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
|Blood and Lymphatic System Disorder (see also sections WARNINGS and PRECAUTIONS)
| Febrile neutropenia
|Nervous System Disorders
|Respiratory, Thoracic and Mediastinal Disorders
| Breath sounds abnormal
| Abdominal pain**
|Skin and Subcutaneous Tissue Disorders
|Musculoskeletal, Connective Tissue, and Bone Disorders
|General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS)
| Administration site reaction*****
| Decreased appetite
| Muscular weakness
| Edema peripheral
|Injury, Poisoning and Procedural Complications
|* 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.
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
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
Immune system disorders: Hypersensitivity.
Metabolism and nutrition disorders: Tumor lysis
Psychiatric disorders: Confusion (including
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).
There are no known drug interactions with LEUSTATIN
Injection. Caution should be exercised if LEUSTATIN Injection is administered
before, after, or in conjunction with other drugs known to cause
immunosuppression or myelosuppression. (see WARNINGS)