Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2749
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LEUSTATIN (Injection, Solution)
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Usual Dose: The recommended dose and schedule of LEUSTATIN Injection for active Hairy Cell Leukemia is as a single course given by continuous infusion for 7 consecutive days at a dose of 0.09 mg/kg/day. Deviations from this dosage regimen are not advised. If the patient does not respond to the initial course of LEUSTATIN Injection for Hairy Cell Leukemia, it is unlikely that they will benefit from additional courses. Physicians should consider delaying or discontinuing the drug if neurotoxicity or renal toxicity occurs . Specific risk factors predisposing to increased toxicity from LEUSTATIN have not been defined. In view of the known toxicities of agents of this class, it would be prudent to proceed carefully in patients with known or suspected renal insufficiency or severe bone marrow impairment of any etiology. Patients should be monitored closely for hematologic and non-hematologic toxicity .<br/>Preparation and Administration of Intravenous Solutions: LEUSTATIN Injection must be diluted with the designated diluent prior to administration. Since the drug product does not contain any anti-microbial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of LEUSTATIN Injection solutions.<br/>To prepare a single daily dose: Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of LEUSTATIN Injection to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP. Infuse continuously over 24 hours. Repeat daily for a total of 7 consecutive days. The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine. Admixtures of LEUSTATIN Injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter ViaflexPVC infusion containers. Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.<br/>To prepare a 7-day infusion: The 7-day infusion solution should only be prepared with Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved). In order to minimize the risk of microbial contamination, both LEUSTATIN Injection and the diluent should be passed through a sterile 0.22��disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir. First add the calculated dose of LEUSTATIN Injection (7 days��0.09 mg/kg or mL/kg) to the infusion reservoir through the sterile filter. Then add a calculated amount of Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved) also through the filter to bring the total volume of the solution to 100 mL. After completing solution preparation, clamp off the line, disconnect and discard the filter. Aseptically aspirate air bubbles from the reservoir as necessary using the syringe and a dry second sterile filter or a sterile vent filter assembly. Reclamp the line and discard the syringe and filter assembly. Infuse continuously over 7 days. Solutions prepared with Bacteriostatic Sodium Chloride Injection for individuals weighing more than 85 kg may have reduced preservative effectiveness due to greater dilution of the benzyl alcohol preservative. Admixtures for the 7-day infusion have demonstrated acceptable chemical and physical stability for at least 7 days in the SIMS Deltec MEDICATION CASSETTE���Reservoir. Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised. Solutions containing LEUSTATIN Injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed. Preparations containing benzyl alcohol should not be used in neonates . Care must be taken to assure the sterility of prepared solutions. Once diluted, solutions of LEUSTATIN Injection should be administered promptly or stored in the refrigerator (2��to 8��C) for no more than 8 hours prior to start of administration. Vials of LEUSTATIN Injection are for single-use only. Any unused portion should be discarded in an appropriate manner (see Handling and Disposal). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A precipitate may occur during the exposure of LEUSTATIN Injection to low temperatures; it may be resolubilized by allowing the solution to warm naturally to room temperature and by shaking vigorously. DO NOT HEAT OR MICROWAVE.<br/>Chemical Stability of Vials: When stored in refrigerated conditions between 2��to 8��C (36��to 46��F) protected from light, unopened vials of LEUSTATIN Injection are stable until the expiration date indicated on the package. Freezing does not adversely affect the solution. If freezing occurs, thaw naturally to room temperature. DO NOT heat or microwave. Once thawed, the vial of LEUSTATIN Injection is stable until expiry if refrigerated. DO NOT refreeze. Once diluted, solutions containing LEUSTATIN Injection should be administered promptly or stored in the refrigerator (2��to 8��C) for no more than 8 hours prior to administration.<br/>Handling and Disposal: The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering LEUSTATIN Injection. The use of disposable gloves and protective garments is recommended. If LEUSTATIN Injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water. Several guidelines on this subject have been published.There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Refer to your Institution's guidelines and all applicable state/local regulations for disposal of cytotoxic waste.
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LEUSTATIN (cladribine) Injection (also commonly known as 2-chloro-2��-deoxy-��-D-adenosine) is a synthetic antineoplastic agent for continuous intravenous infusion. It is a clear, colorless, sterile, preservative-free, isotonic solution. LEUSTATIN Injection is available in single-use vials containing 10 mg (1 mg/mL) of cladribine, a chlorinated purine nucleoside analog. Each milliliter of LEUSTATIN Injection contains 1 mg of the active ingredient and 9 mg (0.15 mEq) of sodium chloride as an inactive ingredient. The solution has a pH range of 5.5 to 8.0. Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the pH to 6.3��0.3. The chemical name for cladribine is 2-chloro-6-amino-9-(2-deoxy-��-D-erythropento-furanosyl) purine and the structure is represented below: cladribine MW 285.7
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Cellular Resistance and Sensitivity: The selective toxicity of 2-chloro-2��-deoxy-��-D-adenosine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase and deoxynucleotidase. Cladribine passively crosses the cell membrane. In cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2��-deoxy-��-D-adenosine monophosphate (2-CdAMP). Since 2-chloro-2��-deoxy-��-D-adenosine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into the active triphosphate deoxynucleotide, 2-chloro-2��-deoxy-��-D-adenosine triphosphate (2-CdATP). It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by 2-chloro-2��-deoxy-��-D-adenosine as toxic deoxynucleotides accumulate intracellularly. Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. The broken ends of DNA activate the enzyme poly (ADP-ribose) polymerase resulting in NAD and ATP depletion and disruption of cellular metabolism. There is evidence, also, that 2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment of DNA synthesis. Thus, 2-chloro-2��-deoxy-��-D-adenosine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.<br/>Pharmacokinetics: In a clinical investigation, 17 patients with Hairy Cell Leukemia and normal renal function were treated for 7 days with the recommended treatment regimen of LEUSTATIN Injection (0.09 mg/kg/day) by continuous intravenous infusion. The mean steady-state serum concentration was estimated to be 5.7 ng/mL with an estimated systemic clearance of 663.5 mL/h/kg when LEUSTATIN was given by continuous infusion over 7 days. In Hairy Cell Leukemia patients, there does not appear to be a relationship between serum concentrations and ultimate clinical outcome. In another study, 8 patients with hematologic malignancies received a two (2) hour infusion of LEUSTATIN Injection (0.12 mg/kg). The mean end-of-infusion plasma LEUSTATIN concentration was 48��19 ng/mL. For 5 of these patients, the disappearance of LEUSTATIN could be described by either a biphasic or triphasic decline. For these patients with normal renal function, the mean terminal half-life was 5.4 hours. Mean values for clearance and steady-state volume of distribution were 978��422 mL/h/kg and 4.5��2.8 L/kg, respectively. Cladribine plasma concentration after intravenous administration declines multi-exponentially with an average half-life of 6.7 +/- 2.5 hours. In general, the apparent volume of distribution of cladribine is approximately 9 L/kg, indicating an extensive distribution in body tissues. Cladribine penetrates into cerebrospinal fluid. One report indicates that concentrations are approximately 25% of those in plasma. LEUSTATIN is bound approximately 20% to plasma proteins. Except for some understanding of the mechanism of cellular toxicity, no other information is available on the metabolism of LEUSTATIN in humans. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumors during a 5-day continuous intravenous infusion of 3.5���8.1 mg/m/day of LEUSTATIN. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.
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LEUSTATIN Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components.
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LEUSTATIN Injection is supplied as a sterile, preservative-free, isotonic solution containing 10 mg (1 mg/mL) of cladribine as 10 mL filled into a single-use clear flint glass 20 mL vial. LEUSTATIN Injection is supplied in 10 mL (1 mg/mL) single-use vials (NDC 59676-201-01) available in a treatment set (case) of seven vials. Store refrigerated 2��to 8��C (36��to 46��F). Protect from light during storage.
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WARNING: LEUSTATIN (cladribine) Injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Serious neurological toxicity (including irreversible paraparesis and quadraparesis) has been reported in patients who received LEUSTATIN Injection by continuous infusion at high doses (4 to 9 times the recommended dose for Hairy Cell Leukemia). Neurologic toxicity appears to demonstrate a dose relationship; however, severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens. Acute nephrotoxicity has been observed with high doses of LEUSTATIN (4 to 9 times the recommended dose for Hairy Cell Leukemia), especially when given concomitantly with other nephrotoxic agents/therapies.
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High doses of LEUSTATIN have been associated with: irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia . There is no known specific antidote to overdosage. Treatment of overdosage consists of discontinuation of LEUSTATIN, careful observation and appropriate supportive measures. It is not known whether the drug can be removed from the circulation by dialysis or hemofiltration.
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cladribine
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LEUSTATIN (Injection, Solution)
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Safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same two centers after the original enrollment cutoff. In Month 1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Other adverse experiences reported frequently during the first 14 days after initiating treatment included: fatigue (45%), nausea (28%), rash (27%), headache (22%) and injection site reactions (19%). Most non-hematologic adverse experiences were mild to moderate in severity. Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC<500��10/L) was noted in 70% of patients, compared with 26% in whom it was present initially. Severe anemia (Hemoglobin<8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets<20��10/L) developed in 12% of patients, compared to 4% in whom it was noted initially. During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease. During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding LEUSTATIN therapy. During the first month, 11% of patients experienced severe fever (i.e.,���104��F). Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viraland 11 (20%) were fungal. Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics. Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/��L. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/��L. Fifteen (15) months after treatment, mean CD4 counts remained below 500/��L. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear. Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of<35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts. The vast majority of rashes were mild and occurred in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause rash. Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine. Adverse reactions reported during the first 2 weeks following treatment initiation (regardless of relationship to drug) by>5% of patients included: Body as a Whole: fever (69%), fatigue (45%), chills (9%), asthenia (9%), diaphoresis (9%), malaise (7%), trunk pain (6%) Gastrointestinal: nausea (28%), decreased appetite (17%), vomiting (13%), diarrhea (10%), constipation (9%), abdominal pain (6%) Hemic/Lymphatic: purpura (10%), petechiae (8%), epistaxis (5%) Nervous System: headache (22%), dizziness (9%), insomnia (7%) Cardiovascular System: edema (6%), tachycardia (6%) Respiratory System: abnormal breath sounds (11%), cough (10%), abnormal chest sounds (9%), shortness of breath (7%) Skin/Subcutaneous Tissue: rash (27%), injection site reactions (19%), pruritis (6%), pain (6%), erythema (6%) Musculoskeletal System: myalgia (7%), arthralgia (5%) Adverse experiences related to intravenous administration included: injection site reactions (9%) (i.e., redness, swelling, pain), thrombosis (2%), phlebitis (2%) and a broken catheter (1%). These appear to be related to the infusion procedure and/or indwelling catheter, rather than the medication or the vehicle. From Day 15 to the last follow-up visit, the only events reported by>5% of patients were: fatigue (11%), rash (10%), headache (7%), cough (7%), and malaise (5%). For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see WARNINGS. The following additional adverse events have been reported since the drug became commercially available. These adverse events have been reported primarily in patients who received multiple courses of LEUSTATIN Injection: Hematologic: bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia, which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported. Hepatic: reversible, generally mild increases in bilirubin and transaminases. Nervous System: Neurological toxicity; however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens. Respiratory System: pulmonary interstitial infiltrates; in most cases, an infectious etiology was identified. Skin/Subcutaneous: urticaria, hypereosinophilia. In isolated cases Stevens-Johnson and toxic epidermal necrolysis have been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes. Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by LEUSTATIN Injection.
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LEUSTATIN
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