VA Class:AN300
Fludarabine phosphate, a synthetic purine antagonist, is an antimetabolite antineoplastic agent.1, 2, 3, 4, 5, 6, 7, 9, 21
Fludarabine is used for the palliative treatment of chronic lymphocytic leukemia (CLL) in patients whose disease does not respond adequately to or progresses during treatment with at least one standard alkylating agent-containing regimen (e.g., chlorambucil with or without prednisone).1, 24, 44, 92
While it has been suggested that chronic lymphocytic leukemia can principally involve T-cell proliferation in some patients12, 24 and fludarabine is active against T cells,2, 4 some experts58, 87 currently believe that all cases of chronic lymphocytic leukemia principally involve monoclonal proliferation of B cells.4, 12, 24, 58 Controlled clinical studies establishing efficacy of fludarabine in the treatment of this leukemia have been limited to a clinical diagnosis of disease phenotypically characterized as B-cell chronic lymphocytic leukemia.1, 4, 9, 12, 14, 15, 80, 87 The role of fludarabine in the treatment of chronic T-cell lymphocytosis remains to be established.80, 87
Fludarabine also has been used in previously untreated patients† and in those whose leukemia contemporaneously was responsive to standard therapy†.1, 2, 4, 6, 14, 24, 46, 58, 59 While the manufacturer states that safety and efficacy of the drug in such patients remain to be established,1 some experts believe that use of the drug in this patient population is clinically reasonable.24, 87 Fludarabine also has been used in the treatment of prolymphocytic leukemia and prolymphocytoid variant of chronic lymphocytic leukemia.36 (See Uses: Prolymphocytic Leukemia and Prolymphocytoid Variant.)
Because chronic lymphocytic leukemia generally is not curable, occurs principally in geriatric patients, and often progresses slowly, the disease generally is treated conservatively unless there is a clear indication for immediate, aggressive therapy.13, 14, 15, 17, 18, 24, 58 Therefore, antineoplastic chemotherapy usually is reserved for patients with progressive, symptomatic disease (e.g., those with disease-related symptoms such as fever, night sweats, or weight loss; progressive bone marrow failure; acquired autoimmune hemolytic anemia or thrombocytopenia; enlarged or painful lymph nodes or spleen; disease-related recurrent infections; or progressive lymphocytosis).14, 15, 17, 18, 19, 24, 44, 58, 61 Most clinicians currently consider chlorambucil, alone or combined with prednisone, the initial treatment of choice for chronic lymphocytic leukemia when antineoplastic therapy is indicated14, 15, 16, 19, 24, 44, 58, 61, 64, 80, 87 and fludarabine the treatment of choice for refractory disease.24, 44, 47, 58, 64, 80, 87 However, some clinicians currently consider fludarabine an alternative to chlorambucil as initial therapy.46, 47, 87 Current chemotherapy regimens are only palliative in this leukemia.15, 24, 44, 64
In clinical studies employing fludarabine dosages of 15-40 mg/m2 daily for 5 days every 28 days in patients with refractory chronic lymphocytic leukemia, clinical response rates (including complete remissions and partial responses as defined by the National Cancer Institute Chronic Lymphocytic Leukemia Working Group [NCIWG])1, 4, 12, 24, 58 ranged from 32-57%, with up to 13% being complete remissions.1, 3, 4, 6, 14, 15, 20, 24 The drug has been reported to induce a complete remission with residual nodular or focal lymphoid infiltration of bone marrow in up to another 16-20% of patients.4, 6, 20 In clinical studies, the median time to response ranged from 7-21 weeks, the median duration of disease control ranged from 65-91 weeks, and the median survival of all patients with refractory disease treated with fludarabine ranged from 43-52 weeks.1, 10, 20 Survival of 36 months or longer has been reported in patients with complete remission or complete remission with residual nodular or focal lymphoid infiltration of bone marrow.20 Rai stage (a clinical staging system for CLL based on groupings of prognostic variables)12, 24, 58 improved to stage II or better in 58-71% of patients whose disease was stage III or IV at baseline1 but returned to stage 0 in only 43 or 19% of those with stage I-III or IV disease, respectively, at baseline.20 Survival appears to correlate with final Rai stage achieved,20 and patients diagnosed with earlier Rai stage disease are more likely to achieve complete remissions compared with patients with later-stage disease.4, 20 In patients who were anemic and/or thrombocytopenic at baseline, mean hemoglobin concentration improved from 9 to 11.8 g/dL and/or mean platelet count improved from 65,500 to 103,300/mm3, respectively, at the time of response.1, 10
The ability of fludarabine to induce responses in chronic lymphocytic leukemia that was refractory to standard therapy suggests minimal cross-resistance with other agents commonly used in the treatment of this leukemia.1 Because of an increased incidence of infections with opportunistic pathogens in patients receiving purine analogs in combination with corticosteroids, prednisone should be omitted from regimens containing fludarabine or other purine analogs.44
Fludarabine also has been used in patients with previously untreated† chronic lymphocytic leukemia.2, 3, 4, 6, 14, 46, 58, 59 In a large randomized trial comparing fludarabine, chlorambucil, and fludarabine plus chlorambucil for the initial treatment of CLL, patients receiving fludarabine had higher rates of complete and overall (complete or partial) response (20 and 63%, respectively) than those receiving chlorambucil (4 and 37%, respectively), but no difference was observed in median survival (66 versus 56 months).46 Both the median duration of response and the median time to progression of disease were longer with fludarabine (25 and 20 months, respectively) than with chlorambucil (14 months for both).46 The combination of fludarabine and chlorambucil was associated with similar response rates as fludarabine alone, but caused excessive toxicity.46 Although either single-drug regimen was considered tolerable, higher rates of infections and severe or life-threatening neutropenia were observed in patients receiving fludarabine.46 Further study is needed to establish the role of fludarabine in patients with previously untreated or nonrefractory disease†.1, 3, 4, 6, 24, 46, 47, 87
Fludarabine is used alone or in combination regimens for the treatment of low-grade, advanced (stage III or IV) adult non-Hodgkin's lymphoma† that failed or relapsed after previous therapy.63, 92 Optimal therapy for advanced stages of low-grade adult non-Hodgkin's lymphoma remains controversial, in part because eventual relapse is common regardless of the therapy employed.63
Overall response rates with fludarabine have ranged from 45-67%2, 6, 23, 38, 39 for patients with low-grade histologies. Response may be particularly likely in follicular small-cleaved cell lymphoma (a low-grade lymphoma).23, 39 Fludarabine in combination with mitoxantrone, with or without dexamethasone, is used in the treatment of advanced, low-grade non-Hodgkin's lymphoma.63, 92
Fludarabine has been used in a limited number of patients with either acute myeloid (myelogenous, nonlymphocytic) leukemia† (AML, ANLL) or acute lymphocytic leukemia† (ALL) whose disease failed to respond adequately to conventional therapy or relapsed following remission; the drug was used at dosages substantially higher than those used in the treatment of chronic lymphocytic leukemia.2, 5, 29, 30, 31, 45, 92 While fludarabine exhibits some activity against these acute leukemias, severe toxicity (e.g., neurotoxicity) associated with the relatively high dosages that would appear necessary for adequate response are thought to preclude the usefulness of the drug as monotherapy for remission induction in these leukemias.5, 29, 30, 31, 45, 80, 87 Whether fludarabine would be beneficial at lower dosages as an adjunct to other antineoplastic agents to reduce leukemic cell burden in these leukemias remains to be established.2, 29, 80, 87
Prolymphocytic Leukemia and Prolymphocytoid Variant
Fludarabine has been used in a limited number of patients for the palliative treatment of prolymphocytic leukemia† (PLL) or prolymphocytoid chronic lymphocytic leukemia† (CLL-Pro) that was refractory to standard chemotherapy (e.g., chlorambucil and prednisone).34, 35, 36, 37, 38, 42 The drug occasionally has produced complete remissions or partial responses in such patients.34, 35, 36, 37, 38, 42 Responses in peripheral blood were most common, with those in bone marrow and the spleen being less common.34, 35, 36, 37, 38, 42 In one small group of patients with these leukemias, complete remissions or partial responses each occurred in 18% of patients (overall response rate of 35%), most of whose disease was refractory at the time fludarabine (alone or combined with prednisone) was initiated.36 Response to previous therapy with other drugs appeared to be an indicator of the likelihood of response to fludarabine, with those whose disease responded initially to other therapy and then relapsed being more likely to respond to fludarabine than those whose disease was resistant to previous therapy.36 While the modest response to fludarabine therapy is encouraging in these poorly responsive leukemias, additional study and experience are needed to establish the role of fludarabine in the treatment of these leukemias, particularly concerning whether efficacy can be improved with combination regimens.34, 35, 36, 37, 38, 80, 87
While other drugs (e.g., cladribine, pentostatin) are considered the initial therapies of choice in the treatment of hairy cell leukemia† (leukemic reticuloendotheliosis),28, 64, 88, 89, 90, 91, 92, 93, 94 limited evidence suggests that fludarabine may be useful in selected patients with this disease.15, 28, 32, 33, 64 At least partial responses have been reported in several patients with hairy cell leukemia whose disease was refractory to interferon alfa or pentostatin.28, 32, 33, 64 Additional study and experience are needed to define further the role of fludarabine in the treatment of hairy cell leukemia.32, 33, 80, 87
Waldenstrom's Macroglobulinemia
Fludarabine has been shown to be somewhat effective in the treatment of refractory macroglobulinemia† in a limited number of patients.6, 21 In one study, 45% of patients responded with a greater than 50% reduction of immunoglobulin M (IgM) tumor mass for a projected median duration of greater than one year.21 Onset of remission was slow; the median time to decrease tumor mass by 50% was greater than 5 months.21 Further study of fludarabine in the treatment of macroglobulinemia, including study of the drug in combination therapy with other treatment modalities, is needed.21, 80, 87
Fludarabine is used in the treatment of mycosis fungoides, a form of cutaneous T-cell lymphoma†.52, 92
Reconstitution and Administration
Fludarabine phosphate is administered by IV infusion.1, 2, 4, 5, 6, 9, 15, 20, 21, 22, 23, 29, 31, 33, 36, 59, 65 The drug also has been administered by rapid IV injection† and by continuous† IV infusion (e.g., over 48 hours),2, 4, 5, 6, 15, 30, 41, 43, 62, 65 but the manufacturer recommends that fludarabine phosphate be administered by IV infusion over 30 minutes.1, 9, 80 While the risk of certain toxic effects (e.g., neurotoxicity) is increased with increasing dosage,1, 2, 3, 4, 5, 6, 9, 29, 30, 31, 45 it remains to be established whether the rate of IV administration of the drug affects the risk of such toxicity, and neurotoxicity has occurred when the drug either was administered by rapid IV injection or slow IV infusion.30, 80, 87
Fludarabine phosphate powder for injection is reconstituted by adding 2 mL of sterile water for injection to a vial labeled as containing 50 mg of the drug to provide a solution containing 25 mg/mL.1 With agitation, the drug should dissolve completely within 15 seconds or less.80 Alternatively, the commercially available aqueous injection containing 25 mg/mL can be used.95 The appropriate dose of the drug should then be withdrawn from the vial and added to a compatible IV fluid; in clinical studies, the drug was administered in 100 or 125 mL of 5% dextrose or 0.9% sodium chloride injection.1
Fludarabine phosphate solutions contain no preservatives and should be used within 8 hours after reconstitution.1 (See Chemistry and Stability: Stability.) Care must be taken to ensure the sterility of prepared solutions.1 The commercially available injection95 and reconstituted and diluted solutions of fludarabine phosphate should be inspected visually for particulate matter and/or discoloration prior to administration.1
Because of the carcinogenic potential of fludarabine (see Cautions: Mutagenicity and Carcinogenicity), the usual cautions for handling and preparing solutions of cytotoxic drugs should be exercised.1 The manufacturer recommends the use of latex gloves and protective eyewear to avoid exposure to the drug in case of breakage of the container or other accidental spilla exposure to the drug via inhalation or direct contact with the skin or mucous membranes should be avoided.1 If fludarabine phosphate powder for injection or a solution of the drug comes in contact with the skin or mucosa, the affected area should be washed immediately and thoroughly with soap and water.1 If the drug comes in contact with the eyes, the affected eye(s) should be flushed thoroughly with water or saline.1, 80
The recommended initial IV dosage of fludarabine phosphate for the treatment of chronic lymphocytic leukemia in adults is 25 mg/m2, administered as single daily doses for 5 consecutive days;1, 3, 6, 68, 80, 87 dosages up to 30 mg/m2, administered as single daily doses for 5 consecutive days, also have been used.3, 4, 6, 58, 87 The possible need for dosage adjustment in patients who may be predisposed to fludarabine-induced toxicity (e.g., geriatric patients, those with impaired renal or bone marrow function) should be considered.1, 41
Each 5-day course of fludarabine phosphate therapy should begin at 28-day intervals.1, 3, 6 Some clinicians initially administer the drug for at least 2 or 3 courses to determine patient response, unless unacceptable toxicity or disease progression occurs.3, 80, 87 Although the optimum duration of therapy remains to be established, it currently is recommended that fludarabine phosphate be continued until a maximal response is achieved or dose-limiting toxicity develops; once a maximal response is achieved in the absence of such toxicity, 3 additional courses of therapy are administered and the drug then is discontinued.1, 3 Dosage may be decreased or therapy temporarily withheld if evidence of hematologic or nonhematologic toxicity is observed.1 Therapy should be delayed or discontinued permanently if neurologic toxicity develops.1 Some patients have received up to at least 15 courses of therapy.1, 3
Relatively low fludarabine phosphate dosages similar to those currently recommended for the treatment of chronic lymphocytic leukemia also have been used for the treatment of other neoplasms† (e.g., 18-30 mg/m2 daily for 5 consecutive days at 28-day intervals),2, 6, 21, 22, 23, 32, 33, 36, 38, 41, 52 but studies currently are ongoing to establish optimum dosages in these conditions.41, 80, 87
While the maximum safe dosage of fludarabine phosphate for the treatment of chronic lymphocytic leukemia or other neoplasms in adults has not been elucidated fully, severe and potentially irreversible or fatal toxicity (e.g., neurotoxicity) has been observed at dosages of 96 mg/m2 or more daily for 5-7 days; such relatively high dosages currently are not recommended.1, 9, 29, 30, 31, 41, 45, 95 Limited data suggest that maximum dosages of up to 40 mg/m2 daily for 5 days may be well tolerated in adults,29 but the relative risk to benefit of dosages exceeding those currently recommended remains to be established, and such dosages currently are not recommended except under controlled clinical conditions (e.g., in investigational protocols).80, 87
Because fludarabine (2-fluoro-ara-A), the principal systemically circulating form of fludarabine phosphate, appears to be eliminated mainly unchanged in urine, with total body clearance of this metabolite being directly correlated with creatinine clearance, the drug should be administered cautiously in patients with impaired renal function, including geriatric patients.1, 41 Close monitoring for potential excessive toxicity is necessary; dosage should be adjusted accordingly.1, 41, 80, 87 The manufacturer recommends a 20% reduction in fludarabine dosage and close monitoring in adults with moderate renal impairment (creatinine clearance 30-70 mL/minute per 1.73 m2).1 Use of fludarabine is not recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m2).1
Fludarabine is a highly toxic drug.1, 3, 4, 5, 6, 29, 30, 31, 45 (See Cautions: Precautions and Contraindications.) Many toxic effects of the drug are dose dependent,1, 2, 3, 4, 5, 6, 29, 30, 31, 45 and the risk of severe and potentially irreversible or fatal toxicity (e.g., neurotoxicity) is increased substantially at relatively high dosages.1, 2, 3, 4, 5, 6, 29, 30, 31, 45 (See Chronic Toxicity.)
The most common adverse effects of fludarabine include dose-related2, 4 myelosuppression (e.g., neutropenia, thrombocytopenia, and anemia), fever and chills, infection, and nausea/vomiting.1, 2, 4, 5, 6 In clinical trials, myelosuppression was the most frequently reported dose-limiting toxicity.2, 4, 6, 9, 15, 20, 23, 34, 39, 41, 43 Other common adverse effects of the drug include malaise, fatigue, anorexia, and weakness.1, 9, 15, 20, 23 Serious opportunistic infections also have occurred in patients receiving the drug for chronic lymphocytic leukemia,1, 51 but infections are common complications of the disease itself.9, 24, 54, 55, 56, 57, 58 (See Cautions: Infectious Complications.)
Much of the information reported by the manufacturer regarding the adverse effect profile of fludarabine was compiled from single-arm, open-label studies of the drug in several hundred patients with chronic lymphocytic leukemia;1 however, the manufacturer states that the spectrum of these effects is similar to that observed in other populations involving several thousand patients who were receiving the drug for other neoplastic diseases (e.g., other leukemias, lymphomas, solid tumors).1 Adverse effects other than myelosuppression and neurotoxicity also may be dose related.1
The major and dose-limiting toxicity of fludarabine is hematologic toxicity. 1, 2, 3, 4, 5, 6, 15, 20, 23, 34, 39, 41, 43 The drug can severely suppress bone marrow function and result in anemia, thrombocytopenia, and neutropenia, even at currently recommended, relatively low dosages (e.g., 25 mg/m2).1, 2, 3, 4, 5, 6, 22, 23, 39 The possibility that certain hematologic effects may partly represent manifestations of the underlying disease (e.g., immune-mediated cytopenias in patients with chronic lymphocytic leukemia) should be considered.58, 61
In clinical trials in patients with chronic lymphocytic leukemia, evidence of hematologic toxicity was present in up to 75% of patients receiving fludarabine, and peripheral blood cell counts eventually decreased in most patients with adequate baseline counts.2, 4, 6, 9, 15, 20, 23, 34, 39, 41, 43 Neutropenia and thrombocytopenia were the most frequent myelosuppressive effects,49, 80, 87 but thrombocytopenia was responsible for most cases of severe and life-threatening hematologic toxicity.9, 80
Approximately 60% of patients with chronic lymphocytic leukemia in one study experienced decreases in absolute neutrophil counts to less than 500/mm3 and/or decreases in hemoglobin concentration of at least 2 g/dL from baseline; platelet count in 55% of these patients decreased by at least 50% from baseline.1, 9 Absolute T-cell counts have been observed to decrease by 90% and B-cell counts by 50%, but, in part, such reductions in lymphocyte counts represent therapeutic responses to the drug in this leukemia.2, 4, 6 In a study in patients with solid tumors, the median time to nadir granulocyte or platelet count was 13 (range: 3-25) or 16 (range: 2-32) days, respectively.1 Many of these patients had baseline abnormalities in hematologic indices either as a result of the disease process or from prior myelosuppressive therapy.1
Several cases of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes fatal, have been reported in patients receiving fludarabine.1 Cases have occurred in both previously treated and untreated patients.1 The duration of clinically significant cytopenia ranged from about 2 months to 1 year.1
Life-threatening and sometimes fatal autoimmune hemolytic anemia has been reported after one or more courses of fludarabine therapy in patients with or without a history of autoimmune hemolytic anemia or a positive Coombs' test and whose disease may or may not be in remission.1 It is not known if administration of corticosteroids is beneficial for management of these hemolytic episodes.1 Hemolytic anemia recurred following rechallenge with the drug.1 The mechanisms that predispose patients to the development of hemolytic anemia are not known, and patients receiving fludarabine should be evaluated and monitored closely for hemolysis.1 Severe anemia requiring hospitalization and transfusion, including fatality, reportedly has occurred.1
Fludarabine-induced myelosuppression can be severe, cumulative, and may affect multiple cell lines.1, 2, 87 While myelosuppression usually is reversible, careful hematologic monitoring is necessary during fludarabine therapy.1, 9 Depending on the severity of hematologic toxicity, dosage adjustment, interruption of therapy, and/or transfusions may be necessary.9 Recovery of neutrophil and platelet count usually is complete within 5-7 weeks after discontinuance of fludarabine therapy, but occasionally may require longer periods.87 Bone marrow fibrosis has occurred rarely.1
In early, dose-ranging studies in patients with acute leukemias, relatively high dosages of fludarabine (e.g., 96-150 mg/m2 daily for 5-7 days, which are approximately 4-6 times the currently recommended dosage for chronic lymphocytic leukemia) were associated with severe, potentially irreversible or fatal neurologic effects (e.g., delayed, progressive encephalopathy and blindness, coma) in approximately 36% of such treated patients.1, 2, 3, 5, 6, 9, 29, 30, 31, 45 (See Chronic Toxicity.)Fludarabine-induced neurotoxicity is a delayed effect, with manifestations usually appearing 21-60 days after completion of the course.1, 2, 29, 30, 31
While the risk of such toxicity clearly appears to be dose related,1, 2, 3, 6, 9, 29, 30, 31, 45 similar neurotoxic effects have been reported rarely in patients receiving relatively low dosages (e.g., equivalent to those currently recommended for chronic lymphocytic leukemia) of the drug.1, 3, 5, 6, 9, 30, 39, 45, 52 The relationship, if any, of neurotoxicity to peak plasma concentrations of the drug or cumulative dose remains unclear; such toxicity has been associated with rapid IV administration as well as with slow IV infusion, and the risk of its development appears to be substantially lower with equal cumulative doses that are administered as repeated low doses rather than as high-dose schedules.30 Rarely, neurotoxicity has been reversible.31
While it has been suggested that the presence of underlying meningeal mycosis fungoides and/or vitamin B12 deficiency may have predisposed to neurotoxicity in at least one patient receiving relatively low dosages of fludarabine,9, 45, 42 factors other than dosage that may predispose to the development of fludarabine-induced neurotoxicity remain to be established.30, 45, 52 The neurotoxicity appears to be leukoencephalopathic and/or myelinoclastic, and may have a predilection for optic fibers.29, 45 Autopsy findings have revealed diffuse, necrotizing leukoencephalopathy characterized by demyelination, vacuolization, and axonal swelling with spheroid formation.29, 30, 31, 45 Demyelination of the optic nerves also has been observed.29, 45 Progressive demyelination in the CNS appears to be principally responsible for, or at least principally contributory to, fatal outcome.29, 30, 31
Adverse nervous system effects reportedly occur in 21-69% of patients receiving fludarabine at currently recommended dosages.1, 9 Objective weakness1, 3, 9 has been reported in up to 65%, pain1, 9 in up to 44%, malaise1, 9, 22 in up to 22%, fatigue1, 9, 22 in up to 38%, paresthesia1, 3, 9 in up to 12%, visual disturbances19, 23, 39 in up to 15%, hearing disturbances (e.g., hearing loss, auditory hallucinations)1, 9, 23, 39 in up to 6%, and sleep disorder1, 9 or headache1, 9 in up to 3% of patients receiving the drug at such dosages.1, 9 Agitation,1 confusion,1, 23 coma,1 peripheral neuropathy,1, 2, 3, 4, 9, 22 depression,1 cerebellar syndrome,1, 9 ambulatory equilibrium disturbance,53 fatigue,4, 5 somnolence,2, 4, 6 and impaired mentation1, 9 also have been reported in patients receiving fludarabine at dosages recommended for chronic lymphocytic leukemia.1 Wrist drop1 has been reported rarely.
The effect of chronic administration of fludarabine on the risk of adverse nervous system effects currently is not known; however, some patients have received the currently recommended dosage for chronic lymphocytic leukemia for up to at least 15 courses of therapy.1, 3, 5 Further study and experience are necessary to elucidate further the risks and mechanisms of fludarabine-induced neurotoxicity and possibly better predict and avoid its development.29, 30, 45 While some clinicians recommended during early studies with the drug that even patients receiving relatively low dosages (e.g., those currently recommended for chronic lymphocytic leukemia) be monitored closely with frequent neurologic evaluation and tests for possible neurotoxic effects,30 most clinicians currently suggest that such evaluation would not be cost-effective and that visual changes generally can be monitored as evidence of neurotoxicity.80, 87
Infection1, 3, 4, 22, 38 has been reported in up to 44% of patients receiving fludarabine for CLL. Infection is a common complication of CLL, in part secondary to associated hypogammaglobulinemia,9, 24, 54, 55, 56, 57, 58 and the frequency of infection in several clinical trials with fludarabine reportedly was comparable to that associated with the disease.9 However, in addition to the underlying immunodysfunction associated with this leukemia, it has been suggested that fludarabine may contribute to this dysfunction by depleting helper/inducer (CD4+, T4+) T cells.51 Prophylactic immune globulin or anti-infective therapy has been suggested for selected patients with CLL considered at risk for infectious complications of the disease (e.g., patients with documented recurrent bacterial infections or low titers of IgG or of antibodies to encapsulated organisms);24, 55, 56, 57, 58, 87 however, the costs and potential benefits of such therapy must be weighed carefully.24, 54, 55, 57, 58, 80, 87
Whereas bacterial infections frequently occur in patients receiving treatment with conventional alkylating agents for CLL, bacterial infections and infections with opportunistic pathogens are common in patients receiving fludarabine.48 Concomitant therapy with corticosteroids increases the risk of infections with opportunistic pathogens, such as Pneumocystis carinii and Listeria , in patients receiving purine analogs such as fludarabine and should be avoided. 44, 48 Herpesvirus infections, particularly with varicella zoster virus, frequently occur in patients receiving fludarabine.48
In a large randomized trial, patients with CLL receiving fludarabine had a greater frequency of infections (77 versus 61%) and major infections (29 versus 17%) than those receiving chlorambucil. 48 Infection with varicella zoster virus, which usually is not fatal but may cause substantial morbidity, occurred more frequently in patients receiving fludarabine rather than chlorambucil.48
Severe pulmonary toxicity, including ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure, has been reported in patients receiving fludarabine.1 Following exclusion of an infectious etiology, administration of corticosteroids has resulted in symptomatic improvement in some patients.1
Adverse respiratory effects have been observed in 14-69% of patients receiving fludarabine therapy for chronic lymphocytic leukemia.1, 2, 5, 6, 9 Pneumonia, which is a frequent manifestation of infection in patients with this leukemia (see Cautions: Infectious Complications), 9, 24, 54, 55, 56, 57 has been observed in 9-22% of patients receiving the drug.1, 4, 20, 51 In some cases, infection with an opportunistic pathogen (e.g., Pneumocystis carinii , cytomegalovirus) may be responsible for the pneumonia.1, 51
Cough1, 4 has been reported in up to 44%, dyspnea1, 4 in up to 22%, upper respiratory infection1, 9 in up to 16%, pharyngitis1, 9 in up to 9%, allergic pneumonitis1, 9 or hemoptysis1, 9 in up to 6%, and sinusitis1, 9 bronchitis,1, 9 epistaxis,1, 9 hypoxia,1, 9 and pulmonary hypersensitivity (e.g., diffuse interstitial pneumonitis characterized by dyspnea, hypoxia, cough, and pulmonary infiltrates)1, 3, 5, 6, 9, 35, 60, 51 in 5% or less of patients receiving fludarabine. This drug-induced interstitial pneumonitis appears to be a delayed effect, usually manifesting 3-28 days after administration of the third or later course of therapy.2, 5, 6, 35, 50 Subsequent lung biopsy in one patient showed an interstitial mononuclear cell infiltrate consistent with this diagnosis.2 Administration of corticosteroid therapy has resulted in prompt resolution of symptoms in several patients;2, 5, 9, 35, 50 however, the symptoms may recur following discontinuance of the steroid.2, 5, 50 In some cases, respiratory dysfunction may resolve spontaneously.9 The precise contribution of fludarabine to the development of this pneumonitis remains to be elucidated further since this effect is a well-documented complication of chemotherapy for chronic lymphocytic leukemia, particularly with alkylating agents, and most such patients receiving fludarabine were exposed previously to such agents.6, 9, 35 In addition, in some cases, an underlying disease-related process, infection, or exposure to some other pulmonotoxic agent may have contributed to the observed effect.9
Adverse GI effects reportedly occur in 46-63% of patients receiving fludarabine for chronic lymphocytic leukemia.1, 9 Nausea and/or vomiting, which generally are mild but occasionally may be severe,1, 2, 3, 4, 6, 9, 22, 23 are reported in up to 36%, anorexia1, 9 in up to 34%, diarrhea1, 3, 4, 6, 22 in up to 15%, GI bleeding1, 9 in up to 13%, stomatitis1, 2, 4 in up to 9%, and esophagitis,1, 9 constipation,1, 9 mucositis,1, 9 and dysphagia1, 9 in less than 5% of treated patients. Altered taste sensation2 also has been reported.
Adverse cardiovascular effects have been reported in 12-38% of patients receiving fludarabine for chronic lymphocytic leukemia.1, 9 Edema1, 3, 9 has been reported in up to 19%, angina1, 9 in up to 6%, and congestive heart failure,1, 9 arrhythmia,1, 9 supraventricular tachycardia,1, 9 myocardial infarction,1, 9 deep vein thrombosis,1, 9 phlebitis,1, 9 transient ischemic attack,1 and aneurysm1 in less than 5% of treated patients, but these effects have not been attributed directly to the drug.1 At least one patient developed a pericardial effusion, which possibly was related to fludarabine therapy.1 Chest pain6 also has been reported rarely.
Adverse genitourinary effects reportedly occur in 12-22% of patients receiving fludarabine for chronic lymphocytic leukemia.1, 9 Urinary tract infection1, 9 has been reported in up to 15%, and dysuria1, 9 , urinary hesitancy,1, 9 hematuria,1, 9 renal failure,1, 9 abnormal renal function tests,1, 9 and proteinuria1, 9 in less than 5% of treated patients. In some cases, tumor lysis syndrome may have been responsible for the observed genitourinary effect (e.g., renal dysfunction, hematuria).1, 3, 6, 9, 53 (See Cautions: Metabolic Effects.) Increased serum creatinine concentration also has been reported in patients receiving the drug at doses higher than those recommended for chronic lymphocytic leukemia.2 Hemorrhagic cystitis has been reported rarely in patients receiving fludarabine.1
Although rapid tumor lysis occurs rarely in patients with chronic lymphocytic leukemia receiving conventional chemotherapy, presumably because of the slow proliferative rate that usually characterizes this neoplasm and the corresponding slow cytolysis induced by such agents,9, 53, 65 the syndrome may be more likely in patients receiving fludarabine for the treatment of this leukemia, especially in those with large initial tumor burdens.1, 3, 6, 9, 53, 87 Patients with advanced lymphoproliferative disease, including those with chronic lymphocytic leukemia accompanied by generalized lymphadenopathy and substantial splenomegaly and lymphocytosis, may be at particular risk of developing this syndrome following initiation of fludarabine therapy secondary to the rapid cytolysis induced by the drug.9, 53, 65 Such patients should be observed closely during initiation of fludarabine therapy, and the potential benefit of prophylactic allopurinol, adequate hydration, and/or urinary alkalinization should be considered.53, 65, 80, 87
Manifestations of fludarabine-induced tumor lysis syndrome may include hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, metabolic acidosis, hematuria, urate crystalluria, and upper-quadrant and/or flank pain; renal dysfunction and/or failure may occur secondarily.1, 6, 9, 53 Flank pain and/or hematuria often are the initial manifestations of the syndrome.1, 53 If the syndrome develops, treatment with allopurinol, analgesics, IV fluids, and urinary alkalinization and correction of acid-base imbalances should be instituted as necessary.53, 65 Metabolic (lactic)6 acidosis also has been reported in patients receiving the drug at dosages higher than those recommended for chronic lymphocytic leukemia.2, 6
Hyperglycemia1 has been reported in 6% or less of patients receiving fludarabine for chronic lymphocytic leukemia.
Adverse dermatologic effects have been reported in up to 18% of patients receiving fludarabine for chronic lymphocytic leukemia.1, 9 Rash1, 2, 3, 4, 6, 9, 22 (e.g., maculopapular)2, 6 has been reported in up to 15% and pruritus1, 6, 9 and seborrhea1, 9 in less than 5% of treated patients. Dermatomal herpes zoster or oral herpes simplex infection also has been reported;4 however, viral and bacterial infections are common complications of chronic lymphocytic leukemia.9, 24, 54, 55, 56, 57, 58, 61 (See Cautions: Infectious Complications.)
Fever1, 3, 4, 22 has been reported in up to 69%, diaphoresis1, 9 in up to 13%, and myalgia1, 9 in up to 16% of patients receiving fludarabine.
Rarely, transfusion-associated graft-versus-host disease has occurred following transfusion of nonirradiated blood products in patients requiring blood transfusions during fludarabine therapy.1
Abnormal liver function test results,1, 9, 41 cholelithiasis,1, 9 liver failure,1, 9 anaphylaxis,1, 9 osteoporosis,1, 9 arthralgia,1, 9 dehydration,1, 9 and/or hemorrhage1, 9 have been reported in 6% or less of treated patients. Reversible hepatotoxicity2 and pancreatitis6 also have been reported in patients receiving the drug.
Precautions and Contraindications
Fludarabine is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity.1, 3, 4, 5, 6, 9, 29, 30, 31, 41, 45 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.1, 9 Most, but not all, adverse effects of fludarabine are reversible if detected promptly.1, 9, 29, 30, 31, 41, 45, 65 If severe adverse effects occur during fludarabine therapy, the drug should be discontinued or dosage reduced and appropriate measures instituted as necessary.1, 9, 65, 87 Fludarabine therapy should be reinstituted with caution if at all (depending on the effect), with adequate consideration of further need for the drug, and with awareness of possible recurrence of toxicity.80, 87
Hematologic function must be monitored frequently and carefully during and after fludarabine therapy.1, 9, 65 Periodic (e.g., prior to each course or more often if clinically indicated) assessment of peripheral blood cell counts is recommended to detect the possible development of anemia, thrombocytopenia, and/or neutropenia.1, 87 Because these complications are potentially fatal, patients receiving fludarabine should be instructed to notify their clinician if fever, sore throat, or unusual bleeding or bruising occurs.80, 87 Since life-threatening and sometimes fatal autoimmune hemolytic anemia that recurred upon rechallenge has been reported after one or more courses of fludarabine therapy, patients receiving fludarabine should be evaluated and monitored closely for hemolysis.1 (See Cautions: Hematologic Effects.)
The use of irradiated blood products should be considered in patients requiring blood transfusions during fludarabine therapy.1 Transfusion-associated graft-versus-host disease has occurred rarely following transfusion of nonirradiated blood products in patients receiving fludarabine.1
Patients also should be observed closely for signs of nonhematologic toxicity during fludarabine therapy.1, 30, 65 While severe and potentially irreversible or fatal neurotoxic effects have been associated principally with dosages higher than those currently recommended for the treatment of chronic lymphocytic leukemia,1, 2, 3, 5, 6, 9, 29, 30, 31, 41, 45 such effects also have occurred rarely at relatively low dosages,1, 3, 5, 9, 30, 45, 52 and even patients receiving dosages currently recommended for this leukemia should be monitored for the possible development of these effects.1, 30, 41, 80, 87 (See Cautions: Nervous System Effects.)
Patients with a large initial tumor burden may be at particular risk of developing tumor lysis syndrome following initiation of fludarabine therapy.1, 3, 6, 9, 53, 65 Since the drug can induce a rapid cytolytic response as early as the first week of therapy, precautions should be taken in patients considered at risk of developing this complication.1, 9, 53, 65 (See Cautions: Metabolic Effects.)
Dosage of fludarabine should be adjusted carefully in patients with impaired renal function since the clearance of fludarabine (2-fluoro-ara-A) has been shown to correlate directly with creatinine clearance, suggesting renal excretion as an important means of elimination of the compound.1, 41, 80, 87 In addition, patients with impaired renal function may be at increased risk of developing fludarabine-induced toxicity.1, 2, 3 Reduction of fludarabine dosage is necessary in patients with moderate renal impairment, and use of the drug is not recommended in patients with severe renal impairment (see Dosage and Administration: Dosage in Renal Impairment).1 The manufacturer states that the possibility that certain other patient populations (e.g., those with preexisting bone marrow impairment, geriatric patients) may be at increased risk for developing fludarabine-induced toxicity should be considered.1 Any such patient should be monitored closely for excessive toxicity and dosage modified or the drug discontinued accordingly.1
Because of an increased incidence of infections with opportunistic agents in patients receiving purine analogs in combination with corticosteroids, prednisone should be omitted from regimens containing fludarabine or other purine analogs.44
Fludarabine is contraindicated in patients with known hypersensitivity to the drug and/or any ingredient in the formulation.1
Current evidence from clinical studies has not demonstrated efficacy of fludarabine for any cancer in pediatric patients.1 Fludarabine was evaluated in 62 pediatric patients (median age: 10 years; range: 1-21 years) with refractory acute leukemia (45 patients) or solid tumors (17 patients).1 Pediatric patients with acute lymphocytic leukemia received an IV loading dose of fludarabine 10.5 mg/m2 daily followed by a continuous IV infusion of 30.5 mg/m2 daily for 5 days.1 Dose-limiting myelosuppression was observed in 12 pediatric patients with solid tumors receiving a loading dose of fludarabine 8 mg/m2 daily followed by a continuous infusion of 23.5 mg/m2 daily for 5 days.1 The maximum tolerated dose of fludarabine was a loading dose of 7 mg/m2 daily followed by a continuous infusion of 20 mg/m2 daily for 5 days.1
Fludarabine-induced toxicity in children included bone marrow suppression, particularly thrombocytopenia.1 Other adverse effects reported in pediatric patients receiving fludarabine included fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection.1 Peripheral neuropathy or pulmonary hypersensitivity reaction was not reported in this age group.1
Safety and efficacy of fludarabine in geriatric patients have not been studied specifically to date; however, chronic lymphocytic leukemia, for which safety and efficacy have been established,1, 2, 3, 4, 6, 9, 14, 15, 20, 21, 58 occurs principally in patients older than 50 years of age.24, 58, 61 Because geriatric patients may have decreased renal function26 and because patients with renal impairment may be at increased risk of fludarabine-induced toxicity,1, 2 the manufacturer states that patients in this age group should be monitored closely and dosage adjusted accordingly.1 In addition, experience from at least one clinical study suggested that geriatric patients with advanced Rai stage chronic lymphocytic leukemia should be monitored particularly closely, and the possible need for substantial dosage reduction should be considered.4
Mutagenicity and Carcinogenicity
There was no evidence of mutagenicity when fludarabine was tested in bacteria (Ames test) or in a mammalian cell system (HGRPT assay in Chinese hamster ovary cells) with or without metabolic activation.1 However, fludarabine has been shown to be clastogenic; chromosomal aberrations were observed in vitro in Chinese hamster ovary cells exposed to the drug with metabolic activation.1 Fludarabine with or without metabolic activation also increased the rate of sister chromatid exchanges in this cell system.1 In addition, fludarabine was clastogenic in vivo (micronucleus test in mice), but was not mutagenic to germ cells (dominant lethal test in male mice).1
Studies in animals to evaluate the carcinogenicity of fludarabine have not been performed.1
Pregnancy, Fertility, and Lactation
Fludarabine can cause fetal harm when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.1 Teratogenicity studies in animals have demonstrated that the drug induces skeletal malformations and external deformities at dosages similar to or less than the usual human dosage (on a mg/kg basis).1 There are no adequate and controlled studies in pregnant women.1 Women of childbearing potential should be advised to avoid becoming pregnant while receiving fludarabine,1 and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.80, 87 If fludarabine is administered during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus.1
Preclinical toxicology studies in animals have demonstrated dose-related effects on the male reproductive system, such as a decrease in mean testicular weight and degeneration and necrosis of spermatogenic epithelium.1 The possible effects of fludarabine on fertility in humans have not been evaluated adequately to date.1
It is not known whether fludarabine is distributed into milk.1 Because of the potential for serious adverse reactions to fludarabine in nursing infants if the drug were distributed into milk, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Concomitant therapy with fludarabine (principally 10 mg/m2 daily for 4 days at 28-day intervals) and pentostatin (4 mg/m2every 2 weeks) may be associated with severe and/or fatal pulmonary toxicity (e.g., pneumonitis).1, 8, 87 In one study, 4 of 6 patients receiving the drugs concomitantly for the treatment of refractory chronic lymphocytic leukemia reportedly developed such toxicity.8, 87 While the mechanism of this possible increased toxicity currently is not known, concomitant therapy with these drugs is not recommended.1, 8, 87
Cytarabine has been shown to decrease substantially the metabolism of subsequently administered fludarabine (2-fluoro-ara-A) to its pharmacologically active triphosphate (fludarabine triphosphate, 2-fluoro-ara-ATP) in vitro7, 74 and in vivo.67 In addition, administration of cytarabine prior to a dose of fludarabine phosphate appeared to inhibit the antineoplastic effect of fludarabine in several patients with leukemia.67 It appears that cytarabine competes for deoxycytidine kinase, the rate-limiting enzyme required for intracellular conversion of both drugs to their active triphosphate.7, 67, 74 In contrast, pretreatment with fludarabine does not appear to inhibit the metabolic activation of cytarabine, but actually may stimulate such activation.43, 74 The clinical importance of these findings requires further elucidation.43, 80, 87
During early studies of fludarabine using relatively high dosages (e.g., up to 96-150 mg/m2 daily for 5-7 days or approximately 4-6 times the currently recommended dosage for chronic lymphocytic leukemia), severe, delayed, potentially irreversible or fatal nervous system toxicity was observed in up to 36% of patients receiving such dosages.1, 2, 3, 5, 6, 9, 29, 30, 31, 41, 45 Manifestations of this toxicity generally appeared 21-60 days1, 2, 29, 30, 31 following initial administration of the drug and included altered mental status (e.g., confusion, dementia),2, 30, 31, 41 incontinence,2, 30 generalized seizure,2, 30, 31, 45 flaccid or spastic paralysis and/or quadriparesis,2, 30, 45 blurred vision,2, 30 blindness (amaurosis),1, 2, 3, 29, 30, 31 and/or coma.1, 2, 41, 29, 30
Some patients with this fludarabine-induced neurotoxicity evidenced little to no abnormality in spinal fluid, EEG, or computed tomographic brain scans;2, 5, 30, 45 however, autopsy findings have revealed focal or diffuse progressive CNS demyelination, particularly in the occipital lobe and spinal cord.2, 5, 6, 29, 30, 31, 45 (See Cautions: Nervous System Effects.) Leukoencephalopathy involving the subcortical white matter, optic nerves, and optical tract has been observed.2, 29, 30, 31, 45 The mechanism by which fludarabine produces this neurologic toxicity remains to be elucidated,2, 29 and no predisposing factors other than dosage have been clearly identified.5, 30, 45, 52 Manifestations of severe neurologic toxicity have been reported rarely in patients receiving the drug at relatively low dosages (e.g., equivalent to those currently recommended for chronic lymphocytic leukemia).1, 3, 5, 6, 30, 45, 52
Other manifestations that are extensions of common adverse effects of fludarabine, such as myelosuppression, also may occur with overdosage.1, 9, 29, 41
The potential for developing long-term cumulative toxicity, particularly neurotoxic effects, with chronic fludarabine therapy at the currently recommended relatively low dosages is unknown.1 (See Cautions: Nervous System Effects.)
The contribution, if any, of 2-fluoroadenine to the toxic effects of fludarabine in humans remains to be established.7 While fludarabine is not metabolized to 2-fluoroadenine by mammalian purine nucleoside phosphorylase,7, 81 the drug can be metabolized to this toxic metabolite by bacterial purine nucleoside phosphorylase.7, 82, 83 Despite the inability of the mammalian enzyme to catalyze the production of 2-fluoroadenine, this metabolite has been identified in plasma, urine, and CSF of animals receiving fludarabine.7, 70, 78, 81, 84, 86 It has been suggested that systemic appearance of 2-fluoroadenine in mammals may result from biliary excretion of fludarabine and subsequent bacterial (e.g., by Escherichia coli ) metabolism in the GI tract to, and enterohepatic circulation of, this toxic metabolite.7, 83
There is no known specific antidote for fludarabine overdosage.1 Management consists of discontinuance of the drug and initiation of supportive and symptomatic treatment.1, 9 Transfusion with blood or blood components may be necessary for the management of substantial myelosuppression.9
Fludarabine phosphate is dephosphorylated in serum to fludarabine (2-fluoro-ara-adenine, 2-fluoro-ara-A),1, 2, 3, 4, 5, 6, 7, 62, 66, 67, 68, 69, 70 which is transported intracellularly via a carrier-mediated process4, 5, 6, 7, 75, 76, 77, 78 and then is converted by deoxycytidine kinase to the nucleotide, fludarabine triphosphate (FATP, 2-fluoroarabinofuranosyladenine triphosphate, 2-fluoro-ara-ATP).1, 2, 3, 4, 5, 6, 7, 62, 66, 67, 68, 69, 70, 71, 75, 76, 78, 79 2-Fluoro-ara-ATP is thought to be the form required for the drug's cytotoxic effect.4, 6, 66, 67, 68, 69, 70, 71, 75, 79 In sensitive malignant cells, the rate-limiting step in this process is the conversion of 2-fluoro-ara-A to 2-fluoro-ara-ATP by deoxycytidine kinase;2, 4, 62 in healthy cells, the importance of the intracellular transport mechanism as potentially rate limiting is increased relative to that in malignant cells.76 However, some evidence from patients with indolent but advanced lymphoproliferative malignancy indicates that response may not depend on intrinsic deoxycytidine kinase activity in tumor cells.41, 62 Intracellular transport of fludarabine occurs preferentially into sensitive malignant cells compared with healthy cells.7, 75, 76, 78
While the exact mechanism(s) of action of fludarabine has not been elucidated fully and may be multifaceted, fludarabine triphosphate appears to inhibit α-DNA polymerase, ribonucleotide reductase, and DNA primase by competing with the physiologic substrate, deoxyadenosine triphosphate, resulting in inhibition of DNA synthesis.1, 2, 3, 4, 5, 6, 7 There also is evidence that the active phosphorylated form of the drug can be incorporated into growing DNA chains as a false nucleotide, thus interfering with chain elongation (prematurely terminating DNA synthesis),4, 7 and/or may interfere with RNA and protein synthesis2, 5, 6, 7 by decreasing the incorporation of uridine and leucine into RNA and protein, respectively.2, 7 However, inhibition of RNA and protein synthesis appears to require drug concentrations higher than those required for inhibition of DNA synthesis.7
Although both in vitro and in vivo studies have shown that T cells are more sensitive than B cells to the cytotoxic effects of fludarabine,2, 4 the drug is highly active against B-cell lymphoproliferative disorders, including chronic lymphocytic leukemia.1, 2, 3, 4, 6, 9, 14, 15, 20, 21, 58, 64 In addition, the cytolytic effect of the drug appears to be relatively rapid even in neoplasms such as chronic lymphocytic leukemia that are characterized by a slow proliferative rate.9, 53
A correlation appears to exist between intracellular accumulation of 2-fluoro-ara-ATP at 1 hour following infusion and the concentration of 2-fluoro-ara-A incorporated into nucleic acids.2 The ability of blast cells to synthesize DNA at 12-24 hours following administration of the drug was shown to be related inversely to the concentration of 2-fluoro-ara-ATP.2
Although fludarabine has exhibited antiviral activity in vitro (e.g., against herpes simplex virus [HSV]types 1 and 2),71 it is unlikely that any clinically important antiviral activity could be achieved at less than toxic dosages of the drug in humans.80, 87 In one study, the concentration of drug required for 99% inhibition of viral replication of HSV-1 and -2 was 100 times that required for 50% inhibition of growth of HeLa cells.71
Pharmacokinetic data for fludarabine phosphate (2-fluoro-ara-AMP) are limited since the drug is dephosphorylated rapidly to fludarabine (2-fluoro-ara-A) following IV administration.1, 2, 3, 7, 9, 66, 67, 68, 69, 70 Pharmacokinetic studies of the drug focus principally on fludarabine and fludarabine triphosphate (2-fluoro-ara-ATP), the active intracellular form.1, 2, 7, 9, 66, 67, 68, 69, 70 Therefore, while the drug is administered as, and dosages are expressed in terms of, the monophosphate salt, pharmacokinetic parameters generally are expressed in terms of fludarabine (2-fluoro-ara-A) and fludarabine triphosphate. A concentration of 1 µg of fludarabine or fludarabine phosphate per mL is approximately equivalent to 3.51 or 2.74 µmol/L, respectively.80, 81
Following IV administration, fludarabine phosphate is rapidly and apparently completely dephosphorylated to fludarabine (2-fluoro-ara-A).1, 2, 3, 4, 6, 7, 9, 66, 67, 68, 69, 70 In plasma, the monophosphate is undetectable or becomes undetectable within several minutes after completion of IV administration.1, 9, 69 Following rapid IV injection over 2-5 minutes of a 260-mg/m2 dose in one study, plasma concentrations of unchanged fludarabine phosphate were undetectable within 2-4 minutes after injection.9, 69 Similar, rapid dephosphorylation of the drug also has been observed following IV administration in animals.70
Following IV infusion over 30 minutes of daily 25-mg/m2 doses in several adult patients, moderate accumulation of the drug was observed, with trough plasma concentrations increasing about twofold over the 5-day treatment period.1 In a limited number of pediatric patients, administration of 5-10 mg/m2 of fludarabine phosphate as an IV loading dose followed by continuous IV infusion of 13-30 mg/m2 daily over 5 days resulted in steady-state plasma fludarabine concentrations of 0.17-2.85 µg/mL.2, 43 Peak concentrations of fludarabine triphosphate were achieved approximately 2 hours following completion of the infusion.2, 43
Areas under the concentration-time curve (AUCs) for fludarabine in plasma and fludarabine triphosphate in blast cells appear to be dose related,2, 6 and a direct correlation reportedly exists between the quantity of fludarabine incorporated into nucleic acids and intracellular accumulation of fludarabine triphosphate.2, 6 In nonleukemic patients, suppression of leukocyte counts appears to correlate with plasma fludarabine concentration and dose.69
Fludarabine phosphate has been administered intraperitoneally in a few patients with solid peritoneal tumors.2, 5, 60, 69 Following intraperitoneal infusion of 4, 8, or 12 mg/m2 of fludarabine phosphate daily for 5 consecutive days, accumulation of fludarabine in peritoneal fluid exceeded that in plasma by a factor of approximately 8-13 based on mean peritoneal and plasma AUCs.2, 5, 60, 69 Peak peritoneal fluid fludarabine concentrations averaged 4.1 or 3 µg/mL following a 4- or 8-mg/m2 dose, respectively.60, 69
An oral preparation of fludarabine phosphate currently is not commercially available in the US, but the drug has been shown to be well absorbed from the GI tract following oral administration in animals.2, 6 Following oral fludarabine phosphate doses of 86.7 or 260 mg/m2 in dogs, peak fludarabine concentrations were achieved within 19-107.7 or 49.1-91.7 minutes, respectively; mean bioavailability was approximately 100 or 80%, respectively.2, 6, 80 Oral pharmacokinetic studies of the drug currently are under way in humans.2, 6
Limited data in animals and humans suggest that fludarabine (2-fluoro-ara-A) is widely distributed.2, 9, 69, 80 In a few patients receiving the currently recommended dosage of 25 mg/m2 of fludarabine phosphate IV daily for 5 days, the volume of distribution at steady state (Vss) reportedly averaged 96-98 L/m2.2, 66 Following IV injection of fludarabine phosphate over 2-5 minutes in high doses (80-260 mg/m2), Vss in a limited number of patients with advanced cancer averaged approximately 44 L/m2.9, 69 Tissue distribution studies in animals indicate that the highest concentrations of the drug are in liver, kidney, and spleen.2, 9, 70, 85
Although the extent to which fludarabine and/or metabolites of the drug distribute into the CNS in humans has not been determined to date, severe neurologic toxicity (e.g., blindness, coma) has been reported in patients receiving the drug, particularly in high dosages.1, 2, 3, 5, 6, 9, 29, 30, 31, 45 (See Cautions: Nervous System Effects.) There is evidence from animal studies that fludarabine distributes into the CNS80 and that a toxic metabolite (2-fluoroadenine, possibly formed by bacteria in the GI tract), can be absorbed systematically via enterohepatic circulation and distributed into CSF.7 (See Chronic Toxicity: Manifestations.)
According to in vitro data, about 19-29% of fludarabine is bound to plasma proteins.1
Fludarabine phosphate is dephosphorylated rapidly to fludarabine (2-fluoro-ara-A) following IV administration.1, 2, 3, 6, 7, 9, 66, 67, 68, 69, 70 (See the introductory discussion in Pharmacokinetics.) Plasma concentrations of fludarabine reportedly decline in a linear, dose-independent manner following IV administration of the drug.68, 69, 80, 87 The elimination profile of fludarabine also has been reported to be either biphasic2, 4, 9, 66, 67, 68 or triphasic,2, 4, 9, 69, 87 possibly because of differences in initial sampling times after IV administration2, 6 and/or assay methods;87 however, reported terminal elimination half-lives have been similar.2, 9, 66, 69 In a few patients receiving 18 or 25 mg/m2 of fludarabine phosphate daily for 5 days, plasma fludarabine concentrations declined in a biphasic manner, with t½α and t½β averaging approximately 36 minutes and 9.3 hours, respectively.66 In patients receiving high doses (80-260 mg/m2) of fludarabine phosphate by rapid IV injection (over 2-5 minutes), elimination reportedly was triphasic, with the half-lives of the first, second, and third phases averaging approximately 5-7 minutes, 1.4-1.7 hours, and approximately 10 hours, respectively;69 however, using more sensitive sampling techniques, recent data describe a terminal elimination phase of 30 hours.87
Fludarabine monophosphate initially is dephosphorylated, with subsequent transport of fludarabine into cells and intracellular phosphorylation to the triphosphate.1, 2, 3, 4, 5, 6, 7, 62, 66, 67, 68, 69, 70, 75, 76, 77, 78, 79 (See Pharmacology.) Following administration of fludarabine phosphate 20-125 mg/m2 as a 30-minute IV infusion daily for 5 days, the terminal elimination half-lives of fludarabine and fludarabine triphosphate were approximately 8-10 and 15 hours, respectively.2, 3, 4, 6 An estimated terminal half-life of fludarabine (2-fluoro-ara-A) of about 20 hours was reported in cancer patients receiving fludarabine 25 mg/m2 as a 30-minute IV infusion daily for 5 days.1
In a limited number of pediatric patients, the plasma concentration profile of fludarabine exhibited both monoexponential and biexponential decay, with a mean t½α of 10.5 hours in patients with monoexponential elimination and a t½α and t½β of 1.2-1.4 and 12.4-19 hours, respectively, in patients with biexponential elimination.6, 43
Total body clearance of fludarabine appears to be directly correlated with creatinine clearance, suggesting renal excretion as an important means of elimination of the compound.1, 6 Renal clearance accounts for about 40% of the total body clearance.1 Renal elimination appears to become more important at high dosages of the drug.9 In patients receiving 18-25 mg/m2 of fludarabine phosphate IV daily for 5 days, approximately 24% of the dose was excreted in urine as fludarabine within 24 hours.2, 3, 66 In contrast, urinary excretion averaged 41-60% at IV doses of 80-260 mg/m2.2, 9
Patients with moderate renal impairment (creatinine clearance 17-41 mL/minute per 1.73 m2) receiving a reduced dose of fludarabine (20% less than the recommended dose) had a similar area under the plasma concentration-time curve (AUC) as patients with normal renal function receiving the usual recommended dose.1 Total body clearance averaged 172 mL/minute in patients with normal renal function and 124 mL/minute in patients with moderate renal impairment.1
Unlike vidarabine, fludarabine is resistant to deamination by adenosine deaminase.1, 2, 3, 4, 5, 6, 7, 9, 69, 72, 73 However, arabinosyl-2-fluorohypoxanthine has been identified in urine of animals receiving fludarabine phosphate.7, 70, 78, 85, 86 It has been suggested that other metabolic pathways (e.g., deamination via adenosine monophosphate deaminase) may be responsible, but additional study is needed.7
Fludarabine phosphate, a synthetic purine nucleoside, is an antineoplastic agent.1, 2, 3, 4, 5, 6, 7, 9 Fludarabine differs from the physiologic nucleosides, adenosine or deoxyadenosine, in that the sugar moiety is arabinose instead of ribose or deoxyribose, respectively, and by the addition of a fluorine atom to the purine base adenine.7, 9, 21 The drug is a purine antagonist antimetabolite.5, 7, 9, 21, 38, 39, 41, 65 Fludarabine also is structurally related to vidarabine (9-β-d-arabinofuranosyladenine, ara-A), differing only by the presence of a fluorine atom at position 2 of the purine moiety and a phosphate group at position 5 of the arabinose moiety.1, 2, 3, 4, 6, 7, 9, 73 Compared with vidarabine, these structural differences result in increased aqueous solubility and resistance to enzymatic degradation by adenosine deaminase.1, 2, 3, 4, 5, 6, 7, 9, 69, 72, 73
Fludarabine (2-fluoro-ara-A) is commercially available as the monophosphate salt (2-fluoro-ara-AMP).1, 9 Potency is expressed in terms of the salt.1, 9 Monophosphorylation of fludarabine increases the drug's aqueous solubility while maintaining pharmacologic activity;7, 69, 72 the monophosphate undergoes rapid dephosphorylation in vivo.1, 2, 3, 4, 6, 7, 66, 67, 68, 69, 70 (See Pharmacokinetics.) Commercially available fludarabine phosphate powder for injection occurs as a white, lyophilized solid cake.1, 9 During manufacture of the powder for injection, sodium hydroxide is added to adjust final pH.1, 9 Following reconstitution of the drug with sterile water for injection to a concentration of 25 mg/mL, the solution has a pH of approximately 7.7 (range: 7.2-8.2).1, 9 Fludarabine phosphate has solubilities of approximately 9 mg/mL in water6, 27, 80 and 28 or 57 mg/mL in aqueous buffers with a pH of 4 or 9, respectively.6
Fludarabine phosphate also is commercially available as an aqueous injection containing 25 mg of the drug per mL.95 The injection also contains mannitol 25 mg/mL and sodium hydroxide to adjust pH to 6.8 (range: 6-7.1).95
Commercially available fludarabine phosphate powder for injection should be stored at 2-8°C.1 When stored as directed, the powder for injection is stable for at least 18 months after the date of manufacture. While early stability studies reported that the powder for injection was stable for at least 36 months when stored at 22-25°C,11, 80 more recent studies employing assays with increased sensitivity have shown that the drug is less stable than this; therefore, the manufacturer currently recommends that fludarabine phosphate powder for injection not be stored at room temperature.80
Fludarabine phosphate is relatively stable in aqueous solutions,11, 65 with optimal stability occurring at an approximately neutral pH.1, 11 When reconstituted to a final concentration of 25 mg/mL, aqueous solutions of the drug are stable for at least 16 days at room temperature and normal light conditions.10, 11, 65 Fludarabine phosphate is compatible with 5% dextrose or 0.9% sodium chloride injection.1, 10, 11 When diluted to a final concentration of 1 mg/mL, the drug is compatible in these diluents for at least 16 days at room temperature and normal light conditions.10, 11 However, because such reconstituted and diluted fludarabine phosphate solutions contain no preservatives, the manufacturer recommends that they be used within 8 hours after preparation.1, 11, 80
Commercially available fludarabine phosphate injection containing 25 mg/mL should be refrigerated at 2-8°C.95 The injection does not contain a preservative;; unused portions should be discarded within 8 hours of initial vial entry.95 The injection is compatible with 5% dextrose or 0.9% sodium chloride injection.95
Fludarabine phosphate has been reported to be physically incompatible with some drugs, including acyclovir sodium, amphotericin B, chlorpromazine hydrochloride, daunorubicin hydrochloride, ganciclovir sodium, hydroxyzine hydrochloride, miconazole (systemic form no longer commercially available in the US), or prochlorperazine edisylate,10 but the compatibility may depend on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).10 Specialized references should be consulted for specific compatibility information.
Fludarabine phosphate is dephosphorylated in vitro by phosphatases present in heparinized whole blood samples.69 The addition of edetic acid (EDTA) to blood or plasma samples can inhibit this dephosphorylation.69 The monophosphate of fludarabine has been shown to be stable in blood containing 1 mg/mL of EDTA for at least 1 hour at 37°C and in plasma containing EDTA for at least 72 hours when refrigerated or for at least 2 weeks when frozen at -20°C.69 However, because the drug is rapidly dephosphorylated in vivo following IV administration, the addition of EDTA to blood specimens generally is not necessary unless pharmacokinetic characterization of the monophosphate during the first several minutes after injection is to be attempted.69
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV use only | 50 mg | Fludarabine Phosphate for Injection | |
Injection, for IV use only | 25 mg/mL* | Fludarabine Phosphate Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Berlex. Fludara® (fludarabine phosphate) for injection prescribing information. Montville, NJ; 2003 Oct.
2. Hood MA, Finley RS. Fludarabine: a review. DICP . 1991; 25:518-24. [PubMed 2068837]
3. Anon. Fludarabine. Med Lett Drugs Ther . 1991; 33:89-90. [PubMed 1886506]
4. Keating MJ. Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol . 1990; 17(Suppl 8):49-62. [PubMed 1699283]
5. Von Hoff DD. Phase I clinical trials with fludarabine phosphate. Semin Oncol . 1990; 17(Suppl 8):33-8. [PubMed 1699281]
6. Chun HG, Leyland-Jones B, Cheson BD. Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. J Clin Oncol . 1991; 9:175-88. [PubMed 1702143]
7. Plunkett W, Huang P, Gandhi V. Metabolism and action of fludarabine phosphate. Semin Oncol . 1990; 17(Suppl 8):3-17. [PubMed 1699280]
8. Parke-Davis. Nipent® (pentostatin) for injection prescribing information. Morris Plains, NJ: 1991 Oct.
9. Berlex Laboratories. Fludara® (fludarabine phosphate) for injection product monograph. Alameda, CA: 1991 Nov.
10. Trissel LA, Parks PT, Santiago NM. Visual compatibility of fludarabine phosphate with antineoplastic drugs, anti-infectives, and other selected drugs during simulated Y-site injection. Am J Hosp Pharm . 1991; 48:2186-9. [PubMed 1781478]
11. National Cancer Institute. Fludarabine. In: NCI investigational drugs pharmaceutical data 1990. 1990:72-4.
12. Cheson BD, Bennett JM, Grever M et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood . 1996; 87:4990-7. [PubMed 8652811]
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