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Cladribine - Leustatin®
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| 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 Viaflex®1 PVC infusion containers. Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.
To prepare a 7-day infusion
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.
Chemical Stability of Vials
|Stability / Miscellaneous|
Cellular Resistance and Sensitivity
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-β-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.
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/m2/day of LEUSTATIN. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.
INDICATIONS FOR USE
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 (see PACKAGE INSERT FOR WARNINGS and PRECAUTIONS).
Preparation and Administration of Intravenous Solutions
To prepare a single daily dose
1.Viaflex® containers, manufactured by Baxter Healthcare Corporation - Code No. 2B8013 (tested in 1991)
To prepare a 7-day infusion
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™ Reservoir2.
2 . MEDICATION CASSETTE™ Reservoir, manufactured by SIMS Deltec, Inc. - Reorder No. 602100A (tested in 1991)
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 (see PACKAGE INSERT FOR WARNINGS).
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.
Chemical Stability of Vials
Handling and Disposal
Store refrigerated 2° to 8°C (36° to 46°F). Protect from light during storage.
[PACKAGE INSERT DATA] : LEUSTATIN (cladribine) injection, solution. Ortho Biotech Products, L.P. Raritan, NJ 08869. Revision Date August 2007.
Handling/disposal/other: Santana VM, Mirro J, Harwood FC, et al: A phase I clinical trial of 2-Chloro-deoxyadenosine in pediatric patients with acute leukemia. J. Clin. Onc., 9: 416 (1991). Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U. S. Government Printing Office, Washington, D. C. 20402. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics, JAMA, March 15 (1985). National Study Commission on Cytotoxic Exposure--Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents, Med. J. Australia 1:425 (1983). Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. Ca--A Cancer Journal for Clinicians, Sept/Oct. 258–263 (1983). American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic Drugs in Hospitals. Am. J. Hosp. Pharm., 42:131 (1985). OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (antineoplastic) Drugs. Am. J. Hosp. Pharm., 43:1193 (1986).