Fludarabine is a purine nucleoside antineoplastic agent indicated for the treatment of adult patients with B-cell chronic lymphocytic leukemia who have not responded to or whose disease has progressed during treatment with at least 1 standard alkylating agent-containing regimen. Life-threatening or fatal autoimmune reactions (e.g., hemolytic anemia, thrombocytopenic purpura, and acquired hemophilia) have been reported with fludarabine therapy; monitor patients for hemolysis.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Oral tablets/capsules: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
-Injectables: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
-Wash the affected area thoroughly with soap and water if the fludarabine solution comes into contact with the skin or mucous membranes; rinse eyes thoroughly with plain water.
Emetic Risk
-IV Doses: Minimal
-Oral Doses: Minimal/Low
-Administer prn antiemetics as necessary.
Extravasation Risk
-Nonvesicant
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Fludarabine phosphate injection is available as a preservative-free 50-mg lyophilized powder vial or as a 25-mg/mL preservative-free solution vial; discard any remaining contents in the vial after 8 hours from reconstitution or initial entry.
Reconstitution:
-Add 2 mL of Sterile Water for injection to the 50-mg lyophilized powder vial for a final concentration of 25 mg/mL.
-The solid cake powder should completely dissolve in 15 seconds or less.
Dilution:
-Dilute the calculated dose of fludarabine in 100 mL or 125 mL of 5% Dextrose injection or 0.9% Sodium Chloride injection.
-Do not mix with other drugs.
Intravenous (IV) infusion
-Administer the diluted admixture IV over approximately 30 minutes.
Pain was reported in 20% and 22% of patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies (MDAH study, n = 101; SWOG study, n = 32).
Transfusion-associated graft-versus-host disease has been reported following transfusion of non-irradiated blood in patients who received fludarabine; some cases were fatal. Patients treated with IV fludarabine phosphate should receive irradiated blood only.
Severe bone marrow suppression including pancytopenia has been reported with fludarabine therapy; some cases resulted in death. Myelosuppression may be cumulative and some cases of cytopenia have lasted from approximately 2 months to 1 year following therapy. Neutropenia (an absolute neutrophil count decreased to < 500/mm3), anemia (hemoglobin concentration decreased from baseline by at least 2 grams percent), and thrombocytopenia (platelet count decreased from baseline by at least 50%) were reported in 59%, 60%, and 55% of previously treated chronic lymphocytic leukemia (CLL) patients, respectively, who received IV fludarabine in 2 single-arm studies (n = 133). One case of bone marrow fibrosis occurred in a CLL patient treated with fludarabine. Monitor complete blood counts prior to and during fludarabine treatment.
Life-threatening and sometimes fatal autoimmune reactions such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported with IV fludarabine therapy. Most patients had a recurrence in the hemolytic process upon rechallenge. The use of steroid therapy may or may not be beneficial for these autoimmune reactions. Monitor patients for signs of hemolysis; discontinue fludarabine in patients who develop hemolysis.
Opportunistic infections and reactivations of latent viral infections such as herpes zoster, Epstein-Barr virus, and JC virus have occurred. Progressive multifocal leukoencephalopathy has been reported in postmarketing surveillance, with an onset time of a few weeks to about 1 year after starting fludarabine therapy; most patients had received prior and/or concurrent chemotherapy and most cases were fatal. In patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies, infection was reported in 33% of patients in a M.D. Anderson Cancer Center study (MDAH study; n = 101) and 44% of patients in a Southwest Oncology Group study (SWOG study; n = 32). Infectious events reported in these studies include pneumonia (MDAH study, 16%; SWOG study, 22%), sinusitis (MDAH study, 5%), urinary infection (MDAH study, 2%; SWOG study, 15%), upper respiratory infection (MDAH study, 2%; SWOG study, 16%), and bronchitis (MDAH study, 1%). Additionally, approximately 50% of the 29 fatalities that occurred during fludarabine therapy in these studies were due to infection. Monitor patients for signs and symptoms of infection.
Fatal pulmonary toxicity was reported in adult patients with refractory chronic lymphocytic leukemia (CLL) who received fludarabine in combination with pentostatin; therefore, this chemotherapy combination is not recommended in CLL patients. Pulmonary hypersensitivity reactions including dyspnea, cough, and interstitial pulmonary infiltrates have occurred with fludarabine therapy. In patients with previously treated CLL who received IV fludarabine in 2 single-arm studies, pulmonary toxicity was reported in 35% of patients in a M.D. Anderson Cancer Center study (MDAH study; n = 101) and 69% of patients in a Southwest Oncology Group study (SWOG study; n = 32). Pulmonary toxicity reported in these studies include cough (MDAH study, 10%; SWOG study, 44%), dyspnea (MDAH study, 16%; SWOG study, 22%), pharyngitis (SWOG study, 9%), allergic pneumonitis (SWOG study, 6%), epistaxis (MDAH study, 1%), hemoptysis (MDAH study, 1%; SWOG study, 6%), and hypoxia (MDAH study, 1%). Acute respiratory distress syndrome (ARDS), respiratory depression, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis, and respiratory failure have been reported with fludarabine use in postmarketing surveillance. Pulmonary symptoms may improve with corticosteroid use.
In patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies, gastrointestinal (GI) toxicity was reported in 46% of patients in a M.D. Anderson Cancer Center study (MDAH study; n = 101) and 63% of patients in a Southwest Oncology Group study (SWOG study; n = 32). GI system adverse events reported in these studies include nausea/vomiting (MDAH study, 36%; SWOG study, 31%), diarrhea (MDAH study, 15%; SWOG study, 13%), GI bleeding (MDAH study, 3%; SWOG study, 13%), anorexia (MDAH study, 7%; SWOG study, 34%), stomatitis (MDAH study, 9%), esophagitis (MDAH study, 3%), mucositis (MDAH study, 2%), hepatic failure (MDAH study, 1%), abnormal liver function tests (LFTs) such as elevated hepatic enzymes (MDAH study, 1%; SWOG study, 3%), cholelithiasis (SWOG study, 3%), constipation (MDAH study, 1%; SWOG study, 3%), and dysphagia (MDAH study, 1%). Additionally, elevations of pancreatic enzyme levels (e.g., hyperamylasemia) have been reported in patients who received fludarabine.
In patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies, cardiotoxicity was reported in 12% of patients in a M.D. Anderson Cancer Center study (MDAH study; n = 101) and 38% of patients in a Southwest Oncology Group study (SWOG study; n = 32). Cardiac adverse events reported in these studies include edema (MDAH study, 8%; SWOG study, 19%), angina (SWOG study, 6%), congestive heart failure (SWOG study, 3%), arrhythmias (SWOG study, 3%), supraventricular tachycardia (SVT) (SWOG study, 3%), myocardial infarction (SWOG study, 3%), deep vein thrombosis (MDAH study, 1%; SWOG study, 3%), phlebitis (MDAH study, 1%; SWOG study, 3%), transient ischemic attack (MDAH study, 1%), aneurysm (MDAH study, 1%), and cerebrovascular accident (stroke) (SWOG study, 3%). Additionally, pericardial effusion was reported in one patient who received fludarabine.
Dose-dependent neurotoxicity has been reported with IV fludarabine use. Weakness, agitation, confusion, seizures, visual impairment, optic neuritis, optic neuropathy, blindness, and coma have been reported in patients with chronic lymphocytic leukemia (CLL) treated at recommended fludarabine doses. In postmarketing surveillance, neurotoxicity was reported in 7 to 225 days. In patients with previously treated CLL who received IV fludarabine in 2 single-arm studies, neurologic toxicity was reported in 21% of patients in a M.D. Anderson Cancer Center study (MDAH study; n = 101) and 69% of patients in a Southwest Oncology Group study (SWOG study; n = 32). Nervous system adverse events reported in these studies include weakness (MDAH study, 9%; SWOG study, 65%), paresthesias (MDAH study, 4%; SWOG study, 12%), headache (MDAH study, 3%), visual impairment (MDAH study, 3%; SWOG study, 15%), hearing loss (MDAH study, 2%; SWOG study, 6%), sleep disorder (MDAH study, 1%; SWOG study, 3%), depression (MDAH study, 1%), acute cerebellar syndrome (MDAH study, 1%), and impaired mentation (MDAH study, 1%). Additionally, peripheral neuropathy including 1 case of wrist-drop and intracranial bleeding have been reported in patients who received fludarabine.
In patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies, genitourinary toxicity was reported in 12% of patients in a M.D. Anderson Cancer Center study (MDAH study; n = 101) and 22% of patients in a Southwest Oncology Group study (SWOG study; n = 32). Genitourinary adverse events reported in these studies include dysuria (MDAH study, 4%; SWOG study, 3%), hematuria (MDAH study, 2%; SWOG study, 3%), renal failure (unspecified) (MDAH study, 1%), abnormal renal function tests (MDAH study, 1%), proteinuria (MDAH study, 1%), and urinary hesitancy (SWOG study, 3%). Additionally, hemorrhagic cystitis was reported in patients who received fludarabine. A dose reduction is recommended in patients with moderate renal impairment (creatinine clearance, 30 to 70 ml/min/1.73 m2); monitor these patients closely. Fludarabine use is not recommended in patients with severe renal impairment.
Tumor lysis syndrome (TLS) was reported in 1% of patients with refractory chronic lymphocytic leukemia who received IV fludarabine in a single-arm study (n = 101). Signs and symptoms of TLS may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, nephrolithiasis, renal failure, pain, and hematuria. Take precautionary measures to prevent TLS prior to starting fludarabine therapy.
New primary malignancy including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has been reported with fludarabine use in postmarketing surveillance; most cases were associated with prior, concomitant, or subsequent treatment with alkylating agents, topoisomerase inhibitors, or radiation therapy. Additionally, worsening or flare-up of preexisting skin cancer lesions, as well as new onset of skin cancer, and rare cases of Epstein-Barr (EBV) associated lymphoproliferative disorders have been reported in patients who received fludarabine. In a large series of chronic lymphocytic leukemia patients randomized to receive chlorambucil, fludarabine, or fludarabine plus chlorambucil, treatment-related myeloid malignancies, specifically treatment-related MDS, treatment-related AML, or treatment-related MDS evolving to AML, have been reported.
In patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies, cutaneous toxicity was reported in 17% of patients in a M.D. Anderson Cancer Center study (MDAH study; n = 101) and 18% of patients in a Southwest Oncology Group study (SWOG study; n = 32). Dermatologic adverse events reported in these studies include rash (unspecified) (MDAH study, 15%; SWOG study, 15%), diaphoresis (MDAH study, 1%; SWOG study, 13%), pruritus (MDAH study, 1%; SWOG study, 3%), alopecia (SWOG study, 3%), and seborrhea (MDAH study, 1%). Additionally, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and pemphigus have been reported in patients who received fludarabine; some cases resulted in death.
In patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies, musculoskeletal toxicity was reported in 7% of patients in a M.D. Anderson Cancer Center study (MDAH study; n = 101) and 16% of patients in a Southwest Oncology Group study (SWOG study; n = 32). Musculoskeletal adverse events reported in these studies include myalgia (MDAH study, 4%; SWOG study, 16%), osteoporosis (MDAH study, 2%), and arthralgia (MDAH study, 1%).
Adverse events reported in patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies (MDAH study, n = 101; SWOG study, n = 32) included fever (MDAH study, 60%; SWOG study, 69%) and chills (MDAH study, 11%; SWOG study, 19%).
Adverse events reported in patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies (MDAH study, n = 101; SWOG study, n = 32) included fatigue (MDAH study, 10%; SWOG study, 38%) and malaise (MDAH study, 8%; SWOG study, 6%).
Anaphylactoid reactions were reported in 1% of patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in a single-arm study (n = 101).
Bleeding was reported in 1% of patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in a single-arm study (n = 101).
Dehydration was reported in 1% of patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in a single-arm study (n = 101).
Hyperglycemia was reported in 1% and 6% of patients with previously treated chronic lymphocytic leukemia who received IV fludarabine in 2 single-arm studies (MDAH study, n = 101; SWOG study, n = 32).
Bone marrow suppression such as severe anemia, neutropenia, and thrombocytopenia and pancytopenia resulting in death has been reported with fludarabine therapy; toxicity is cumulative and typically reversible. Clinically significant cytopenias may last from about 2 months to 1 year. Monitor complete blood counts prior to and periodically during treatment with fludarabine; therapy delay or a dosage reduction may be necessary in patients who develop myelosuppression. Fludarabine administration requires an experienced clinician knowledgeable in the use of antineoplastic therapy.
Severe dose-dependent neurotoxicity has been reported with fludarabine therapy. High-dose fludarabine (approximately 4-times more than the recommended CLL dose) resulted in vision loss, coma, and death. Additionally, central nervous system toxicity (e.g., coma, seizures, agitation, and confusion) has occurred in CLL patients treated at the recommended fludarabine dosage. Monitor patients for signs and symptoms of neurotoxicity; therapy delay, a dose reduction, or discontinuation may be necessary in patients who develop neurologic toxicity. Due to the risk of fatigue, confusion, and visual disturbance, patients should use caution when driving or operating machinery.
A high rate of fatal pulmonary toxicity occurred in patients with CLL who received fludarabine in combination with pentostatin (off-label use) in a clinical study; therefore, use with pentostatin is not recommended.
Tumor lysis syndrome (TLS) has been reported with fludarabine therapy; CLL patients with large tumor burdens are at the highest risk of developing TLS. Because TLS may occur during the first week of therapy, institute prophylactic measures (e.g., anti-hyperuricemic agents, hydration) and monitor patients closely for signs and symptoms of TLS when initiating fludarabine therapy.
Use fludarabine with caution in patients with renal impairment; an initial dose adjustment may be necessary. Evaluate renal function prior to and during fludarabine therapy. Monitor patients with renal impairment closely for signs of toxicity. Avoid fludarabine use in patients with a creatinine clearance of less than 30 mL/min.
Life-threatening and sometimes fatal autoimmune disease (e.g., hemolytic anemia, immune thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia) has been reported with fludarabine therapy. Monitor patients closely for signs or symptoms of hemolysis (e. g., reticulocyte count, indirect bilirubin level, LDH level).
Serious infection including opportunistic infection and viral infection reactivation (e.g., herpes infection (zoster), Epstein-Barr, and JC viruses) has occurred in CLL patients who received fludarabine therapy; some cases were fatal. Consider prophylactic treatment to prevent opportunistic infections. Monitor patients for signs of infection during fludarabine therapy.
Vaccination with live virus vaccines should be avoided during and after treatment with fludarabine.
Fludarabine is classified as FDA pregnancy risk category D. It may cause fetal harm when administered to a pregnant woman based on its mechanism of action and data from animal studies; therefore, females of reproductive potential who are receiving fludarabine should avoid pregnancy. Advise pregnant women of the potential risk to the fetus with fludarabine therapy. Fludarabine was embryolethal and teratogenic in rats and rabbits in animal studies.
Counsel patients about the reproductive risk and contraception requirements during fludarabine treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with fludarabine. Patients who become pregnant while receiving fludarabine should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during therapy and for at least 6 months following the final dose of fludarabine. Infertility may occur in male patients who receive fludarabine due to testicular tissue and spermatozoa damage.
It is not known if fludarabine is secreted in human milk. Due to the potential for serious adverse reactions in nursing infants including tumorigenicity, breast-feeding is not recommended during fludarabine therapy.
For the treatment of chronic lymphocytic leukemia (CLL):
-for the treatment of B-cell CLL in patients who have not responded to or whose disease has progressed during treatment with at least 1 standard alkylating agent-containing regimen:
NOTE: Fludarabine has been designated an orphan drug by the FDA for B-cell CLL and refractory CLL.
Intravenous dosage:
Adults: 25 mg/m2 IV once daily on days 1, 2, 3, 4, and 5 repeated every 28 days for up to 3 cycles past the achievement of maximal response. Therapy delay, dose reduction, or discontinuation may be necessary in patients who develop toxicity.
-for the first-line treatment of CLL, in combination with chlorambucil*:
Intravenous dosage:
Adults: Dosage not established. Severe and life-threatening adverse effects were reported more often with fludarabine plus chlorambucil compared with fludarabine alone in patients with previously untreated CLL in a randomized, 3-arm, phase 3 trial. There is not sufficient evidence to support the use of this drug combination for this indication.
-for the first-line treatment of CLL, in combination with rituximab*:
Intravenous dosage:
Adults: 25 mg/m2 IV daily on days 1, 2, 3, 4, and 5 repeated every 28 days for 6 cycles followed by rituximab 375 mg/m2 IV for 4 weekly doses in patients with stable disease or better after 2 months of observation (sequential therapy) or fludarabine 25 mg/m2 IV daily on days 1, 2, 3, 4, and 5 repeated every 28 days for 6 cycles with rituximab 375 mg/m2 IV on day 1 and 4 on cycle 1 then 375 mg/m2 IV on day 1 only on cycles 2 to 6 concurrently followed by rituximab 375 mg/m2 IV for 4 weekly doses in patients who had stable disease or better 2 months after therapy (concurrent therapy) was studied in 104 patients in a randomized, noncomparative, phase 2 trial. Because the first 44 patients treated with concurrent therapy experienced infusion-related adverse effects, the last 7 patients received stepped up therapy on cycle 1 with rituximab.
-for the first-line treatment of CLL, in combination with cyclophosphamide*:
Intravenous dosage:
Adults: 25 mg/m2 IV daily on days 1, 2, and 3 plus cyclophosphamide 250 mg/m2 IV daily on days 1, 2, and 3 repeated every 28 days for up to 6 cycles was evaluated in a randomized, phase 3 studies. In one study, patients with severe lymphopenia for more than 7 days received prophylactic antibiotics. In another study, patients received prophylactic antibiotic therapy with cotrimoxazole for 6 months after treatment and allopurinol daily for 7 days during the first 2 to 3 courses; prophylactic antiviral therapy was recommended.
Oral dosage:
Adults: 24 mg/m2 orally daily on days 1, 2, 3, 4, and 5 plus cyclophosphamide 150 mg/m2 orally daily on days 1, 2, 3, 4, and 5 repeated every month for up to 6 cycles was evaluated in a randomized, phase 3 study. Patients received prophylactic antibiotic therapy with cotrimoxazole for 6 months after treatment and allopurinol daily for 7 days during the first 2 to 3 courses; prophylactic antiviral therapy was recommended. No significant differences in efficacy were found between patients who received oral or IV fludarabine plus cyclophosphamide therapy in a retrospective analysis in 65 patients.
-for the treatment of CD20-positive CLL, in combination with cyclophosphamide and rituximab*:
NOTE: Rituximab in combination with fludarabine and cyclophosphamide is FDA approved for use for the treatment of CD20-positive CLL.
Intravenous dosage:
Adults: 25 mg/m2 IV daily on days 1, 2, and 3 plus cyclophosphamide 250 mg/m2 daily on days 1, 2, and 3 (FC regimen) and rituximab 375 mg/m2 IV on day 0 (the day prior to FC) on cycle 1, then rituximab 500 mg/m2 IV on day 1 on cycles 2 to 6 repeated every 28 days (R-FC regimen) for 6 cycles has been studied in randomized, phase 3 trials. Treatment with R-FC (mean of 5.2 cycles) resulted in a significantly improved progression-free survival (PFS) time (primary endpoint) compared with FC alone (51.8 vs. 32.8 months; p less than 0.0001) in 817 previously untreated CLL patients in a multinational, randomized, phase 3 trial. The 3-year PFS (65% vs. 45% hazard ratio (HR) = 0.56; 95% CI, 0.46 to 0.69) and overall survival (OS) (87% vs. 83%; HR = 0.67; 95% CI, 0.48 to 0.92) rates were also significantly improved with R-FC. The median PFS time (primary endpoint) was 30.6 months with R-FC compared with 20.6 months with FC (HR = 0.65; 95% CI, 0.51 to 0.82; p less than 0.001) in another multinational, randomized, phase 3trial in 552 CLL patients who had relapsed or refractory disease following 1 prior line of therapy. All patients in this study received tumor lysis and antibiotic/antiviral prophylaxis. At a median follow-up time of 25 months, the median OS was not significantly different between treatment arms (R-FC, median time not reached; FC, 52 months).
-for the treatment of relapsed or refractory CLL, in combination with alemtuzumab*:
Intravenous dosage:
Adults: 30 mg/m2 IV daily on days 1, 2, and 3 in combination with alemtuzumab 30 mg IV daily on days 1, 2, and 3 repeated every 28 days for up to 6 cycles has been studied in a randomized, phase 3 trial. Alemtuzumab was titrated to 30 mg on the first cycle of treatment as follows: 3 mg IV over 2 hours on day 1, 10 mg IV over 2 hours on day 2, 30 mg IV over 2 hours on day 3. The same dose was repeated daily if grade 3 or 4 infusion-related toxicity occurred until it was well tolerated (grade 2 or lower toxicity) with appropriate premedication; a maximum of 14 days was allowed for titration to 30 mg. After escalation, fludarabine was administered first followed by alemtuzumab IV over 4 to 6 hours on the first day of each cycle and over 2 hours on days 2 and 3. All patients received acetaminophen and an antihistamine 30 minute prior to each alemtuzumab infusion and hydrocortisone 100 mg IV (or equivalent) prior to each alemtuzumab infusion during the dose escalation phase and then on day 1 of each subsequent cycles. Patients also received prophylaxis with co-trimoxazole (or equivalent) and famciclovir starting at the beginning of therapy and continuing until CD4 counts were at least 200 cells/microL.
For the treatment of prolymphocytic leukemia (PLL)*:
Intravenous dosage:
Adults: 30 mg/m2/day IV over 30 minutes for 5 days repeated every 4 weeks has been studied in patients with prolymphocytic leukemia. Some patients also received prednisone 60 mg/m2/day PO for 5 days repeated every 4 weeks; however, overall response rates did not appear improved with combination therapy compared with fludarabine alone.
For the treatment of non-Hodgkin's lymphoma (NHL)*:
-for the treatment of previously untreated follicular NHL*, in combination with mitoxantrone and rituximab:
Intravenous dosage:
Adults: 25 mg/m2 IV daily on days 1, 2, and 3 in combination with mitoxantrone 10 mg/m2 IV on day 1 and rituximab 375 mg/m2 IV on day 1 repeated every 21 days for 6 cycles followed by 2 additional rituximab 375 mg/m2 IV doses given at 21-day intervals has been evaluated in patients with previously untreated follicular lymphoma in a randomized, phase III trial.
For the treatment of acute myelogenous leukemia (AML)*:
-for the treatment of relapsed or refractory acute myelogenous leukemia (AML) in combination with cytarabine and filgrastim*:
Intravenous dosage:
Adults: 30 mg/m2 IV over 30 minutes on days 1-5, followed 3.5 hours later each day by cytarabine 2 g/m2 IV over 4 hours on days 1-5 and G-CSF (filgrastim or lenograstim) 5 mcg/kg from day 0 (24 hours before starting chemotherapy) until the ANC > 500/mm3.
For use in stem cell transplant preparation*:
-for stem cell transplant preparation, in combination with cyclophosphamide, prior to reduced intensity allogeneic hematopoietic stem cell transplantation for advanced indolent B cell malignancies*:
Intravenous dosage:
Adults: Fludarabine 30 mg/m2/day IV for 5 consecutive days (days -7 to -3) in combination with cyclophosphamide 1 g/m2/day IV on 3 consecutive days (days -5 to -3). Low dose methotrexate was given in combination with tacrolimus or cyclosporine for the prevention of graft-versus-host-disease. Infection prophylaxis with fluconazole, acyclovir, and TMP/SMX was given per institutional standards.
-for stem cell transplant preparation prior to nonmyeloablative allogeneic hematopoietic stem cell transplant in combination with cyclophosphamide*:
Intravenous dosage:
Adults: Cyclophosphamide 60 mg/kg/day IV on 2 consecutive days (days -7 and -6) in combination with fludarabine 25 mg/m2/day IV for 5 consecutive days (days -5 to -1). Cyclosporine alone or in combination with mycophenolate was used for GVHD prevention. For obese patients (> 120% ideal body weight), chemotherapy dosing weight was calculated by using the formula: dosing weight = ideal body weight + (actual/ideal weight)/2.
For the treatment of advanced cutaneous T-cell lymphoma (CTCL)*, including mycosis fungoides* and Sezary syndrome*:
Intravenous dosage:
Adults: 25 mg/m2/day IV for 5 days repeated every 28 days has been evaluated in clinical trials; overall response rates ranged from 19% to 29.5%. In a nonrandomized study, treatment was continued for a mean of 5 cycles (range, 2-8 cycles) and 43.2% of patients received extracorporeal photochemotherapy (ECP) after fludarabine.
Maximum Dosage Limits:
-Adults
25 mg/m2 IV daily for 5 days repeated every 28 days; 30 mg/m2 IV daily for 5 days has been studied for off-label uses.
-Geriatric
25 mg/m2 IV daily for 5 days repeated every 28 days; 30 mg/m2 IV daily for 5 days has been studied for off-label uses.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Creatinine clearance (CrCl) of 50 to 79 mL/min: Reduce initial dose to 20 mg/m2 IV daily for 5 days.
CrCl of 30 to 49 mL/min: Reduce initial dose to 15 mg/m2 IV daily for 5 days.
CrCl less than 30 mL/min: Use not recommended.
Alternatively, reduce the initial dose by 20% in patients with CrCL of 30 to 70 mL/min; do not administer in patients with CrCl less than 30 mL/min.
*non-FDA-approved indication
Abciximab: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Albuterol; Budesonide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Anagrelide: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Aspirin, ASA; Dipyridamole: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Azelastine; Fluticasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Basiliximab: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents may result in additive effects. A dosage reduction of the purine analog may be indicated when used in combination with other myelosuppressive chemotherapy.
Beclomethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Betamethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Budesonide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Budesonide; Formoterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Budesonide; Glycopyrrolate; Formoterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Chikungunya Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciclesonide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Cilostazol: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Clopidogrel: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Corticosteroids: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Cortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Cyclosporine: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
Cytarabine, ARA-C: (Minor) Prior or concurrent administration of cytarabine, ARA-C with fludarabine results in inhibition of the metabolism of fludarabine to its active triphosphate. Fludarabine administration should generally precede cytarabine, ARA-C administration.
Deflazacort: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexamethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Dipyridamole: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Eptifibatide: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Fludrocortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Flunisolide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Fluticasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Fluticasone; Salmeterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Fluticasone; Umeclidinium; Vilanterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Fluticasone; Vilanterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Formoterol; Mometasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Hydrocortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Methylprednisolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Mometasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Olopatadine; Mometasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Pentostatin: (Contraindicated) The combined use of pentostatin and fludarabine phosphate is not recommended because it may be associated with an increased risk of fatal pulmonary toxicity. A boxed warning about this potentially fatal interaction exists in the product label. In a clinical investigation in patients with refractory chronic lymphocytic leukemia using pentostatin at the recommended dose in combination with fludarabine phosphate, 4 of 6 patients entered in the study had severe or fatal pulmonary toxicity.
Pentoxifylline: (Minor) Additive cytotoxic effects of fludarabine may be seen when the drug is given in combination with pentoxyfylline. Pentoxifylline disrupts DNA repair mechanisms by preventing cell cycle arrest at the G2/M checkpoint. By not allowing DNA repair, pentoxifylline is thought to increase fludarabine-induced cytotoxicity.
Platelet Inhibitors: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Prasugrel: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Prednisolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Prednisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Ropeginterferon alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Ticagrelor: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Tirofiban: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Triamcinolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Vorapaxar: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Fludarabine acts as a cytotoxic purine antimetabolite. Upon administration, fludarabine is rapidly dephosphorylated in the plasma to free nucleoside 9-beta-D-arabinosyl-2 fluoroadenine (F-ara-A), which then enters into the cell via high and low affinity transport systems. The rate of transport of fludarabine into malignant cells is greater than that into normal cells. Intracellularly, F-ara-A is converted to the 5'-triphosphate, F-ara-ATP. The rate limiting step in this process is the formation of the monophosphate, which is catalyzed by deoxycytidine kinase. Cells that lack deoxycytidine kinase are resistant to fludarabine. The cytotoxicity of F-ara-ATP is primarily due to its effects on DNA. F-ara-ATP competes with deoxyadenosine triphosphate for incorporation into DNA. Once incorporated into DNA, F-ara-ATP functions as a DNA chain terminator, preventing the elongation of DNA strands at the 3'-terminal. F-ara-ATP also inhibits DNA repair by specifically inhibiting DNA polymerase alpha, gamma, and delta.
In addition, F-ara-ATP decreases deoxynucleotide pools by inhibiting ribonucleoside diphosphate reductase. By decreasing deoxynucleotide pools, fludarabine enhances the activity of deoxycytidine kinase, the enzyme required for phosphorylation of F-ara-A. F-ara-A also inhibits DNA primase and DNA ligase I resulting in DNA deletions and mutations. Incorporation into RNA and inhibition of RNA transcription occurs leading to decreased mRNA and protein production, and may be relevant to the activity of fludarabine in indolent diseases. However, 10-fold higher intracellular concentrations are required to inhibit DNA versus RNA. Fludarabine depletes CD4+ cells leading to immunosuppression. Combination chemotherapy regimens have been designed to enhance the cytotoxicity of fludarabine by enhancing the accumulation of the triphosphate form or by combining fludarabine with DNA damaging agents that inhibit DNA repair mechanisms.
Fludarabine is administered intravenously or orally.
-Route-Specific Pharmacokinetics
Oral Route
Pharmacokinetic studies of the oral form have demonstrated an oral bioavailability of 50-65%; similar systemic exposure is observed after a single oral dose of fludarabine 40 mg/m2 and a single intravenous dose of fludarabine 25 mg/m2. The time to Cmax and bioavailability were dose independent. The oral bioavailability of fludarabine is unaffected by food.
Intravenous Route
The intravenous formulation is administered as the monophosphate salt, which increases the drug's solubility. Following IV infusion, rapid dephosphorylation of fludarabine phosphate to the active metabolite 2-fluoro-ara-A (F-ara-A) occurs. This dephosphorylation of fludarabine phosphate is so rapid that within minutes the parent drug is undetectable in plasma. Fludarabine is widely distributed and bound to body tissues. A biphasic decline in F-ara-A plasma levels has been described with a terminal elimination half-life of 7-12 hours. The intracellular half-life of F-ara-ATP is about 15 hours. Moderate accumulation of F-ara-A has been shown following 5 daily doses. During a 5-day treatment, F-ara-A trough plasma levels increased by a factor of 2. F-ara-A is excreted primarily in the urine. The rate of fludarabine total body clearance correlates closely with creatinine clearance. Renal clearance represents about 40% of total body clearance. The severity of fludarabine-induced neutropenia is directly related to total body clearance, AUC, and half-life.
-Special Populations
Renal Impairment
Patients with moderate renal impairment (17-41 mL/min/m2) receiving fludarabine dose reduced by 20% had a similar exposure (AUC 20 nM-hour/mL) compared to patients with normal renal function receiving the recommended dose of fludarabine. The mean total body clearance was 172 mL/min for patients with normal renal function and 124 mL/min for patients with moderate renal impairment. Fludarabine dosage reduction is recommended for patients with impaired renal function.