Cladribine 1 mg/mL Injection

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 injection, 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 injection, 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 injection 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 four to eight weeks after treatment with cladribine injection, is recommended (see PRECAUTIONS ). Fever (T ≥ 100°F) was associated with the use of cladribine injection 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 ≤ 1,000), including 62 patients (32%) with severe neutropenia (i.e., ANC ≤ 500). In a Phase I investigational study using cladribine injection in high doses (four to nine 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 (two cases) received cladribine for 7 to 14 days prior to bone marrow transplantation. During infusion, eight 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, six patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine, etc.) and five required dialysis. Several of these patients were also being treated with other medications having known nephrotoxic potential. Renal dysfunction was reversible in two of these patients.

In the four patients whose renal function had not recovered at the time of death, autopsies were performed; in two 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 four 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…

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…