CLADRIBINE

INDICATIONS AND USAGE: Cladribine Injection, USP is indicated for the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms.

DOSAGE AND ADMINISTRATION: Usual Dosage The recommended dose and schedule of cladribine injection for active Hairy Cell Leukemia is as a single course given by continuous infusion for seven 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 cladribine 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 WARNINGS ). Specific risk factors predisposing to increased toxicity from cladribine injection 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 WARNINGS and PRECAUTIONS ). Preparation and Administration of Intravenous Solutions Cladribine injection must be diluted with the designated diluent prior to administration. Since the drug product does not contain any antimicrobial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of cladribine injection solutions . To prepare a single daily dose Cladribine injection should be passed through a sterile 0.22 μ m disposable hydrophilic syringe filter prior to introduction into the infusion bag, prior to each daily infusion. Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of cladribine injection through the sterile filter 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 seven consecutive days. The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine. Admixtures of cladribine injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex ® PVC infusion containers. Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised. Dose of Cladribine Injection Recommended Diluent Quantity of Diluent 24-hour infusion method 1 (day) x 0.09 mg/kg 0.9% Sodium Chloride Injection, USP 500 mL To prepare a 7-day infusion The seven-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 cladribine injection and the diluent should be passed through a sterile 0.22 μ m disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir. First add the calculated dose of cladribine 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 seven 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 seven-day infusion have demonstrated acceptable chemical and physical stability for at least seven days in the SIMS Deltec MEDICATION CASSETTETM Reservoir. Dose of Cladribine Injection Recommended Diluent Quantity of Diluent 7-day infusion method (use sterile 0 …

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

ADVERSE REACTIONS: Clinical Trials Experience Adverse drug reactions reported by ≥ 1% of cladribine-treated patients with HCL noted in the HCL clinical dataset (studies K90-091 and L91-048, n=576) are shown in the table below. Adverse Drug Reactions in ≥ 1% of Patients Treated with Cladribine in HCL Clinical Trials System Organ Class Preferred Term Cladribine (n=576) % Blood and Lymphatic System Disorder (see also sections WARNINGS and PRECAUTIONS ) Anemia 1 Febrile neutropenia 8 Psychiatric Disorders Anxiety 1 Insomnia 3 Nervous System Disorders Dizziness 6 Headache 14 Cardiac Disorders Tachycardia 2 Respiratory, Thoracic and Mediastinal Disorders Breath sounds abnormal 4 Cough 7 Dyspnea* 5 Rales 1 Gastrointestinal Disorders Abdominal pain** 4 Constipation 4 Diarrhea 7 Flatulence 1 Nausea 22 Vomiting 9 Skin and Subcutaneous Tissue Disorders Ecchymosis 2 Hyperhidrosis 3 Petechiae 2 Pruritus 2 Rash*** 16 Musculoskeletal, Connective Tissue, and Bone Disorders Arthralgia 3 Myalgia 6 Pain**** 6 General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS ) Administration site reaction***** 11 Asthenia 6 Chills 2 Decreased appetite 8 Fatigue 31 Malaise 5 Muscular weakness 1 Edema peripheral 2 Pyrexia 33 Injury, Poisoning and Procedural Complications Contusion 1 * Dyspnea includes dyspnea, dyspnea exertional, and wheezing ** Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper) *** Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous) **** Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity *****Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction (erythema, edema, and pain) The following 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%. 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 x 10 6 /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 x 10 9 /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 cladribine 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 viral and 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 …

Drug Interactions There are no known drug interactions with cladribine. Caution should be exercised if cladribine is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression (see WARNINGS ). Carcinogenesis No animal carcinogenicity studies have been conducted with cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of cladribine. Mutagenesis As expected for compounds in this class, the actions of cladribine yield DNA damage. In mammalian cells in culture, cladribine caused the accumulation of DNA strand breaks. Cladribine was also incorporated into DNA of human lymphoblastic leukemia cells. Cladribine was not mutagenic in vitro (Ames and Chinese hamster ovary cell gene mutation tests) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However, cladribine was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test). Impairment of Fertility The effect on human fertility is unknown. When administered intravenously to Cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells.

DESCRIPTION Cladribine Injection, USP (also commonly known as 2-chloro-2 ́-deoxy-ß-D-adenosine) is a synthetic antineoplastic agent for continuous intravenous infusion. It is a clear, colorless, sterile, preservative-free, isotonic solution. Cladribine Injection, USP is available in single-use vials containing 10 mg (1 mg/mL) of cladribine, a chlorinated purine nucleoside analog. Each mL of cladribine injection, USP 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-ß-D- erythro -pentofuranosyl)purine and the structure is represented below: Molecular Formula = C 10 H 12 ClN 5 O 3 Molecular Weight = 285.69 structure

OVERDOSAGE High doses of cladribine have been associated with: irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia (see WARNINGS ). There is no known specific antidote to overdosage. Treatment of overdosage consists of discontinuation of cladribine, careful observation and appropriate supportive measures. It is not known whether the drug can be removed from the circulation by dialysis or hemofiltration. When used in other clinical settings the following ADRs were reported: bacteremia, cellulitis, localized infection, pneumonia, anemia, thrombocytopenia (with bleeding or petechiae), phlebitis, purpura, crepitations, localized edema and edema. For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see WARNINGS .

HOW SUPPLIED Cladribine Injection, USP 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, individually boxed. NDC 0143-9871-01. Store refrigerated 2° to 8°C (36° to 46°F). Protect from light during storage. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689.