Cladribine – Leustatin®

Cladribine - Leustatin®

Usual Diluents

Dilution Data

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 0.22µ disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir. First add the calculated dose of LEUSTATIN Injection (7 days x 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.

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.

CLINICAL PHARMACOLOGY

Cellular Resistance and Sensitivity
The selective toxicity of 2-chloro-2'-deoxy-β-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-β-D-adenosine monophosphate (2-CdAMP). Since 2-chloro-2'-deoxy-β-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-β-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-β-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-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.

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/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
LEUSTATIN Injection is indicated for the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms.

CONTRAINDICATIONS
LEUSTATIN Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components.

DOSAGE AND ADMINISTRATION

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 (see PACKAGE INSERT FOR WARNINGS).

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
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.

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.

1.Viaflex® containers, manufactured by Baxter Healthcare Corporation - Code No. 2B8013 (tested in 1991)

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 0.22µ 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™ 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.

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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.

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.(2–8) 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.

HOW SUPPLIED
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.

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).