Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4226
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Fludarabine Phosphate (Injection)
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Usual Dose The recommended adult dose of fludarabine phosphate injection is 25 mg/madministered 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 Insufficiency Adult patients with moderate impairment of renal function (creatinine clearance 30���70 mL/min/1.73 m) should have a 20% dose reduction of fludarabine phosphate injection. Fludarabine phosphate injection should not be administered to patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m). Preparation of Solutions Fludarabine phosphate injection: Each mL contains 25 mg fludarabine phosphate, 25 mg mannitol, water for injection, qs; and sodium hydroxide to adjust the pH to 6.8. The pH range for the final product is 6.0���7.1. In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% dextrose injection USP or 0.9% sodium chloride USP. Fludarabine phosphate injection contains no antimicrobial preservative and thus should be used within 8 hours of initial entry. Care must be taken to assure the sterility of prepared solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Handling and Disposal Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Procedures for proper handling and disposal should be considered. Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published.1���8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Caution should be exercised in the handling of fludarabine phosphate injection. The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.
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Fludarabine phosphate injection contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-��-Darabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each mL contains 25 mg of the active ingredient fludarabine phosphate, 25 mg of mannitol, water for injection, qs; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0���7.1. Fludarabine phosphate injection is a sterile solution intended for intravenous administration. The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2fluoro-9-(5-O-phosphono-��-D-arabinofuranosyl) (2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is CHFNOP (MW 365.2) and the structure is:
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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. 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. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/mto cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoroara-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).<br/>Special Populations:<br/>Pediatric Patients: Limited pharmacokinetic data for fludarabine phosphate for injection are available from a published study of children (ages 1���21 years) with refractory acute leukemias or solid tumors (Children's Cancer Group Study 097). When fludarabine phosphate for injection was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.<br/>Patients with Renal Impairment: 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���41 mL/min/m) receiving 20% reduced fludarabine 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.
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Fludarabine phosphate injection is contraindicated in those patients who are hypersensitive to this drug or its components.
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Fludarabine Phosphate Injection is supplied as a clear, sterile solution. Each mL contains 25 mg of fludarabine phosphate, 25 mg of mannitol, water for injection, qs; and sodium hydroxide to adjust pH to 6.8. The pH range for the final product is 6.0���7.1. Store under refrigeration, between 2�����8��C (36�����46��F). Fludarabine Phosphate Injection is supplied in a single dose vial and packaged in a unit carton.
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WARNING: Fludarabine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Fludarabine can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, fludarabine 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/m/day for 5���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. Patients undergoing treatment with fludarabine should be evaluated and closely monitored for hemolysis. In a clinical investigation using fludarabine 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 in combination with pentostatin is not recommended.
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High doses of fludarabine phosphate injection (see WARNINGS section) 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 injection overdosage. Treatment consists of drug discontinuation and supportive therapy.
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Fludarabine Phosphate
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Fludarabine Phosphate (Injection)
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The most common adverse events 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. The most frequently reported adverse events 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. During fludarabine treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mmin 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. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in postmarketing 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 anemia have been reported to occur in patients receiving fludarabine (see WARNINGS section). The majority of patients rechallenged with fludarabine developed a recurrence in the hemolytic process. Metabolic Tumor lysis syndrome has been reported in CLL patients treated with fludarabine. 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 (See WARNINGS section) Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in CLL patients treated with fludarabine at the recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine and one case of wrist-drop was reported. Pulmonary System Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16% and 22% of those treated with fludarabine in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to fludarabine 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 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. Cardiovascular Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine. No other severe cardiovascular events were considered to be drug related. Genitourinary System Rare cases of hemorrhagic cystitis have been reported in patients treated with fludarabine. Skin Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with fludarabine. Data in the following table are derived from the 133 patients with CLL who received fludarabine in the MDAH and SWOG studies. More than 3000 adult patients received fludarabine 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.
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Fludarabine phosphate injection is indicated for the treatment of 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.
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Fludarabine Phosphate
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