Cladribine

INDICATIONS FOR USE 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 Dose The recommended dose and schedule of cladribine injection, USP 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 cladribine injection, USP 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 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, USP 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, USP should be passed through a sterile 0.22µm 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, USP 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 7 consecutive days. The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine. Admixtures of cladribine injection, USP 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, USP Recommended Diluent Quantity of Diluent 24-hour infusion method 1(day) × 0.09 mg/kg 0.9% Sodium Chloride Injection, USP 500 mL 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 cladribine injection, USP and the diluent should be passed through a sterile 0.22 µm disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir. First add the calculated dose of cladribine injection, USP (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. Dose of Cladribine Injection, USP Recommended Diluent Quantity of Diluent 7-day infusion method (use st…

WARNINGS Due to increased risk of infection in the setting of immunosuppression with chemotherapy including cladribine, it is recommended not to administer live attenuated vaccines to patients receiving cladribine injection. Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine, especially at high doses. At initiation of treatment, most patients in the clinical studies had hematologic impairment as a manifestation of active Hairy Cell Leukemia. Following treatment with cladribine, further hematologic impairment occurred before recovery of peripheral blood counts began. During the first two weeks after treatment initiation, mean Platelet Count, ANC, and Hemoglobin concentration declined and subsequently increased with normalization of mean counts by Day 12, Week 5 and Week 8, respectively. The myelosuppressive effects of cladribine were most notable during the first month following treatment. Forty-four percent (44%) of patients received transfusions with RBCs and 14% received transfusions with platelets during Month 1. Careful hematologic monitoring, especially during the first 4 to 8 weeks after treatment with cladribine injection, is recommended (see PRECAUTIONS ). Fever (T ≥ 100°F) was associated with the use of cladribine in approximately two-thirds of patients (131/196) in the first month of therapy. Virtually all of these patients were treated empirically with parenteral antibiotics. Overall, 47% (93/196) of all patients had fever in the setting of neutropenia (ANC ≤ 1000), including 62 patients (32%) with severe neutropenia (i.e., ANC ≤ 500). In a Phase I investigational study using cladribine in high doses (4 to 9 times the recommended dose for Hairy Cell Leukemia) as part of a bone marrow transplant conditioning regimen, which also included high dose cyclophosphamide and total body irradiation, acute nephrotoxicity and delayed onset neurotoxicity were observed. Thirty-one (31) poor-risk patients with drug-resistant acute leukemia in relapse (29 cases) or non-Hodgkins Lymphoma (2 cases) received cladribine for 7 to 14 days prior to bone marrow transplantation. During infusion, 8 patients experienced gastrointestinal symptoms. While the bone marrow was initially cleared of all hematopoietic elements, including tumor cells, leukemia eventually recurred in all treated patients. Within 7 to 13 days after starting treatment with cladribine, 6 patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine, etc.) and 5 required dialysis. Several of these patients were also being treated with other medications having known nephrotoxic potential. Renal dysfunction was reversible in 2 of these patients. In the 4 patients whose renal function had not recovered at the time of death, autopsies were performed; in 2 of these, evidence of tubular damage was noted. Eleven (11) patients (35%) experienced delayed onset neurologic toxicity. In the majority, this was characterized by progressive irreversible motor weakness (paraparesis/quadriparesis) of the upper and/or lower extremities, first noted 35 to 84 days after starting high dose therapy with cladribine. Non-invasive testing (electromyography and nerve conduction studies) was consistent with demyelinating disease. Severe neurologic toxicity has also been noted with high doses of another drug in this class. Axonal peripheral polyneuropathy was observed in a dose escalation study at the highest dose levels (approximately 4 times the recommended dose for Hairy Cell Leukemia) in patients not receiving cyclophosphamide or total body irradiation. Severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens. In patients with Hairy Cell Leukemia treated with the recommended treatment regimen (0.09 mg/kg/day for 7 consecutive days), there have been no reports of nephrologic toxicities. Serious (e.…

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

Drug Interactions There are no known drug interactions with cladribine injection. Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression. (see WARNINGS )

Pregnancy Pregnancy Category D (see WARNINGS ).

Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

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 Dyspnea includes dyspnea, dyspnea exertional, and wheezing 5 Rales 1 Gastrointestinal Disorders Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper) 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 Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous) 16 Musculoskeletal, Connective Tissue, and Bone Disorders Arthralgia 3 Myalgia 6 Pain Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity 6 General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS ) Administration site reaction Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction(erythema, edema, and pain) 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 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 × 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 × 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 treatment. Virtually all of these pa…