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Clinical Trials Experience

Adverse drug reactions reported by ≥ 1% of LEUSTATIN-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 LEUSTATIN in HCL Clinical Trials

System Organ Class Preferred Term LEUSTATIN
(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 106/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 109/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 LEUSTATIN 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 patients were treated empirically with antibiotics. (see WARNINGS and PRECAUTIONS)

Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/μL. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/μL. Fifteen (15) months after treatment, mean CD4 counts remained below 500/μL. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear.

Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts.

The vast majority of rashes were mild. Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.

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.

Postmarketing Experience

The following additional adverse reactions have been reported since the drug became commercially available. These adverse reactions have been reported primarily in patients who received multiple courses of LEUSTATIN Injection:

Infections and infestations: Septic shock. Opportunistic infections have occurred in the acute phase of treatment.

Blood and lymphatic system disorders: Bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia (including autoimmune hemolytic anemia), which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported.

Immune system disorders: Hypersensitivity.

Metabolism and nutrition disorders: Tumor lysis syndrome.

Psychiatric disorders: Confusion (including disorientation).

Hepatobiliary disorders: Reversible, generally mild increases in bilirubin (uncommon) and transaminases.

Nervous System disorders: Depressed level of consciousness, neurological toxicity (including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, paraparesis); however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens.

Eye disorders: Conjunctivitis.

Respiratory, thoracic and mediastinal disorders: Pulmonary interstitial infiltrates (including lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis); in most cases, an infectious etiology was identified.

Skin and tissue disorders: Urticaria, hypereosinophilia; Stevens-Johnson. In isolated cases toxic epidermal necrolysis has been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes.

Renal and urinary disorders: Renal failure (including renal failure acute, renal impairment).