Fludarabine

Dosage Forms

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)

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss: 11 to 96 L/m² (Johnson 2000)

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)

Excretion

Urine (primarily) (Johnson 2000)

Time to Peak

Oral: 1 to 2 hours

Half-Life Elimination

2-fluoro-ara-A: Adults: ~20 hours

Protein Binding

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

Use in Specific Populations

Special Populations: Renal Function Impairment

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%.

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

Acute myeloid leukemia (newly diagnosed)b

Data from a large phase III trial support the use of fludarabine in combination with cytarabine, idarubicin, and G-CSF [FLAG-IDA regimen] followed by consolidation therapy) in the treatment of younger adults with newly diagnosed acute myeloid leukemia Burnett 2013. Data from a small study in newly diagnosed acute myeloid leukemia also support the use of fludarabine (in combination with cytarabine with or without filgrastim) in the treatment of acute myeloid leukemia Borthakur 2008. Additional trials may be necessary to further define the role of fludarabine in this condition.

Acute myeloid leukemia (refractory or high/poor risk)b

Data from a small open-label study in adult patients with relapsed or refractory acute myeloid leukemia (AML) support the use of fludarabine (in combination with cytarabine and G-CSF [FLAG regimen]) for induction treatment of this condition Montillo 1998. Data from a study in poor risk acute leukemias and myelodysplastic syndrome support the use of fludarabine (in combination with cytarabine, idarubicin, and filgrastim [FLAG-IDA regimen]) for remission induction treatment of poor risk acute myeloid leukemia Virchis 2004. Additional trials may be necessary to further define the role of fludarabine in this condition.

Hematopoietic stem cell transplant (allogeneic) myeloablative conditioning regimen (older adults)a

Data from an open label, multicenter, phase III study support the use of fludarabine (in combination with busulfan) as a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation in older adults Rambaldi 2015.

Hematopoietic stem cell transplant (allogeneic) nonmyeloablative conditioning regimenb

Data from a small phase II study support the use of fludarabine (in combination with cyclophosphamide and rituximab) as part of a nonmyeloablative transplant conditioning regimen Khouri 2008. Data from two additional studies support the use of fludarabine (in combination with total body irradiation) as a nonmyeloablative conditioning regimen in older patients unable to tolerate a myeloablative regimen Hegenbart 2006, Rezvani 2008.

Hematopoietic stem cell transplant (allogeneic) reduced-intensity conditioning regimenb

Data from a small study support the use of fludarabine (in combination with melphalan and alemtuzumab) as a reduced-intensity conditioning regimen in allogeneic transplant patients ineligible for a myeloablative regimen Tauro 2005. Data from a retrospective study also support the use of fludarabine (in combination with busulfan ± antithymocyte globulin) as part of a reduced-intensity conditioning regimen for allogeneic transplantation Schetelig 2003. Additional studies may be necessary to further define the role of fludarabine in the condition.

Non-Hodgkin lymphoma: Follicular lymphoma (relapsed/refractory)b

Data from a small multicenter phase II study support the use of fludarabine (in combination with cyclophosphamide and rituximab [FCR regimen]) in the management of recurrent follicular lymphoma Sacchi 2007. Data from a small phase III study support the use of fludarabine (in combination with cyclophosphamide, mitoxantrone, and rituximab [FCMR regimen]) in the management of relapsed or refractory follicular lymphoma (Forstpointner 2004). Data from a small phase II study support the use of fludarabine (in combination with rituximab [FR regimen]) in the management of follicular lymphoma Czuczman 2005. Fludarabine (in combination with mitoxantrone, dexamethasone, and rituximab [FNDR regimen]) was studied in patients with indolent lymphomas, and may be considered for the management of follicular lymphoma McLaughlin 2000. Additional studies may be necessary to further define the role of fludarabine in the condition.

Non-Hodgkin lymphoma: Mantle cell lymphoma (relapsed/refractory)b

Data from a small study support the use of fludarabine (in combination with cyclophosphamide [FC regimen]) in the treatment of mantle cell lymphoma Cohen 2001. Additional studies may be necessary to further define the role of fludarabine in the condition.

Waldenström macroglobulinemiab

Data from two multicenter phase II studies support the use of fludarabine as a single-agent for newly diagnosed Waldenström macroglobulinemia Foran 1999 or in combination with rituximab for previously treated disease Treon 2009.

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

Dosage and Administration

Dosing: Adult

Chronic lymphocytic leukemia (CLL), 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

CLL combination regimens (off-label dosing): IV:

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

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

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

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 (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)

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 (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)

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)

Non-Hodgkin lymphomas (off-label use): IV:

Follicular lymphoma, relapsed/refractory

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

FCMR regimen: 25 mg/m²/day for 3 days every 28 days for 4 cycles (in combination with cyclophosphamide, mitoxantrone, and rituximab) (Forstpointner 2004; Forstpointner 2006)

FNDR regimen: 25 mg/m²/day for 3 days every 28 days for up to 8 cycles (in combination with mitoxantrone, dexamethasone, and rituximab) (McLaughlin 2000)

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

Mantle cell lymphoma, relapsed or refractory:

FC regimen: 20 mg/m²/day for 4 to 5 days or 25 mg/m²/day for 3 to 5 days (in combination with cyclophosphamide) (Cohen 2001)

Waldenstrom macroglobulinemia (off-label use): IV: 25 mg/m²/day for 5 days every 28 days (Foran 1999) or 25 mg/m² once daily for 5 days during weeks 5, 9, 13, 19, 23, and 27 (in combination with rituximab) (Treon 2009)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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)

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: Adjustment for Toxicity

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

Hemolysis: Discontinue treatment.

Neurotoxicity: Consider treatment delay or discontinuation.

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes leukemias and HSCT 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 nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

American Society for Blood and Marrow Transplantation (ASBMT) 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 (Bubalo 2014).

Reconstitution

Reconstitute lyophilized powder with 2 mL SWFI to a concentration of 25 mg/mL.

Dilute for infusion in 100 to 125 mL D5W or NS.

Administration

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.

Storage

IV: Store intact vials under refrigeration or at room temperature, as specified according to each manufacturer's labeling. Protect from light. Reconstituted solution or vials of the solution for injection that have been punctured (in use) should be used within 8 hours.

Tablet [Canadian product]: Store at 15°C to 30°C (59°F to 86°F); should be kept within packaging until use.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

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

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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

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

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

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

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. 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. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

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

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Imatinib: May diminish the myelosuppressive effect of Fludarabine. Imatinib may decrease the serum concentration of Fludarabine. More specifically, imatinib may decrease the formation of fludarabine active metabolite F-ara-ATP Management: Due to the risk for impaired fludarabine response, consider discontinuing imatinib therapy at least 5 days prior to initiating fludarabine conditioning therapy in CML patients undergoing HSCT. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. 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. 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. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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. Consider therapy modification

Pentostatin: Fludarabine may enhance the adverse/toxic effect of Pentostatin. Pentostatin may enhance the adverse/toxic effect of Fludarabine. Pulmonary toxicity is of specific concern. Avoid combination

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

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

Warnings/Precautions

Concerns related to adverse effects:

• Autoimmune effects: [US Boxed Warning]: Life-threatening (and sometimes fatal) autoimmune effects, including hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have occurred; evaluate and monitor closely for hemolysis. 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. Corticosteroids may or may not effectively control the hemolytic episodes. Discontinue fludarabine if hemolysis occurs. The hemolytic effects recurred in most patients when rechallenged with fludarabine.
• Bone marrow suppression: [US Boxed Warning]: 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). Monitor patients with bone marrow impairment closely for excess toxicity; may require dosage reductions.
• 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. Prophylactic anti-infectives should be considered for patients with an increased risk for developing opportunistic infections. Use with caution in patients with documented infection, fever, immunodeficiency, or with a history of opportunistic infection.
• Neurotoxicity: [US Boxed Warning]: 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 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 (PML) (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. Evaluate any neurological change promptly.
• Reproductive effects: Fludarabine may damage testicular tissue and spermatozoa.
• 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. Hydration and prophylactic antihyperuricemic therapy should be considered in patients at risk for tumor lysis syndrome.

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. Dosage reductions are recommended (monitor closely for excessive toxicity) in patients with creatinine clearance between 30 and 79 mL/minute; use is not recommended if CrCl <30 mL/minute.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Pentostatin: [US Boxed Warning]: The use of fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia has resulted in an unacceptably high incidence of fatal pulmonary toxicity. The use of fludarabine in combination with pentostatin is not recommended.

Special populations:

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

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
• Live vaccines: Avoid vaccination with live vaccines during and after fludarabine treatment.

Monitoring Parameters

CBC with differential, platelet count, AST, ALT, serum creatinine, serum albumin, uric acid; monitor for signs of infection, neurotoxicity, and tumor lysis syndrome.

Pregnancy

Pregnancy Considerations

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

Females of reproductive potential and fertile males should use effective contraception during therapy and for 6 months after the last fludarabine dose.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia. It may be given for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Diarrhea
• Mouth irritation
• Mouth sores
• Muscle pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes
• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Chest pain
• Agitation
• Confusion
• Seizures
• Unable to pass urine
• Severe loss of strength and energy
• Dark urine
• Yellow skin
• Skin growths
• Mole changes
• Burning or numbness feeling
• Lack of appetite
• Edema
• Vision changes
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.