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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(floo DARE a been)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Treatment of progressive or refractory B-cell chronic lymphocytic leukemia (CLL)
Canadian labeling: Second-line treatment of chronic lymphocytic leukemia (CLL); second-line treatment of low-grade, refractory non-Hodgkin's lymphoma (NHL)
Use: Unlabeled
Treatment of non-Hodgkin's lymphomas (NHL); acute myeloid leukemia (AML), either refractory or in poor risk patients; relapsed acute lymphocytic leukemia (ALL) or AML in pediatric patients; Waldenström's macroglobulinemia (WM); reduced-intensity conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (generally administered in combination with busulfan or cyclophosphamide and antithymocyte globulin or lymphocyte immune globulin, or in combination with melphalan and alemtuzumab)
Pregnancy Risk Factor
D
Pregnancy Considerations
Teratogenic effects were observed in animal studies. Based on the mechanism of action, fludarabine has the potential to cause fetal harm if administered during pregnancy. There are no adequate and well-controlled studies in pregnant women. Effective contraception is recommended during and for 6 months after treatment for women and men with female partners of reproductive potential.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Contraindications
Hypersensitivity of fludarabine or any component of the formulation
Canadian labeling: Additional contraindications (not in U.S. labeling): Severe renal impairment (Clcr <30 mL/minute); decompensated hemolytic anemia; concurrent use with pentostatin
Warnings/Precautions
Boxed warnings:
• Autoimmune effects: See “Concerns related to adverse effects” below.
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
• Neurotoxicity: See “Concerns related to adverse effects” below.
• Pentostatin: See “Concurrent drug therapy issues” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Autoimmune effects: [U.S. Boxed Warning]: Life-threatening (and sometimes fatal) autoimmune effects, including hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have occurred; monitor closely for hemolysis; discontinue fludarabine if hemolysis occurs. The hemolytic effects usually recur with fludarabine rechallenge.
• Bone marrow suppression: [U.S. Boxed Warning]: Severe bone marrow suppression (anemia, thrombocytopenia, and neutropenia) may occur; may be cumulative. 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). Use with caution in patients with pre-existing hematological disorders (particularly granulocytopenia).
• Neurotoxicity: [U.S. Boxed Warning]: Higher than recommended doses (up to 96 mg/m2/day for 5-7 days) are associated with severe neurologic toxicity (delayed blindness, coma, death); similar neurotoxicity (agitation, coma, confusion, seizure) has been reported with standard CLL doses. Symptoms of neurotoxicity due to high doses appeared from 21-60 days following the last fludarabine dose, although neurotoxicity has been reported as early as 7 days and up to 225 days. Possible neurotoxic effects of chronic administration are unknown. Caution patients about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients with pre-existing central nervous system disorder (epilepsy), spasticity, or peripheral neuropathy.
• Progressive multifocal leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) (usually fatal) due to JC virus has been reported with use; 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.
• Tumor lysis syndrome: May cause tumor lysis syndrome; risk is increased in patients with large tumor burden prior to treatment.
Disease-related concerns:
• Infection: Use with caution in patients with documented infection, fever, immunodeficiency, or with a history of opportunistic infection. Prophylactic anti-infectives should be considered for patients with an increased risk for developing opportunistic infections.
• 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); use of the I.V. formulation is not recommended if Clcr <30 mL/minute.
Concurrent drug therapy issues:
• Pentostatin: [U.S. Boxed Warning]: Do not use in combination with pentostatin; may lead to severe, even fatal pulmonary toxicity. Concomitant use is contraindicated in the Canadian labeling.
Other warnings/precautions:
• Blood products: Patients receiving blood products should only receive irradiated blood products due to the potential for transfusion related GVHD.
• Experienced physician: [U.S. 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.
Adverse Reactions
>10%:
Cardiovascular: Edema (8% to 19%)
Central nervous system: Fever (11% to 69%), fatigue (10% to 38%), pain (5% to 22%), chills (11% to 19%)
Dermatologic: Rash (4% to 15%)
Gastrointestinal: Nausea/vomiting (1% to 36%), anorexia (≤34%), diarrhea (5% to 15%), gastrointestinal bleeding (3% to 13%)
Genitourinary: Urinary tract infection (2% to 15%)
Hematologic: Myelosuppression (nadir: 10-14 days; recovery: 5-7 weeks; dose-limiting toxicity), anemia (14% to 60%), neutropenia (grade 4: 37% to 59%; nadir: ~13 days), thrombocytopenia (17% to 55%; nadir: ~16 days)
Neuromuscular & skeletal: Weakness (9% to 65%), myalgia (4% to 16%), paresthesia (4% to 12%)
Ocular: Visual disturbance (3% to 15%)
Respiratory: Cough (≤44%), pneumonia (3% to 22%), dyspnea (1% to 22%), upper respiratory infection (2% to 16%), rhinitis (≤11%)
Miscellaneous: Infection (12% to 44%), diaphoresis (≤14%)
1% to 10%:
Cardiovascular: Peripheral edema (≤7%), angina (≤6%), chest pain (≤5%), CHF (≤3%), arrhythmia (≤3%), cerebrovascular accident (≤3%), MI (≤3%), supraventricular tachycardia (≤3%), deep vein thrombosis (1% to 3%), phlebitis (1% to 3%), aneurysm (≤1%), transient ischemic attack (≤1%)
Central nervous system: Headache (≤9%), malaise (6% to 8%), sleep disorder (1% to 3%), cerebellar syndrome (≤1%), depression (≤1%), mentation impaired (≤1%)
Dermatologic: Alopecia (≤3%), pruritus (1% to 3%), seborrhea (≤1%)
Endocrine & metabolic: Hyperglycemia (1% to 6%), LDH increased (≤6%), dehydration (≤1%)
Gastrointestinal: Abdominal pain (≤10%), stomatitis (≤9%), weight loss (≤6%), esophagitis (≤3%), constipation (1% to 3%), mucositis (≤2%), dysphagia (≤1%)
Genitourinary: Dysuria (3% to 4%), hesitancy (≤3%)
Hematologic: Hemorrhage (≤1%), myelodysplastic syndrome/acute myeloid leukemia (usually associated with prior or concurrent treatment with other anticancer agents)
Hepatic: Cholelithiasis (≤3%), liver function tests abnormal (1% to 3%), liver failure (≤1%)
Neuromuscular & skeletal: Back pain (≤9%), osteoporosis (≤2%), arthralgia (≤1%)
Otic: Hearing loss (2% to 6%)
Renal: Hematuria (2% to 3%), renal failure (≤1%), renal function test abnormal (≤1%), proteinuria (≤1%)
Respiratory: Bronchitis (≤9%), pharyngitis (≤9%), allergic pneumonitis (≤6%), hemoptysis (1% to 6%), sinusitis (≤5%), epistaxis (≤1%), hypoxia (≤1%)
Miscellaneous: Flu-like syndrome (5% to 8%), herpes simplex infection (≤8%), anaphylaxis (≤1%), tumor lysis syndrome (1%)
<1%, postmarketing, and/or case reports: Acute respiratory distress syndrome, agitation, blindness, blurred vision, bone marrow fibrosis, coma, confusion, diplopia, eosinophilia, Epstein-Barr virus (EBV) associated lymphoproliferation, EBV reactivation, erythema multiforme, Evans syndrome, flank pain, hemolytic anemia (autoimmune), hemophilia (acquired), hemorrhagic cystitis, herpes zoster reactivation, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, interstitial pneumonitis, metabolic acidosis, opportunistic infection, optic neuritis, optic neuropathy, pancreatic enzymes abnormal, pancytopenia, pemphigus, pericardial effusion, peripheral neuropathy, photophobia (primarily with high doses), progressive multifocal leukoencephalopathy (PML), pulmonary fibrosis, pulmonary hemorrhage, pulmonary infiltrate, respiratory distress, respiratory failure, Richter's syndrome, seizure, skin cancer (new onset or exacerbation), Stevens-Johnson syndrome, thrombocytopenia (autoimmune), thrombocytopenic purpura (autoimmune), toxic epidermal necrolysis, trilineage bone marrow aplasia, trilineage bone marrow hypoplasia, urate crystalluria, wrist drop
Also observed: Neurologic syndrome characterized by cortical blindness, coma, and paralysis [36% at doses >96 mg/m2 for 5-7 days; <0.2% at doses <125 mg/m2/cycle (onset of neurologic symptoms may be delayed for 3-4 weeks)]
Metabolism/Transport Effects
None known.
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
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. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. 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. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Storage
I.V.: Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Reconstituted vials are stable for 16 days at room temperature of 15°C to 30°C (59°F to 86°F) or refrigerated, although the manufacturer recommends use within 8 hours. Solutions diluted in saline or dextrose are stable for 48 hours at room temperature or under refrigeration.
Tablet: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); should be kept within packaging until use.
Reconstitution
Use appropriate precautions for handling and disposal. Reconstitute vials with SWI, NS, or D5W to a concentration of 10-25 mg/mL. Standard I.V. dilution: 100-125 mL D5W or NS.
Compatibility
Stable in D5W, NS, sterile water for injection.
Y-site administration: Compatible: Allopurinol, amifostine, amikacin, aminophylline, ampicillin, ampicillin/sulbactam, amsacrine, aztreonam, bleomycin, butorphanol, carboplatin, carmustine, cefazolin, cefepime, cefotaxime, cefotetan, ceftazidime, cefuroxime, cimetidine, cisplatin, clindamycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dexamethasone sodium phosphate, diphenhydramine, doxorubicin, doxycycline, droperidol, etoposide, etoposide phosphate, famotidine, filgrastim, floxuridine, fluconazole, fluorouracil, furosemide, gemcitabine, gentamicin, granisetron, haloperidol lactate, heparin, hydrocortisone sodium succinate, hydromorphone, ifosfamide, imipenem/cilastatin, lorazepam, magnesium sulfate, mannitol, mechlorethamine, melphalan, meperidine, mesna, methotrexate, methylprednisolone sodium succinate, metoclopramide, minocycline, mitoxantrone, morphine, multivitamins, nalbuphine, ondansetron, pentostatin, piperacillin, piperacillin/tazobactam, potassium chloride, promethazine, ranitidine, sodium bicarbonate, sulfamethoxazole/trimethoprim, teniposide, thiotepa, ticarcillin/clavulanate, tobramycin, vancomycin, vinblastine, vincristine, vinorelbine, zidovudine. Incompatible: Acyclovir, amphotericin B, chlorpromazine, daunorubicin HCl, ganciclovir, hydroxyzine, prochlorperazine edisylate. Variable (consult detailed reference): Ceftriaxone.
Compatibility in syringe: Incompatible: Ceftriaxone.
Mechanism of Action
Fludarabine inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase; also inhibits DNA primase and DNA ligase I
Pharmacodynamics/Kinetics
Distribution: Vd: 38-96 L/m2; widely with extensive tissue binding
Protein binding: 2-fluoro-ara-A: ~19% to 29%
Metabolism: I.V.: 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: ~20 hours
Time to peak, plasma: Oral: 1-2 hours
Excretion: Urine (60%, 23% as 2-fluoro-ara-A) within 24 hours
Dosage
Details concerning dosing in combination regimens should also be consulted.
Oral: Adults: CLL: 40 mg/m2 once daily for 5 days every 28 days
I.V.:
Children (unlabeled use):
AML: 10.5 mg/m2 bolus over 15 minutes followed by a continuous infusion of 30.5 mg/m2/day for 48 hours (Lange, 2008)
ALL or AML, relapsed: 10.5 mg/m2 bolus over 15 minutes followed by a continuous infusion of 30.5 mg/m2/day for 48 hours (Avramis, 1998)
Stem cell transplant (allogeneic) conditioning regimen, reduced-intensity: 30 mg/m2/dose for 6 doses beginning 7-10 days prior to transplant (in combination with busulfan and antithymocyte globulin) (Pulsipher, 2009)
Adults:
CLL: 25 mg/m2/day for 5 days every 28 days
CLL combination regimens (unlabeled dosing):
CFAR: 20 mg/m2/day for 3 days every 28 days for 6 cycles (in combination with cyclophosphamide, rituximab and alemtuzumab) (Wierda, 2008)
FC: 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: 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)
FluCam: 30 mg/m2/day for 3 days every 28 days for 4-6 cycles (in combination with alemtuzumab) (Elter, 2005)
FR: 25 mg/m2/day for 5 days every 28 days for 6 cycles (in combination with rituximab) (Byrd, 2003)
OFAR: 30 mg/m2/day for 2 days every 28 days for 6 cycles (in combination with oxaliplatin, cytarabine, and rituximab) (Tsimberidou, 2008)
AML, high-risk patients (unlabeled use): 30 mg/m2/day for 5 days induction therapy, followed by post remission therapy of 30 mg/m2/day for 4 days every other cycle (in combination with cytarabine with or without filgrastim) (Borthakur, 2008)
AML, refractory (unlabeled use): 30 mg/m2/day for 5 days (in combination with cytarabine and filgrastim), 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) (Virchis, 2004)
Non-Hodgkin's lymphomas (unlabeled uses):
Follicular lymphoma:
FCR: 25 mg/m2/day for 3 days every 21 days for 4 cycles (in combination with cyclophosphamide and rituximab) (Sacchi, 2007)
FCMR: 25 mg/m2/day for 3 days every 28 days for 4 cycles (in combination with cyclophosphamide, mitoxantrone, and rituximab) (Forstpointner, 2004; Forstpointner, 2006)
FND: 25 mg/m2/day for 3 days every 28 days for up to 8 cycles (in combination with mitoxantrone and dexamethasone) (McLaughlin, 1996; Tsimberidou, 2002)
FNDR: 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: 25 mg/m2/day for 5 days every 28 days for 6 cycles (in combination with rituximab) (Czuczman, 2005)
Mantle cell lymphoma:
FC: 20 mg/m2/day for 4-5 days or 25 mg/m2/day for 3-5 days (in combination with cyclophosphamide) (Cohen, 2001)
FCMR: 25 mg/m2/day for 3 days every 28 days for 4 cycles (in combination with cyclophosphamide, mitoxantrone, and rituximab) (Forstpointner, 2004; Forstpointner, 2006)
Waldenstron's macroglobulinemia (unlabeled use): 25 mg/m2/day for 5 days every 28 days (Foran, 1999) or 25 mg/m2/day for 5 days every 28 days for 6 cycles (in combination with rituximab) (Treon, 2009)
Stem cell transplant (allogeneic) conditioning regimen, reduced-intensity, (unlabeled use): 30 mg/m2/dose for 6 doses beginning 10 days prior to transplant or 30 mg/m2/dose for 5 days beginning 6 days prior to transplant (in combination with busulfan with or without antithymocyte globulin) (Schetelig, 2003)
Stem cell transplant (allogeneic) nonmyeloablative conditioning regimen (unlabeled use): 30 mg/m2/dose for 3 doses beginning 5 days prior to transplant (in combination with cyclophosphamide and rituximab) (Khouri, 2008) or 30 mg/m2/dose for 3 doses beginning 4 days prior to transplant (in combination with total body irradiation) (Rezvani, 2008)
Dosage 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 in renal impairment:
FDA-approved labeling contains the following adjustment recommendations: Adults: CLL:
I.V.:
Clcr 50-79 mL/minute: Decrease dose to 20 mg/m2
Clcr 30-49 mL/minute: Decrease dose to 15 mg/m2
Clcr <30 mL/minute: Avoid use
Oral:
Clcr 30-70 mL/minute: Administer 80% of dose
Clcr <30 mL/minute: Administer 50% of dose
Canadian labeling contains the following adjustment recommendations: CLL, NHL:
Clcr 30-70 mL/minute: Reduce dose by up to 50%
Clcr <30 mL/minute: Use is contraindicated
The following guidelines have been used by some clinicians: Aronoff, 2007: I.V.:
Children:
Clcr 30-50 mL/minute: Administer 80% of dose
Clcr <30 mL/minute: Not recommended
Hemodialysis: Administer 25% of dose
Continuous ambulatory peritoneal dialysis (CAPD): Not recommended
Continuous renal replacement therapy (CRRT): Administer 80% of dose
Adults:
Clcr 10-50 mL/minute: Administer 75% of dose
Clcr <10 mL/minute: Administer 50% of dose
Hemodialysis: Administer after dialysis
Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of dose
Continuous renal replacement therapy (CRRT): Administer 75% of dose
Dosage: Combination Regimens
Leukemia, acute myeloid:
FLAG (AML Induction)
FLAG-IDA (AML Induction)
Leukemia, chronic lymphocytic:
Cyclophosphamide-Fludarabine-Alemtuzumab-Rituximab (CLL)
Fludarabine-Alemtuzumab (CLL)
Fludarabine-Cyclophosphamide (CLL)
Fludarabine-Cyclophosphamide-Rituximab (CLL)
Fludarabine-Rituximab (CLL)
OFAR (CLL)
Lymphoma, non-Hodgkin's:
Fludarabine-Cyclophosphamide-Mitoxantrone-Rituximab
Fludarabine-Cyclophosphamide-Rituximab (NHL-Follicular)
Fludarabine-Mitoxantrone
Fludarabine-Mitoxantrone-Dexamethasone (NHL)
Fludarabine-Mitoxantrone-Dexamethasone-Rituximab
Fludarabine-Mitoxantrone-Rituximab
Fludarabine-Rituximab (NHL-Follicular)
Lymphoma, non-Hodgkin's (Mantle Cell): Fludarabine-Cyclophosphamide (NHL-Mantle Cell)
Administration: Oral
Tablet may be administered with or without food; should be swallowed whole with water; do not chew, break, or crush.
Administration: I.V.
Administer I.V. over 30 minutes; continuous infusions (unlabeled administration rate) are occasionally used
Administration: I.V. Detail
pH: 7.2-8.2
Monitoring Parameters
CBC with differential, platelet count, AST, ALT, serum creatinine, serum albumin, uric acid; monitor for signs of infection and neurotoxicity
Dietary Considerations
Tablet may be taken with or without food.
Patient Education
If this drug is administered by infusion, report any burning, pain, redness, or swelling at infusion site. It is important to maintain adequate nutrition and hydration, unless instructed to restrict fluid intake. You will be more susceptible to infection. May cause fatigue, weakness, visual disturbances, nausea, vomiting, loss of hair (reversible), or mouth sores. Report severe or persistent GI upset or diarrhea; extreme fatigue or weakness; pain or numbness in muscles; any unusual bleeding or bruising; fever, chills, or sore throat; vaginal discharge; difficulty or pain on urination; unusual cough or respiratory difficulty; or changes in vision.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Sedation is common; may cause agitation, confusion, coma
Mental Health: Effects on Psychiatric Treatment
Myelosuppression is common; use caution with clozapine and carbamazepine; concurrent use with low potency antipsychotics and TCAs may produce additive sedation. May cause nausea, vomiting, diarrhea, and GI bleeding; concomitant use with SSRIs may produce additive risk (use caution).
Nursing: Physical Assessment/Monitoring
Use caution in the presence of infection, fever, or history of opportunistic infection; renal insufficiency; hematological disorders; central nervous system disorders; or peripheral neuropathy.
Oncology: Emetic Potential
Oral: Low (10% to 30%)
I.V.: Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Injection, powder for reconstitution, as phosphate: 50 mg
Fludara®: 50 mg
Injection, solution, as phosphate [preservative free]: 25 mg/mL (2 mL)
Tablet, oral, as phosphate:
Oforta™: 10 mg [DSC]
References
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Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 99, 172.
Avramis VI, Wiersma S, Krailo MD, et al, “Pharmacokinetic and Pharmacodynamic Studies of Fludarabine and Cytosine Arabinoside Administered as Loading Boluses Followed by Continuous Infusions After a Phase I/II Study in Pediatric Patients With Relapsed Leukemias. The Children's Cancer Group,” Clin Cancer Res, 1998, 4(1):45-52.
Bacigalupo A, “Second EBMT Workshop on Reduced Intensity Allogeneic Hemopoietic Stem Cell Transplants (RI-HSCT),” Bone Marrow Transplant, 2002, 29(3):191-5.
Boogaerts MA, Van Hoof A, Catovsky D, et al, “Activity of Oral Fludarabine Phosphate in Previously Treated Chronic Lymphocytic Leukemia,” J Clin Oncol, 2001, 19(22):4252-8.
Borthakur G, Kantarjian H, Wang X, et al, “Treatment of Core-Binding-Factor in Acute Myelogenous Leukemia With Fludarabine, Cytarabine, and Granulocyte Colony-Stimulating Factor Results in Improved Event-Free Survival,” Cancer, 2008, 113(11):3181-5.
Byrd JC, Peterson BL, Morrison VA, et al, “Randomized Phase 2 Study of Fludarabine With Concurrent vs Sequential Treatment With Rituximab in Symptomatic, Untreated Patients With B-Cell Chronic Lymphocytic Leukemia: Results From Cancer and Leukemia Group B 9712 (CALGB 9712),” Blood, 2003, 101(1):6-14.
Cohen BJ, Moskowitz C, Straus D, et al, “Cyclophosphamide/Fludarabine (CF) is Active in the Treatment of Mantle Cell Lymphoma,” Leuk Lymphoma, 2001, 42(5):1015-22.
Czuczman MS, Koryzna A, Mohr A, et al, “Rituximab in Combination With Fludarabine Chemotherapy in Low-Grade or Follicular Lymphoma,” J Clin Oncol, 2005, 23(4):694-704.
Eichhorst BF, Busch R, Hopfinger G, et al, “Fludarabine Plus Cyclophosphamide Versus Fludarabine Alone in First-Line Therapy of Younger Patients With Chronic Lymphocytic Leukemia,” Blood, 2006, 107(3):885-91.
Elter T, Borchmann P, Schulz H, et al, “Fludarabine in Combination With Alemtuzumab Is Effective and Feasible in Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia: Results of a Phase II Trial,” J Clin Oncol, 2005, 23(28):7024-31.
Flinn IW, Neuberg DS, Grever MR, et al, “Phase III Trial of Fludarabine Plus Cyclophosphamide Compared With Fludarabine for Patients With Previously Untreated Chronic Lymphocytic Leukemia: US Intergroup Trial E2997,” J Clin Oncol, 2007, 25(7):793-8.
Foran JM, Rohatiner AZ, Coiffier B, et al, “Multicenter Phase II Study of Fludarabine Phosphate for Patients With Newly Diagnosed Lymphoplasmacytoid Lymphoma, Waldenström's Macroglobulinemia, and Mantle-Cell Lymphoma,” J Clin Oncol, 1999, 17(2):546-53.
Forstpointner R, Dreyling M, Repp R, et al, “The Addition of Rituximab to a Combination of Fludarabine, Cyclophosphamide, Mitoxantrone (FCM) Significantly Increases the Response Rate and Prolongs Survival as Compared With FCM Alone in Patients With Relapsed and Refractory Follicular and Mantle Cell Lymphomas: Results of a Prospective Randomized Study of the German Low-Grade Lymphoma Study Group,” Blood, 2004, 104(10):3064-71.
Forstpointner R, Unterhalt M, Dreyling M, et al, “Maintenance Therapy With Rituximab Leads to a Significant Prolongation of Response Duration After Salvage Therapy With a Combination of Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone (R-FCM) in Patients With Recurring and Refractory Follicular and Mantle Cell Lymphomas: Results of a Prospective Randomized Study of the German Low Grade Lymphoma Study Group (GLSG),” Blood, 2006, 108(13):4003-8.
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Last full review/revision January 2012
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