Fludara Information
Fludara () Description
Fludara () FOR INJECTION contains Fludara () bine phosphate, 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 vial of sterile lyophilized solid cake contains 50 mg of the active ingredient Fludara () bine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2-8.2. Reconstitution with 2 mL of Sterile Water for Injection, USP, results in a solution containing 25 mg/mL of Fludara () bine phosphate intended for intravenous administration.
The chemical name for Fludara () bine phosphate is 9-Purin-6-amine, 2-fluoro-9-(5--phosphono-β-D-arabino-furanosyl) (2-fluoro-ara-AMP). The molecular formula of Fludara () bine phosphate is CHFNOP (MW 365.2) and the structure is:
Fludara () Clinical Pharmacology
Fludara () bine 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 Fludara () bine 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/m 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. , plasma protein binding of Fludara () bine 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).
Fludara () Clinical Studies
Two single-arm, open-label studies of Fludara () FOR INJECTION have been conducted in adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In a study conducted by M.D. Anderson Cancer Center (MDAH), 48 patients were treated with a dose of 22-40 mg/m daily for 5 days every 28 days. Another study conducted by the Southwest Oncology Group (SWOG) involved 31 patients treated with a dose of 15-25 mg/m daily for 5 days every 28 days. The overall objective response rates were 48% and 32% in the MDAH and SWOG studies, respectively. The complete response rate in both studies was 13%; the partial response rate was 35% in the MDAH study and 19% in the SWOG study. These response rates were obtained using standardized response criteria developed by the National Cancer Institute CLL Working Group and were achieved in heavily pretreated patients. The ability of Fludara () FOR INJECTION to induce a significant rate of response in refractory patients suggests minimal cross-resistance with commonly used anti-CLL agents.
The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks) and 21 weeks (range of 1 to 53 weeks), respectively. The median duration of disease control was 91 weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with Fludara () FOR INJECTION was 43 weeks and 52 weeks in the MDAH and SWOG studies, respectively.
Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of anemic patients. Similarly, average platelet count improved from 63,500/mm to 103,300/mm at the time of response in a subgroup of patients who were thrombocytopenic at baseline.
Fludara () Indications And Usage
Fludara () FOR 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 Fludara () FOR INJECTION in previously untreated or non-refractory patients with CLL have not been established.
Fludara () Contraindications
Fludara () FOR INJECTION is contraindicated in those patients who are hypersensitive to this drug or its components.
Fludara () Warnings
Array
There are clear dose-dependent toxic effects seen with Fludara () FOR INJECTION. Dose levels approximately 4 times greater (96 mg/m/day for 5 to 7 days) than that recommended for CLL (25 mg/m/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 Fludara () FOR INJECTION at high doses (96 mg/m/day for 5 to 7 days) developed this severe neurotoxicity. Similar severe central nervous system toxicity, including coma, seizures, agitation and confusion, has been reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.
In postmarketing experience neurotoxicity has been reported to occur either earlier or later than in clinical trials (range 7 to 225 days).
The effect of chronic administration of Fludara () FOR INJECTION on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy.
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with Fludara () FOR INJECTION. In a Phase I study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3-25 days) for granulocytes and 16 days (range, 2-32) 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 Fludara () FOR 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.
Based on its mechanism of action, Fludara () bine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Fludara () FOR INJECTION in pregnant women. Fludara () bine administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformations and decreased fetal body weights. If Fludara () FOR 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.
Males with female sexual partners of childbearing potential should use contraception during and after cessation of Fludara () FOR INJECTION therapy. Fludara () bine may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain. [See ]
Fludara () Precautions
Fludara () FOR INJECTION is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of hematologic and nonhematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of anemia, neutropenia and thrombocytopenia.
In patients with impaired state of health, Fludara () FOR INJECTION should be given with caution and after careful risk/benefit consideration. This applies especially for patients with severe impairment of bone marrow function (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency or with a history of opportunistic infection. Prophylactic treatment should be considered in patients at increased risk of developing opportunistic infections.
Fludara () FOR INJECTION may reduce the ability to drive or use machines, since fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.
Fludara () FOR INJECTION must be administered cautiously in patients with renal impairment. The total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with creatinine clearance 30-79 mL/min should have their Fludara () FOR INJECTION dose reduced and be monitored closely for excessive toxicity. Fludara () FOR INJECTION should not be administered to patients with creatinine clearance less than 30 mL/min. (See section).
In patients aged 65 years or older, creatinine clearance should be measured before start of treatment.
Pregnancy Category D (see section).
Based on its mechanism of action, Fludara () bine phosphate can cause fetal harm when administered to a pregnant woman. There are not adequate and well-controlled studies of Fludara () bine phosphate in pregnant women. Fludara () bine phosphate was embryolethal and teratogenic in rats and rabbits. If Fludara () FOR 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.
In rats, repeated intravenous doses of Fludara () bine phosphate at 2.4 times and 7.2 times the recommended human IV dose (25 mg/m) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 2.4 times the human IV dose, and was limited to slight body weight decreases at 7.2 times the human IV dose. In rabbits, repeated intravenous doses of Fludara () bine phosphate at 3.8 times the human IV dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (≥ 0.5 times the human IV dose).
Fludara () Adverse Reactions
Very common adverse events include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, fatigue, weakness, infection, pneumonia, cough, nausea, vomiting, and diarrhea. Other commonly reported events include malaise, mucositis and anorexia. Serious opportunistic infections (such as latent viral reactivation, herpes zoster virus, Epstein-Barr virus, and progressive multifocal leukoencephalopathy) have occurred in CLL patients treated with Fludara () FOR INJECTION. Adverse events and those reactions which are more clearly related to the drug are arranged below according to body system.
Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with Fludara () FOR INJECTION. During Fludara () FOR INJECTION treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm 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 Fludara () FOR INJECTION.
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 phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving Fludara () FOR INJECTION (see section). The majority of patients rechallenged with Fludara () FOR INJECTION developed a recurrence in the hemolytic process.
In post-marketing experience, cases of myelodysplastic syndrome and acute myeloid leukemia, mainly associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors, or irradiation have been reported.
Serious and sometimes fatal infections, including opportunistic infections and reactivations of latent viral infections such as VZV (herpes zoster), Epstein-Barr virus and JC virus (progressive multifocal leukoencephalopathy) have been reported in patients treated with Fludara () FOR INJECTION.
Rare cases of Epstein-Barr virus (EBV) associated lymphoproliferative disorders have been reported in patients treated with Fludara () FOR INJECTION.
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 time to onset has ranged from a few weeks to approximately one year after initiating treatment.
Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study, approximately 50% of which were due to infection.
(see section)
Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with Fludara () FOR INJECTION at the recommended dose. Peripheral neuropathy has been observed in patients treated with Fludara () FOR INJECTION and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known.
Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16% and 22% of those treated with Fludara () FOR INJECTION in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to Fludara () FOR INJECTION characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed.
In post-marketing experience, cases of severe pulmonary toxicity have been observed with Fludara () FOR INJECTION use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis and respiratory failure. After an infectious origin has been excluded, some patients experienced symptom improvement with corticosteroids.
Elevations of hepatic enzyme levels have been reported.
Data in the following table are derived from the 133 patients with CLL who received Fludara () FOR INJECTION in the MDAH and SWOG studies.
More than 3000 adult patients received Fludara () FOR INJECTION 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.
Fludara () Overdosage
High doses of Fludara () FOR INJECTION (see 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 Fludara () FOR INJECTION overdosage. Treatment consists of drug discontinuation and supportive therapy.
Fludara () Dosage And Administration
The recommended adult dose of Fludara () FOR INJECTION is 25 mg/m 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 Fludara () FOR INJECTION. These include advanced age, renal impairment, 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 Fludara () FOR INJECTION be administered following the achievement of a maximal response and then the drug should be discontinued.
Fludara () FOR INJECTION should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP. When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg of Fludara () bine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2-8.2. 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.
Reconstituted Fludara () FOR INJECTION contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution. 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.
Fludara () FOR INJECTION should not be mixed with other drugs.
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.
Caution should be exercised in the handling and preparation of Fludara () FOR INJECTION solution. 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.
Fludara () How Supplied
Fludara () FOR INJECTION is supplied as a white, lyophilized solid cake. Each vial contains 50 mg of Fludara () bine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2-8.2. Store under refrigeration, between 2º-8ºC (36º-46ºF).
Fludara () FOR INJECTION is supplied in a clear glass single dose vial (6 mL capacity) and packaged in a single dose vial carton in a shelf pack of five.
NDC 58468-0170-1
Manufactured by: Ben Venue Laboratories, Bedford, OH 44146Manufactured for: Genzyme Corporation, Cambridge, MA 02142
Fludara () References
1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.
2. OSHA Technical Manual, TED 1-0. 15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. 2006: 63: 1172-1193.
4. Polvich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2 ed.). Pittsburgh, PA: Oncology Nursing Society.
Fludara () Package Label - Principal Display Panel – Pack Shelf Carton
Dosage: See package insert.
Each vial contains Fludara () bine phosphate 50 mg, mannitol 50 mg and sodium hydroxide to adjust pH to 7.7. The pH range is 7.2-8.2.
Reconstitute each vial with 2 mL Sterile Water for Injection, USP, resulting in a solution containing 25 mg/mL Fludara () bine phosphate. Use within 8 hours of reconstitution.
Contains no preservative.
Store under refrigeration, between 2-8ºC (36-46ºF).
Contains 5 Single Dose Vials
