg/m2/day for 5 days every 28 days for 6 cycles (in combination with rituximab) (Byrd 2003).

OFAR regimen: IV: 30 mg/m2/day for 2 days every 28 days for 6 cycles (in combination with oxaliplatin, cytarabine, and rituximab) (Tsimberidou 2008).

Chronic lymphocytic leukemia, refractory or progressive:

IV: 25 mg/m2 once daily for 5 consecutive days every 28 days; continue for at least 3 additional cycles after maximal response is achieved.

Oral (Canadian product; not available in US): 40 mg/m2 once daily for 5 consecutive days every 28 days.

Hematopoietic stem cell transplant, allogeneic, myeloablative conditioning regimen

Hematopoietic stem cell transplant, allogeneic, myeloablative conditioning regimen (off-label use): IV: 40 mg/m2/day for 4 days (in combination with busulfan) beginning 6 days prior to transplantation (Rambaldi 2015).

Hematopoietic stem cell transplant, allogeneic, reduced-intensity conditioning regimen

Hematopoietic stem cell transplant, allogeneic, reduced-intensity conditioning regimen (off-label use): IV: 30 mg/m2/day for 5 days (in combination with melphalan and alemtuzumab) prior to transplant (Tauro 2005) or 30 mg/m2/day for 6 days beginning 10 days prior to transplant or 30 mg/m2/day for 5 days beginning 6 days prior to transplant (in combination with busulfan with or without antithymocyte globulin) (Schetelig 2003) or 30 mg/m2/day for 2 days beginning 4 days prior to transplant (in combination with cyclophosphamide and thiotepa) (Corradini 2002).

Hematopoietic stem cell transplant, allogeneic, nonmyeloablative conditioning regimen

Hematopoietic stem cell transplant, allogeneic, nonmyeloablative conditioning regimen (off-label use): IV: 30 mg/m2/day for 3 doses beginning 5 days prior to transplant (in combination with cyclophosphamide and rituximab) (Khouri 2008) or 30 mg/m2/day for 3 doses beginning 4 days prior to transplant (in combination with total body irradiation) (Hegenbart 2006; Rezvani 2008).

Lymphodepleting therapy prior to chimeric antigen receptor T-cell immunotherapy

Lymphodepleting therapy prior to chimeric antigen receptor T-cell immunotherapy (off-label use):

Prior to axicabtagene ciloleucel: IV: 30 mg/m2/day for 3 days (in combination with cyclophosphamide) beginning 5 days (on days −5, −4, and −3) prior to chimeric antigen receptor (CAR) T-cell infusion on day 0 (Locke 2019; Neelapu 2017).

Prior to brexucabtagene autoleucel: IV: 30 mg/m2/day for 3 days (in combination with cyclophosphamide; for relapsed/refractory mantle cell lymphoma) beginning 5 days (on days −5, −4, and −3) prior to CAR T-cell infusion on day 0 (Wang 2020) or 25 mg/m2/day for 3 days beginning 4 days (on days −4, −3, and −2) prior to CAR T-cell infusion on day 0 (in combination with cyclophosphamide; for relapsed/refractory B-cell precursor acute lymphoblastic leukemia) (Shah 2021).

Prior to ciltacabtagene autoleucel: IV: 30 mg/m2/day for 3 days (in combination with cyclophosphamide) followed 2 to 4 days later by CAR T-cell infusion (Berdeja 2021).

Prior to idecabtagene vicleucel: IV: 30 mg/m2/day for 3 days (in combination with cyclophosphamide) beginning 5 days (on days −5, −4, and −3) prior to CAR T-cell infusion on day 0 (Munshi 2021).

Prior to lisocabtagene maraleucel: IV: 30 mg/m2/day for 3 days (in combination with cyclophosphamide) followed 2 to 7 days later by CAR T-cell infusion (Abramson 2020).

Prior to tisagenlecleucel : IV: 25 mg/m2/day for 3 days (in combination with cyclophosphamide; for relapsed/refractory diffuse large B-cell lymphoma) followed 2 to 11 days later by CAR T-cell infusion (Schuster 2019) or 30 mg/m2/day for 4 days (in combination with cyclophosphamide; for relapsed/refractory B-cell acute lymphoblastic leukemia) followed 2 to 14 days later by CAR T-cell infusion (Maude 2018).

Non-Hodgkin lymphoma, follicular lymphoma, relapsed/refractory

Non-Hodgkin lymphoma, follicular lymphoma, relapsed/refractory (off-label use):

FCR regimen: IV: 25 mg/m2/day for 3 days every 21 days for 4 cycles (in combination with cyclophosphamide and rituximab) (Sacchi 2007).

FR regimen: IV: 25 mg/m2/day for 5 days every 28 days for 6 cycles (in combination with rituximab) (Czuczman 2005).

Waldenstrom macroglobulinemia

Waldenstrom macroglobulinemia (off-label use):

Fludarabine monotherapy: IV: 25 mg/m2/day for 5 days every 28 days for 2 cycles after achieving complete or maximum response, up to a maximum of 8 cycles (Foran 1999).

FR regimen: IV: 25 mg/m2 once daily for 5 days during weeks 5, 9, 13, 19, 23, and 27 (in combination with rituximab) (Treon 2009).

FCR regimen: IV: 25 mg/m2/day on days 2 to 4 every 28 days (in combination with cyclophosphamide and rituximab) for up to 6 cycles (Tedeschi 2012).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Chronic lymphocytic leukemia :

IV:

CrCl ≥80 mL/minute: No dosage adjustment necessary (administer the usual dose of 25 mg/m2).

CrCl 50 to 79 mL/minute: Reduce dose to 20 mg/m2.

CrCl 30 to 49 mL/minute: Reduce dose to 15 mg/m2.

CrCl <30 mL/minute: Use is not recommended.

Oral (Canadian product; not available in US):

CrCl 30 to 70 mL/minute: Reduce dose by up to 50%.

CrCl <30 mL/minute: Use is contraindicated.

The following adjustments have also been recommended: IV:

Krens 2019:

eGFR >70 mL/minute: No dosage adjustment necessary.

eGFR 30 to 70 mL/minute: Reduce dose to 80% of the original dose.

eGFR <30 mL/minute: Use is not recommended.

Hemodialysis: Reduce dose to 80% of the original dose; start dialysis 12 hours after fludarabine administration.

Aronoff 2007:

CrCl 10 to 50 mL/minute: Reduce dose to 75% of usual dose.

CrCl <10 mL/minute: Reduce dose to 50% of usual dose.

CAPD: Reduce dose to 50% of usual dose.

CRRT: Reduce dose to 75% of usual dose.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, dosage adjustment for hepatic impairment is not likely necessary (Krens 2019).

Dosing: Pediatric

(For additional information see "Fludarabine: Pediatric drug information")

Refer to individual protocols; details concerning dosing in combination regimens should also be consulted.

Acute lymphocytic leukemia (ALL) or AML, relapsed: Limited data available: Children and Adolescents: IV:

Continuous IV infusion: 10.5 mg/m2 bolus followed by 30.5 mg/m2/day for 48 hours in combination with cytarabine (Avramis 1998)

Intermittent IV dosing: 25 mg/m2 once daily for 5 days in combination with cytarabine and daunorubicin was used for ALL (Parker 2010)

Stem cell transplant (allogeneic) conditioning regimen, reduced-intensity (hematologic malignancy): Limited data available: Children and Adolescents: IV: 30 mg/m2 once daily for 6 doses beginning 7 to 10 days prior to transplant (in combination with busulfan and thymoglobulin (Pulsipher 2009)

Stem cell transplant (allogeneic) conditioning regimen, reduced-toxicity (myeloid malignancies and non-malignant diseases [eg, sickle cell cisease]): Limited data available: Children and Adolescents: IV: 30 mg/m2 once daily for 6 doses days -8 to -3 (in combination with busulfan and alemtuzumab) (Bhatia 2014)

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.

Adult:

Hematologic or nonhematologic toxicity (other than neurotoxicity): Consider treatment delay or dosage reduction.

Hemolysis: Discontinue treatment.

Neurotoxicity: Consider treatment delay or discontinuation.

Dosing: Kidney Impairment: Pediatric

Infants, Children, and Adolescents: The following guidelines have been used by some clinicians (Aronoff 2007): IV:

GFR >50 mL/minute/1.73 m2: No adjustment required

GFR 30 to 50 mL/minute/1.73 m2: Administer 80% of dose.

GFR <30 mL/minute/1.73 m2: Not recommended.

Hemodialysis: Administer 25% of dose

Continuous ambulatory peritoneal dialysis (CAPD): Not recommended.

Continuous renal replacement therapy (CRRT): Administer 80% of dose.

Dosing: Older Adult

Refer to adult dosing. Monitor closely for excess toxicity; may require reduced doses.

Dosing: Obesity: Adult

American Society of Clinical Oncology guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2 (Note: Excludes hematopoietic stem cell transplantation dosing): Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing with subsequent cycles if cause of toxicity (eg, hepatic or renal impairment) is clearly established and fully resolved and performance status has markedly improved (ASCO [Griggs 2021]).

American Society for Blood and Marrow Transplantation practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area in fludarabine dosing for hematopoietic stem cell transplant conditioning regimens in adults (ASBMT [Bubalo 2014]).

Dosing: Adjustment for Toxicity: Adult

Hematologic or nonhematologic toxicity (other than neurotoxicity): Consider treatment delay or dosage reduction. Patients with bone marrow impairment may require dosage reductions for excess toxicity.

Hemolysis: Discontinue treatment (corticosteroids may or may not effectively control hemolytic episodes).

Neurotoxicity: Consider treatment delay or discontinuation.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous, as phosphate:

Generic: 50 mg/2 mL (2 mL)

Solution, Intravenous, as phosphate [preservative free]:

Generic: 50 mg/2 mL (2 mL)

Solution Reconstituted, Intravenous, as phosphate:

Generic: 50 mg (1 ea [DSC])

Solution Reconstituted, Intravenous, as phosphate [preservative free]:

Generic: 50 mg (1 ea)

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous, as phosphate:

Generic: 25 mg/mL ([DSC])

Solution Reconstituted, Intravenous, as phosphate:

Generic: 50 mg (1 ea, 2 mL)

Tablet, Oral:

Fludara: 10 mg

Administration: Adult

IV: The manufacturer recommends administering over ~30 minutes (for the treatment of CLL). Continuous infusions and IV bolus over 15 minutes have been used for some off-label protocols (refer to individual studies for infusion rate details).

Oral: Tablet [Canadian product] may be administered with or without food; should be swallowed whole with water; do not chew, break, or crush.

Administration: Pediatric

Parenteral: Consult specific protocols; IV infusion rates may vary by pediatric protocol.

Intermittent IV infusion: Infuse over 30 minutes; a shorter infusion has been used in some protocols (Avramis 1998)

Continuous IV infusion with loading dose (bolus):

Loading dose: Administer over 15 minutes (Avramis 1998)

Continuous IV infusion: Administer at a constant rate of 10 mL/hour

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use: Labeled Indications

Chronic lymphocytic leukemia (refractory or progressive): Treatment of B-cell chronic lymphocytic leukemia (CLL) in adults who have not responded to or have progressed during treatment with at least one standard regimen containing an alkylating agent.

Use: Off-Label: Adult

Acute myeloid leukemia (newly diagnosed); Acute myeloid leukemia (refractory or high/poor risk); Hematopoietic stem cell transplant (allogeneic) myeloablative conditioning regimen (older adults); Hematopoietic stem cell transplant (allogeneic) nonmyeloablative conditioning regimen; Hematopoietic stem cell transplant (allogeneic) reduced-intensity conditioning regimen; Lymphodepleting therapy prior to chimeric antigen receptor T-cell immunotherapy; Non-Hodgkin lymphoma: Follicular lymphoma (relapsed/refractory); Waldenström macroglobulinemia

Medication Safety Issues
Sound-alike/look-alike issues:

Fludarabine may be confused with cladribine, floxuridine, flucytosine, Flumadine

Fludara may be confused with FUDR

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not always defined.

>10%:

Cardiovascular: Edema (8% to 19%)

Central nervous system: Fatigue (10% to 38%), neurological signs and symptoms (doses >96 mg/m2 /day for 5 to 7 days: 36%; doses <125 mg/m2/cycle: <1%; characterized by cortical blindness, coma, and paralysis; symptom onset may be delayed for 3 to 4 weeks), pain (20% to 22%), chills (11% to 19%), paresthesia (4% to 12%)

Dermatologic: Skin rash (15%), diaphoresis (1% to 13%)

Gastrointestinal: Nausea and vomiting (31% to 36%), anorexia (7% to 34%), diarrhea (13% to 15%), gastrointestinal hemorrhage (3% to 13%)

Genitourinary: Urinary tract infection (2% to 15%)

Hematologic & oncologic: Anemia (60%), neutropenia (grade 4: 59%; nadir: ~13 days), thrombocytopenia (55%; nadir: ~16 days), bone marrow depression (nadir: 10 to 14 days; recovery: 5 to 7 weeks; dose-limiting toxicity)

Infection: Infection (33% to 44%)

Neuromuscular & skeletal: Asthenia (9% to 65%), myalgia (4% to 16%)

Ophthalmic: Visual disturbance (3% to 15%)

Respiratory: Cough (10% to 44%), pneumonia (16% to 22%), dyspnea (9% to 22%), upper respiratory tract infection (2% to 16%)

Miscellaneous: Fever (60% to 69%)

1% to 10%:

Cardiovascular: Angina pectoris (≤6%), cardiac arrhythmia (≤3%), cardiac failure (≤3%), cerebrovascular accident (≤3%), myocardial infarction (≤3%), supraventricular tachycardia (≤3%), deep vein thrombosis (1% to 3%), phlebitis (1% to 3%), aneurysm (≤1%), transient ischemic attacks (≤1%)

Central nervous system: Malaise (6% to 8%), headache (≤3%), sleep disorder (1% to 3%), cerebellar syndrome (≤1%), depression (≤1%), difficulty thinking (≤1%)

Dermatologic: Alopecia (≤3%), pruritus (1% to 3%), seborrhea (≤1%)

Endocrine & metabolic: Hyperglycemia (1% to 6%), dehydration (≤1%)

Gastrointestinal: Stomatitis (≤9%), cholelithiasis (≤3%), esophagitis (≤3%), constipation (1% to 3%), mucositis (≤2%), dysphagia (≤1%)

Genitourinary: Dysuria (3% to 4%), urinary hesitancy (≤3%), hematuria (2% to 3%), proteinuria (≤1%)

Hematologic & oncologic: Hemorrhage (≤1%), tumor lysis syndrome (≤1%)

Hepatic: Abnormal hepatic function tests (1% to 3%), hepatic failure (≤1%)

Hypersensitivity: Anaphylaxis (≤1%)

Neuromuscular & skeletal: Osteoporosis (≤2%), arthralgia (≤1%)

Otic: Hearing loss (2% to 6%)

Renal: Renal failure (≤1%), renal function test abnormality (≤1%)

Respiratory: Pharyngitis (≤9%), hypersensitivity pneumonitis (≤6%), hemoptysis (1% to 6%), sinusitis (≤5%), bronchitis (≤1%), epistaxis (≤1%), hypoxia (≤1%)

<1%, postmarketing, and/or case reports: Acquired blood coagulation disorder, acute myelocytic leukemia (usually associated with prior or concurrent treatment with other anticancer agents), adult respiratory distress syndrome, agitation, autoimmune hemolytic anemia, autoimmune thrombocytopenia, blindness, bone marrow aplasia (trilineage), bone marrow depression (trilineage), cerebral hemorrhage, coma, confusion, Epstein-Barr-associated lymphoproliferative disorder, erythema multiforme, Evans syndrome, flank pain, hemorrhagic cystitis, herpes zoster infection (reactivation), hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, immune thrombocytopenia (autoimmune), increased liver enzymes, interstitial pneumonitis, lactic acidosis (Smith 2019), malignant neoplasm of skin (new-onset or exacerbation), metabolic acidosis, myelodysplastic syndrome (usually associated with prior or concurrent treatment with other anticancer agents), myelofibrosis, opportunistic infection, optic neuritis, optic neuropathy, pancreatic disease (pancreatic enzymes abnormal), pancytopenia, pemphigus, pericardial effusion, peripheral neuropathy, pneumonitis, progressive multifocal leukoencephalopathy (PML), pulmonary fibrosis, pulmonary hemorrhage, reactivation of latent Epstein-Barr virus, respiratory distress, respiratory failure, seizure, Stevens-Johnson syndrome, toxic epidermal necrolysis, urate crystalluria, wrist-drop

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to fludarabine or any component of the formulation; severe renal impairment (CrCl <30 mL/minute); decompensated hemolytic anemia; concurrent use with pentostatin

Warnings/Precautions

Concerns related to adverse effects:

• Autoimmune effects: Life-threatening (and sometimes fatal) autoimmune effects, including hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura, Evans syndrome, and acquired hemophilia, have occurred. This has occurred in patients with and without a history of autoimmune hemolytic anemia or a positive Coombs test, and who may or may not be in remission from their disease. Following fludarabine discontinuation, hemolytic effects recurred in most patients when rechallenged with fludarabine.

• Bone marrow suppression: Severe bone marrow suppression (anemia, thrombocytopenia, and neutropenia) may occur; may be cumulative. The median time to nadir was 13 days (range: 3 to 25 days) for granulocytes and 16 days (range: 2 to 32 days) for platelets. Severe myelosuppression (trilineage bone marrow hypoplasia/aplasia) has been reported (rare) with a duration of significant cytopenias ranging from 2 months to 1 year. First-line combination therapy is associated with prolonged cytopenias, with anemia lasting up to 7 months, neutropenia up to 9 months, and thrombocytopenia up to 10 months; increased age is predictive for prolonged cytopenias (Gill 2010).

• Infection: Serious and sometimes fatal infections, including opportunistic infections and reactivations of latent viral infections such as VZV (herpes zoster) and Epstein-Barr virus have been reported with fludarabine. Use with caution in patients with documented infection, fever, immunodeficiency, or with a history of opportunistic infection.

• Neurotoxicity: Higher than recommended doses (up to 96 mg/m2/day for 5 to 7 days) are associated with severe neurologic toxicity (delayed blindness, coma, death); similar neurotoxicity (agitation, coma, confusion, seizure) has been reported (rare) with standard chronic lymphocytic leukemia (CLL) doses (25 mg/m2/day for 5 days). Symptoms of neurotoxicity due to high doses appeared from 21 to 60 days following the last fludarabine dose, although neurotoxicity has been reported as early as 7 days and up to 225 days. Although administration of up to 15 courses of treatment have been used, the possible neurotoxic effects of chronic administration are unknown. Fatigue, weakness, visual disturbances, confusion, and seizures may occur; caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).

• Progressive multifocal leukoencephalopathy: Progressive multifocal leukoencephalopathy (usually fatal) due to JC virus has been reported; most cases were in patients who had received prior and/or other concurrent chemotherapy. Onset may be a few weeks or may be delayed up to 1 year.

• Transfusion-associated graft-versus-host disease: Graft-versus-host disease (GVHD) has been observed following transfusion of non-irradiated blood in patients treated with fludarabine; fatal outcome has been observed. Patients receiving fludarabine should only receive irradiated blood products due to the potential for transfusion-related GVHD.

• Tumor lysis syndrome: May cause tumor lysis syndrome; risk is increased in patients with large tumor burden prior to treatment.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; clearance of the primary metabolite 2-fluoro-ara-A is decreased in patients with renal impairment.

Concurrent drug therapy issues:

• Pentostatin: The use of fludarabine in combination with pentostatin is not recommended. When fludarabine has been used in combination with pentostatin for the treatment of refractory CLL, an unacceptably high incidence of fatal pulmonary toxicity has occurred.

Special populations:

• Elderly: Monitor closely for excessive toxicity; may require reduced doses.

Other warnings/precautions:

• Live vaccines: Avoid vaccination with live vaccines during and after fludarabine treatment.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Risk X: Avoid combination

Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA vaccine at least 28 days after the primary vaccine dose. Patients should also receive 2 booster doses of mRNA vaccine - one 2 months after the 2nd (additional) dose and another 4 months after the first booster dose. Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series, and a booster dose 3 months after the 3rd dose in the primary series, to patients taking immunosuppressive medications. Patients 12 years of age and older should also receive a 2nd booster 4 months after the first booster. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification

Pentostatin: May enhance the adverse/toxic effect of Fludarabine. Specifically, the risk of fatal pulmonary toxicity may be increased. Risk X: Avoid combination

Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy

Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Reproductive Considerations

Patients who could become pregnant should use effective contraception during therapy and for at least 6 months after the last fludarabine dose.

Fludarabine may damage testicular tissue and spermatozoa. Patients with partners who could become pregnant should use contraception during therapy and for at least 6 months after the last fludarabine dose (duration of effect is uncertain).

Pregnancy Considerations

Based on the mechanism of action, fludarabine may cause fetal harm if administered during pregnancy.

Breastfeeding Considerations

It is not known if fludarabine is present in breast milk.

Due to the potential for serious adverse reactions in the breastfed infant, a decision should be made to discontinue breastfeeding or fludarabine, considering the importance of treatment to the breastfeeding patient.

Monitoring Parameters

CBC with differential, platelet count, AST, ALT, serum creatinine, serum albumin, uric acid. Monitor for signs/symptoms of hemolysis, infection, neurotoxicity, progressive multifocal leukoencephalopathy (evaluate any neurologic change promptly), and tumor lysis syndrome. Monitor patients with bone marrow impairment or renal impairment closely for excess toxicity.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Fludarabine inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase; also inhibits DNA primase and DNA ligase I

Pharmacokinetics

Distribution: Vss: 11 to 96 L/m2 (Johnson 2000)

Protein binding: 2-fluoro-ara-A: ~19% to 29%

Metabolism: IV: Fludarabine phosphate is rapidly dephosphorylated in the plasma to 2-fluoro-ara-A (active metabolite), which subsequently enters tumor cells and is phosphorylated by deoxycytidine kinase to the active triphosphate derivative (2-fluoro-ara-ATP)

Bioavailability: Oral: 2-fluoro-ara-A: 50% to 65%

Half-life elimination: 2-fluoro-ara-A: Adults: ~20 hours

Time to peak, plasma: Oral: 1 to 2 hours

Excretion: Urine (primarily) (Johnson 2000)

Pharmacokinetics: Additional Considerations

Altered kidney function: Total body clearance of the principal metabolite correlates with creatinine clearance (CrCl). Mean body clearance is 124 mL/minute for patients with moderate renal impairment and 71 mL/minute for patients with severe renal impairment. In 2 patients with a median CrCl of 22 mL/minute/m2, clearance was reduced by 56%.

Pricing: US

Solution (reconstituted) (Fludarabine Phosphate Intravenous)

50 mg (per each): $113.40 - $132.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Asoleudox (CR, DO, GT, HN, NI, PA, SV);
  • Beneflur (CR, DO, ES, GT, HN, MX, NI, PA, SV);
  • Eupifluda (EG);
  • Evoflubina (BR);
  • Flucozol (EC);
  • Fludabine (LK);
  • Fludacel (PE);
  • Fludakebir (AR);
  • Fludamin (BD);
  • Fludara (AU, BE, BG, BR, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EE, EG, FI, FR, GB, GR, GT, HK, HN, HU, ID, IE, IL, IN, IS, IT, JO, JP, KR, KW, LT, LU, LV, MT, MY, NI, NL, NO, NZ, PA, PH, PL, RO, RU, SA, SE, SG, SI, SK, SV, TH, TR, TW, VN, ZA);
  • Forclina (AR);
  • Neoflubin (AT)


For country abbreviations used in Lexicomp (show table)
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