ONS (5.5)].
Laboratory Abnormalities
Neutropenia
In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections.
In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see WARNINGS AND PRECAUTIONS (5.3)].
Thrombocytopenia
In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.5% 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 24 week controlled clinical studies [see WARNINGS AND PRECAUTIONS (5.3)].
Elevated Liver Enzymes
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-IV, or reduction in ACTEMRA-IV dose, resulted in decrease or normalization of liver enzymes [see DOSAGE AND ADMINISTRATION (2.5)]. 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 24 Week Controlled Period of Studies I to V*
ACTEMRA
8 mg per kg MONOTHERAPY Methotrexate ACTEMRA
4 mg per kg + DMARDs ACTEMRA
8 mg per 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 3× ULN 22 26 34 41 17
> 3× ULN to 5× ULN 0.3 2 1 2 0.3
> 5× ULN 0.7 0.4 0.1 0.2 < 0.1
ALT (U/L)
> ULN to 3× ULN 36 33 45 48 23
> 3× ULN to 5× ULN 1 4 5 5 1
> 5× ULN 0.7 1 1.3 1.5 0.3
In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials
Lipids
Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of ACTEMRA-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stab |
