% of patients on placebo plus DMARD, without associated bleeding events.
In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical studies [see Warnings and Precautions (5.3)].
Liver Function Tests
Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of ACTEMRA, or reduction in ACTEMRA dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.3)]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Precautions (5.3)].
Table 1 Incidence of Liver Enzyme Abnormalities in the 6-Month Controlled Period of Studies I-V* ACTEMRA
8 mg/kg MONOTHERAPY Methotrexate ACTEMRA
4 mg/kg + DMARDs ACTEMRA
8 mg/kg + DMARDs Placebo + DMARDs
N = 288
(%) N = 284
(%) N = 774
(%) N = 1582
(%) N = 1170
(%)
ULN = Upper Limit of Normal
*
For a description of these studies, see Section 14, Clinical Studies
AST (U/L)
> ULN to 3x ULN 22 26 34 41 17
> 3x ULN to 5x ULN 0.3 2 1 2 0.3
> 5x ULN 0.7 0.4 0.1 0.2 < 0.1
ALT (U/L)
> ULN to 3x ULN 36 33 45 48 23
> 3x ULN to 5x ULN 1 4 5 5 1
> 5x ULN 0.7 1 1.3 1.5 0.3
Lipids
Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of ACTEMRA in the controlled 6-month clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg/dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were eva luated and are summarized below:
–
Mean LDL increased by 13 mg/dL in the TCZ 4 mg/kg+DMARD arm, 20 mg/dL in the TCZ 8 mg/kg+DMARD, and 25 mg/dL in TCZ 8 mg/kg monotherapy.
–
Mean HDL increased by 3 mg/dL in the TCZ 4 mg/kg+DMARD arm, 5 mg/dL in the TCZ 8 mg/kg+DMARD, and 4 mg/dL in TCZ 8 mg/kg monotherapy.
–
Mean LDL/HDL ratio increased by an average of 0.14 in the TCZ 4 mg/kg+DMARD arm, 0.15 in the TCZ 8 mg/kg+DMARD, and 0.26 in TCZ 8 mg/kg monotherapy.
–
ApoB/ApoA1 ratios were essentially unchanged in ACTEMRA-treated patients.
Elevated lipids responded to lipid lowering agents.
Immunogenicity
In the 6-month, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.
The data reflect the percentage of patients whose test results were positive for antibodies to tocilizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab with the inc |
