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Black Box Warning
WARNING
See full prescribing information for complete Boxed Warning.
CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY
Fludarabine Phosphate Injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Fludarabine phosphate can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, fludarabine phosphate was associated with severe neurologic effects, including blindness, coma, and death. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m2/day for 5 to 7 days) than the recommended dose. Similar severe central nervous system toxicity has been rarely (≤0.2%) reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.
Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine phosphate. Patients undergoing treatment with Fludarabine Phosphate Injection should be evaluated and closely monitored for hemolysis. [See WARNINGS AND PRECAUTIONS (5.2)]
In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended
Overview
Fludarabine (injection) is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Condition1
Fludarabine Phosphate Injection is indicated for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. The safety and effectiveness of Fludarabine Phosphate Injection in previously untreated or non-refractory patients with CLL have not been established.
Important Limitations
Fludarabine Phosphate Injection should not be used in patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2).
Dosing Information
Chronic Lymphocytic Leukemia (CLL)
The recommended adult dose of Fludarabine Phosphate Injection is 25 mg/m2 diluted in 100 to 125 cc of 5% dextrose injection USP or 0.9% sodium chloride USP administered intravenously over a period of approximately 30 minutes daily for five consecutive days. Each 5-day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.
A number of clinical settings may predispose to increased toxicity from Fludarabine Phosphate Injection. These include advanced age, renal insufficiency, and bone marrow impairment. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.
The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of Fludarabine Phosphate Injection be administered following the achievement of a maximal response and then the drug should be discontinued.
Renal Impairment
Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have a 20% dose reduction of Fludarabine Phosphate Injection.
Use of Infusion Solutions
Fludarabine Phosphate Injection contains no antimicrobial preservative and should be used within 8 hours of opening. Care must be taken to assure sterility of infusion solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fludarabine (injection) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fludarabine (injection) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Fludarabine (injection) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fludarabine (injection) in pediatric patients.
Contraindications
None
Warnings
WARNING
See full prescribing information for complete Boxed Warning.
CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY
Fludarabine Phosphate Injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Fludarabine phosphate can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, fludarabine phosphate was associated with severe neurologic effects, including blindness, coma, and death. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m2/day for 5 to 7 days) than the recommended dose. Similar severe central nervous system toxicity has been rarely (≤0.2%) reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.
Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine phosphate. Patients undergoing treatment with Fludarabine Phosphate Injection should be evaluated and closely monitored for hemolysis. [See WARNINGS AND PRECAUTIONS (5.2)]
In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended
Neurotoxicity
There are clear dose dependent toxic effects seen with fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m2/day for 5 to 7 days) than that recommended for CLL (25 mg/m2/day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients (36%) who received fludarabine phosphate at high doses (96 mg/m2/day for 5 to 7 days) developed this severe neurotoxicity. This syndrome has been reported rarely in patients treated with doses in the range of the recommended CLL dose of 25 mg/m2/day for 5 days every 28 days. The effect of chronic administration of fludarabine phosphate on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy.
Hematological Adverse Reactions
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a Phase I study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of Fludarabine Phosphate Injection requires careful hematologic monitoring.
Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients.
Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine phosphate in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs' test and who may or may not be in remission from their disease. Steroids may or may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with Fludarabine Phosphate Injection should be evaluated and closely monitored for hemolysis.
Infections
Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study. Approximately 50% of the fatalities were due to infection and 25% due to progressive disease.
Tumor Lysis Syndrome
Tumor lysis syndrome associated with fludarabine phosphate treatment has been reported in CLL patients with large tumor burdens. Since fludarabine phosphate can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.
Use of Transfusions
Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of non-irradiated blood in fludarabine phosphate treated patients. Consideration should, therefore, be given to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with Fludarabine Phosphate Injection.
Pulmonary Toxicity
In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended.
Precautions
Description
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common adverse reactions include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in CLL patients treated with fludarabine phosphate. The most frequently reported adverse reactions and those reactions which are more clearly related to the drug are arranged below according to body system.
Hematopoietic Systems
Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with fludarabine phosphate. During fludarabine phosphate treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with fludarabine phosphate.
Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in post-marketing surveillance. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients.
Life-threatening and sometimes fatal autoimmune hemolytic anemias have been reported to occur in patients receiving fludarabine phosphate. [See WARNINGS AND PRECAUTIONS (5.2)] The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process.
Metabolic
Tumor lysis syndrome has been reported in CLL patients treated with fludarabine phosphate. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria.
Nervous System
Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in CLL patients treated with fludarabine phosphate at the recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine phosphate and one case of wrist-drop was reported. [See WARNINGS AND PRECAUTIONS (5.1)]
In post marketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or concurrent chemotherapy. The median time to onset was approximately one year.
Pulmonary System
Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16%, and 22% of those treated with fludarabine phosphate in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to fludarabine phosphate characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed.
In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure. After an infectious origin has been excluded, some patients experienced symptom improvement with corticosteroids.
Gastrointestinal System
Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding have been reported in patients treated with fludarabine phosphate.
Cardiovascular
Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine phosphate. No other severe cardiovascular events were considered to be drug related.
Genitourinary System
Hemorrhagic cystitis has been reported in patients treated with fludarabine phosphate.
Skin
Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with fludarabine phosphate.
Adverse Reactions from Clinical Trials
Data in Table 1 are derived from the 133 patients with CLL who received fludarabine phosphate in the MDAH and SWOG studies.
table 02
More than 3000 adult patients received fludarabine phosphate in studies of other leukemias, lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was consistent with the data presented above.
<--postmarketingperience-->
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Fludarabine (injection) in the drug label.
Drug Interactions
Pentostatin
The use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity.
Fludarabine phosphate may cause fetal harm when administered to a pregnant woman. Fludarabine phosphate was teratogenic in rats and in rabbits. Fludarabine phosphate was administered intravenously at doses of 0, 1, 10 or 30 mg/kg/day to pregnant rats on days 6 to 15 of gestation. At 10 and 30 mg/kg/day in rats, there was an increased incidence of various skeletal malformations. Fludarabine phosphate was administered intravenously at doses of 0, 1, 5 or 8 mg/kg/day to pregnant rabbits on days 6 to 15 of gestation. Dose-related teratogenic effects manifested by external deformities and skeletal malformations were observed in the rabbits at 5 and 8 mg/kg/day. Drug-related deaths or toxic effects on maternal and fetal weights were not observed. There are no adequate and well controlled studies in pregnant women.
If Fludarabine Phosphate Injection is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fludarabine (injection) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Fludarabine (injection) during labor and delivery.
Nursing Mothers
It is not known whether fludarabine phosphate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions including tumorigenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
Pediatric Use
Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy.
Limited pharmacokinetic data for fludarabine phosphate are available from a published study of children (ages 1 to 21 years) with refractory acute leukemias or solid tumors (Children's Cancer Group Study 097). When fludarabine phosphate was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.
Geriatic Use
There is no FDA guidance on the use of Fludarabine (injection) with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Fludarabine (injection) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Fludarabine (injection) with respect to specific racial populations.
Renal Impairment
There are inadequate data on dosing of patients with renal insufficiency. Fludarabine Phosphate Injection must be administered cautiously in patients with renal insufficiency. The total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have their fludarabine phosphate dose reduced by 20% and be monitored closely. Fludarabine phosphate is not recommended for patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).
The total body clearance of the principal metabolite 2-fluoro-ara-A correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represents approximately 40% of the total body clearance. Patients with moderate renal impairment (17 to 41 mL/min/m2) receiving 20% reduced fludarabine phosphate dose had a similar exposure (AUC; 21 versus 20 nM∙h/mL) compared to patients with normal renal function receiving the recommended dose. The mean total body clearance was 172 mL/min for normal and 124 mL/min for patients with moderately impaired renal function.
Hepatic Impairment
There is no FDA guidance on the use of Fludarabine (injection) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fludarabine (injection) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Fludarabine (injection) in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Intravenous
Monitoring
There is limited information regarding Monitoring of Fludarabine (injection) in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Fludarabine (injection) in the drug label.
Overdosage
High doses of fludarabine phosphate [See INDICATIONS AND USAGE (1.1) and WARNINGS AND PRECAUTIONS (5.1, 5.2)] have been associated with an irreversible central nervous system toxicity characterized by delayed blindness, coma and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for fludarabine phosphate overdosage. Treatment consists of drug discontinuation and supportive therapy.
Pharmacology
There is limited information regarding Fludarabine (injection) Pharmacology in the drug label.
Mechanism of Action
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.
Structure
Fludarabine Phosphate Injection contains fludarabine phosphate, a nucleotide metabolic inhibitor. Fludarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A), that is relatively resistant to deamination by adenosine deaminase.
Each mL contains 25 mg of the active ingredient fludarabine phosphate, 1.78 mg disodium phosphate dihydrate, water for injection, qs; and sodium hydroxide to adjust pH to 7.5. The pH range for the final product is 7.3 to 7.7. Fludarabine Phosphate Injection is a sterile solution intended for intravenous administration.
The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-β-D-arabinofuranosyl)(2-fluoro-ara-AMP).
The molecular formula of fludarabine phosphate is C10H13FN5O7P (MW 365.2) and the structure is provided in Figure 1
Figure 1: Chemical Structure of Fludarabine Phosphate
Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion.
Pharmacokinetics
Clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro, plasma protein binding of fludarabine ranged between 19% and 29%. A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Fludarabine (injection) in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Fludarabine (injection) in the drug label.
How Supplied
Storage
There is limited information regarding Fludarabine (injection) Storage in the drug label.
Images
Drug Images
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