Discontinuations

Of the CTCL patients who received the 400-mg once daily dose, 9.3% (8/86) of patients discontinued ZOLINZA due to adverse events. These adverse events, regardless of causality, included anemia, angioneurotic edema, asthenia, chest pain, exfoliative dermatitis, death, deep vein thrombosis, ischemic stroke, lethargy, pulmonary embolism, and spinal cord injury.

Dose Modifications

Of the CTCL patients who received the 400-mg once daily dose, 10.5% (9/86) of patients required a dose modification of ZOLINZA due to adverse events. These adverse events included increased serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, thrombocytopenia and vomiting. The median time to the first adverse event resulting in dose reduction was 42 days (range 17 to 263 days).

Laboratory Abnormalities

Laboratory abnormalities were reported in all of the 86 CTCL patients who received the 400-mg once-daily dose.

Increased serum glucose was reported as a laboratory abnormality in 69% (59/86) of CTCL patients who received the 400-mg once daily dose; only 4 of these abnormalities were severe (Grade 3). Increased serum glucose was reported as an adverse event in 8.1% (7/86) of CTCL patients who received the 400-mg once daily dose. [See Warnings and Precautions (5.4).]

Transient increases in serum creatinine were detected in 46.5% (40/86) of CTCL patients who received the 400-mg once daily dose. Of these laboratory abnormalities, 34 were NCI CTCAE Grade 1, 5 were Grade 2, and 1 was Grade 3.

Proteinuria was detected as a laboratory abnormality (51.4%) in 38 of 74 patients tested. The clinical significance of this finding is unknown.

Dehydration

Based on reports of dehydration as a serious drug-related adverse event in clinical trials, patients were instructed to drink at least 2 L/day of fluids for adequate hydration. [See Warnings and Precautions (5.3, 5.5).]

Adverse Reactions in Non-CTCL Patients

The frequencies of individual adverse events were substantially higher in the non-CTCL population. Drug-related serious adverse events reported in the non-CTCL population which were not observed in the CTCL population included single events of blurred vision, asthenia, hyponatremia, tumor hemorrhage, Guillain-Barré syndrome, renal failure, urinary retention, cough, hemoptysis, hypertension, and vasculitis.

Table 1: Clinical or Laboratory Adverse Events Occurring in CTCL Patients (Incidence ≥10% of patients)  ZOLINZA 400 mg once daily (N=86) 
Adverse Events  All Grades  Grades 3-5No Grade 5 events were reported. 
 n  %  n  % 
Fatigue 45 52.3 3 3.5
Diarrhea 45 52.3 0 0.0
Nausea 35 40.7 3 3.5
Dysgeusia 24 27.9 0 0.0
Thrombocytopenia 22 25.6 5 5.8
Anorexia 21 24.4 2 2.3
Weight Decreased 18 20.9 1 1.2
Muscle Spasms 17 19.8 2 2.3
Alopecia 16 18.6 0 0.0
Dry Mouth 14 16.3 0 0.0
Blood Creatinine Increased 14 16.3 0 0.0
Chills 14 16.3 1 1.2
Vomiting 13 15.1 1 1.2
Constipation 13 15.1 0 0.0
Dizziness 13 15.1 1 1.2
Anemia 12 14.0 2 2.3
Decreased Appetite 12 14.0 1 1.2
Peripheral Edema 11 12.8 0 0.0
Headache 10 11.6 0 0.0
Pruritus 10 11.6 1 1.2
Cough 9 10.5 0 0.0
Upper Respiratory Infection 9 10.5 0 0.0
Pyrexia 9 10.5 1 1.2

Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) we