le on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with ACTEMRA-IV. One patient in the placebo group escaped to ACTEMRA-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had ACTEMRA-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the ACTEMRA-IV SJIA clinical development experience; however no definitive conclusions can be made.
Infusion Reactions
Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of ACTEMRA-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.
Within 24 hours after infusion, 16% of patients in the ACTEMRA-IV treatment group and 5% of patients in the placebo group experienced an event. In the ACTEMRA-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.
Anaphylaxis
Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with ACTEMRA-IV during the controlled and open label extension study [see WARNINGS AND PRECAUTIONS (5.5)].
Immunogenicity
All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.
Laboratory Abnormalities
Neutropenia
During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 109 per L occurred in 7% of patients in the ACTEMRA-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the ACTEMRA-IV group. There was no clear relationship between decrease in neutrophils below 1 × 109 per L and the occurrence of serious infections.
Thrombocytopenia
During routine monitoring in the 12 week controlled phase, 1% of patients in the ACTEMRA-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100 × 103 per mcL.
In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the ACTEMRA-IV group, with no associated bleeding.
Elevated Liver Enzymes
During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3× ULN occurred in 5% and 3% of patients, respectively in the ACTEMRA-IV group and in 0% of placebo patients.
In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3× ULN occurred in 13% and 5% of ACTEMRA-IV treated patients, respectiv |
