ADVERSE REACTIONS

Most patients treated for hairy cell leukemia in the five NCI-sponsored Phase 2 studies and the Phase 3 SWOG study experienced an adverse event. The following table lists the most frequently occurring adverse events in patients treated with NIPENT (both frontline and IFN-refractory patients) compared with IFN (frontline only), regardless of drug association. The drug association of some adverse events is uncertain as they may be associated with the disease itself (e.g., infection, hematologic suppression), but other events, such as the gastrointestinal symptoms, rashes, and abnormal liver function tests, can in many cases be attributed to the drug. Most adverse events that were assessed for severity were either mild or moderate, and diminished in frequency with continued therapy.

The total incidence for all types of infections is considerably higher for both treatment groups in the SWOG 8691 study than is listed in the table above. An intent-to-treat analysis of infections found that 38% of patients treated with NIPENT and 34% of patients treated with IFN averaged 2.4 and 1.9 documented infections during treatment, respectively. The following table lists the different types of infections that were reported as adverse events during the initial phase of the SWOG study. There were no apparent differences in the types of infection between the 2 treatment groups, with the possible exception of herpes zoster which was reported more frequently for NIPENT (8%) than for IFN (1%).

The drug relatedness of the adverse events listed below cannot be excluded. The following adverse events occurred in 3% to 10% of NIPENT-treated patients in the initial phase of the SWOG study:

Body as a Whole—Chest Pain, Death, Face Edema, Peripheral Edema

Cardiovascular System—Hemorrhage, Hypotension

Digestive System—Dental Abnormalities, Dyspepsia, Flatulence, Gingivitis

Hematologic System—Agranulocytosis

Laboratory Deviations—Elevated Creatinine

Musculoskeletal System—Arthralgia

Nervous System—Confusion, Dizziness, Insomnia, Paresthesia, Somnolence

Psychobiologic Function—Anxiety, Depression, Nervousness

Respiratory System—Asthma

Skin & Appendages—Skin Dry, Urticaria

The remaining adverse events which occurred in less than 3% of NIPENT-treated patients during the initial phase of the SWOG study:

Body as a Whole—Flu-like Symptoms, Hangover Effect, Neoplasm

Cardiovascular System—Angina Pectoris, Arrhythmia, A-V Block, Bradycardia, Extrasystoles Ventricular, Heart Arrest, Heart Failure, Hypertension, Pericardial Effusion, Phlebitis, Pulmonary Embolus, Sinus Arrest, Tachycardia, Thrombophlebitis Deep, Vasculitis

Digestive System—Constipation, Dysphagia, Glossitis, Ileus

Hematologic System—Acute Leukemia, Anemia-Hemolytic, Aplastic Anemia

Laboratory Deviations—Hypercalcemia, Hyponatremia

Musculoskeletal System—Arthritis, Gout

Nervous System—Amnesia, Ataxia, Convulsions, Dreaming Abnormal, Dysarthria, Encephalitis, Hyperkinesia, Meningism, Neuralgia, Neuritis, Neuropathy, Paralysis, Syncope, Twitching, Vertigo

Psychobiologic Function—Decrease/Loss Libido, Emotional Lability, Hallucination, Hostility, Neurosis, Thinking Abnormal

Respiratory System—Bronchospasm, Larynx Edema

Skin and Appendages—Acne, Alopecia, Eczema, Petechial Rash, Photosensitivity Reaction

Special Senses—Amblyopia, Deafness, Earache, Eyes Dry, Labyrinthitis, Lacrimation Disorder, Nonreactive Eye, Photophobia, Retinopathy, Tinnitus, Unusual Taste, Vision Abnormal, Watery Eyes

Urogenital System—Amenorrhea, Breast Lump, Impotence, Kidney Function Abnormal, Nephropathy, Renal Failure, Renal Insufficiency, Renal Stone

One patient with hairy cell leukemia treated with NIPENT during another clinical study developed unilateral uveitis with vision loss.

Nineteen (5%) patients withdrew from the Phase 3 SWOG 8691 study because of adverse events; 9 during initial NIPENT treatment, 4 during NIPENT crossover, 5 during initial IFN treatment, and 1 during both initial IFN treatment and NIPENT crossover. In the Phase 2 studies in IFN-refractory hairy cell leukemia, 11% of patients withdrew from treatment with NIPENT due to an adverse event.