The safety and tolerability profile of ACTEMRA/RoACTEMRA (tocilizumab) in combination with DMARDs or as monotherapy has been evaluated in the most comprehensive Phase III development programme for a biologic RA treatment. The programme comprised four placebo-controlled studies (OPTION, TOWARD, RADIATE and LITHE), one methotrexate (MTX)-controlled study (AMBITION) and their extension periods. These studies included a wide range of patient populations, including MTX-naïve patients (AMBITION) and patients with an inadequate response to DMARDs (OPTION, TOWARD, LITHE) or anti-TNFs (RADIATE).
The double-blind controlled period was 6 months in four studies (AMBITION, OPTION, TOWARD and RADIATE) and was up to 2 years in one study (LITHE). The long‑term exposure population includes all patients who received at least one dose of ACTEMRA/RoACTEMRA either in the double-blind control period or open label extension phase in the studies. Of the 4,009 patients in this population, 3,577 received treatment for at least 6 months, 3,296 for at least one year, 2,806 received treatment for at least 2 years and 1,222 for 3 years.
|Treatment||Number of patients|
|ACTEMRA/RoACTEMRA 4 mg/kg plus MTX||774|
|ACTEMRA/RoACTEMRA 8 mg/kg plus MTX/other DMARDs||1,870|
|ACTEMRA/RoACTEMRA 8 mg/kg monotherapy||288|
The adverse drug reactions (ADRs) presented in the table below are based on the safety of ACTEMRA/RoACTEMRA in these five studies, and are presented by system, organ, class and frequency categories, defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10) or uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The most commonly reported ADRs (occurring in ≥5% of patients treated with ACTEMRA/RoACTEMRA monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased alanine aminotransferase (ALT).
(>1/100 to <1/10)
(>1/1000 to <1/100)
|Infections and infestations||Upper respiratory tract infections||Cellulitis, pneumonia, oral herpes simplex, herpes zoster||Diverticulitis|
|Gastrointestinal disorders||Abdominal pain, mouth ulceration, gastritis||Stomatitis, gastric ulcer|
|Skin and subcutaneous tissue disorders||Rash, pruritus, urticaria|
|Nervous system disorders||Headache, dizziness|
|Investigations||Hepatic transaminases increased, weight increased||Total bilirubin increased|
|Blood and lymphatic system disorders||Leukopenia, neutropenia|
|Metabolism and nutrition disorders||Hypercholesterolaemia||Hypertriglyceridaemia|
|General disorders and administration site conditions||Peripheral oedema hypersensitivity reactions|
In the 6-month controlled studies, the rate of all infections reported with ACTEMRA/RoACTEMRA 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared with 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population the overall rate of infections with ACTEMRA/RoACTEMRA plus DMARDs was 108 events per 100 patient years exposure.
In 6-month controlled clinical studies, the overall rate of serious infections with ACTEMRA/RoACTEMRA 8 mg/kg plus DMARDs was 5.3 events per 100 patient years of exposure compared to 3.9 events per 100 patient years of exposure in the placebo plus DMARD group. In the monotherapy study, the rate of serious infections was 3.6 events per 100 patient years of exposure in the ACTEMRA/RoACTEMRA group and 1.5 events per 100 patient years of exposure in the MTX group.
In the long-term exposure population the overall rate of serious infections (bacterial, viral and fungal) observed with ACTEMRA/RoACTEMRA plus DMARD treatment was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.
During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient years with ACTEMRA/RoACTEMRA therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years.
Reports of gastrointestinal perforation on ACTEMRA/RoACTEMRA were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.
In the 6-month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the ACTEMRA/RoACTEMRA 8 mg/kg plus DMARD group and 5.1% of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.
The rate of anaphylactic reactions (occurring in a total of six out of 3,778 patients, 0.2%) was several fold higher with the 4 mg/kg dose, compared with the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with ACTEMRA/RoACTEMRA and requiring treatment discontinuation were reported in a total of 13 out of 3,778 patients (0.3%) treated with ACTEMRA/RoACTEMRA during the controlled and open-label clinical studies. These reactions were generally observed during the second to fifth infusions of ACTEMRA/RoACTEMRA.
A total of 2,876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6%) who developed anti-tocilizumab antibodies, six had an associated medically significant hypersensitivity reaction, of which five led to permanent discontinuation of treatment. Thirty patients (1.1%) developed neutralising antibodies.
In healthy subjects administered ACTEMRA/RoACTEMRA in doses from 2 to 28 mg/kg, absolute neutrophil counts decreased to their lowest 3-5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following ACTEMRA/RoACTEMRA administration.
In the 6-month controlled trials, decreases in neutrophil counts below 1 x 109/l occurred in 3.4% of patients on ACTEMRA/RoACTEMRA 8 mg/kg plus DMARDs compared with <0.1% of patients on placebo plus DMARDs. Approximately half of the patients who developed an absolute neutrophil count (ANC) <1 x 109/l did so within 8 weeks after starting therapy. Decreases below 0.5 x 109/l were reported in 0.3% patients receiving ACTEMRA/RoACTEMRA 8 mg/kg plus DMARDs. There was no clear association between decreases in neutrophils and the occurrence of serious infections.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.
In the 6-month controlled trials, decreases in platelet counts below 100 x 103/µl occurred in 1.7% of patients on ACTEMRA/RoACTEMRA 8 mg/kg plus DMARDs compared to <1% on placebo plus DMARDs. These decreases occurred without associated bleeding events.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.
During the 6-month controlled trials, elevations in ALT/aspartate aminotransferase (AST) >3 x upper limit of normal (ULN) were observed in 2.1% of patients on ACTEMRA/RoACTEMRA 8 mg/kg compared with 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg ACTEMRA/RoACTEMRA plus DMARDs compared with 1.5% of patients on placebo plus DMARDs.
The addition of potentially hepatotoxic drugs (e.g. MTX) to ACTEMRA/RoACTEMRA monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST >5 x ULN were observed in 0.7% of ACTEMRA/RoACTEMRA monotherapy patients and 1.4% of ACTEMRA/RoACTEMRA plus DMARD patients, the majority of whom were discontinued permanently from ACTEMRA/RoACTEMRA treatment. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment. The incidence of indirect bilirubin greater than the upper limit of normal is 6.2% in patients treated with 8 mg/kg ACTEMRA/RoACTEMRA.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.
During the 6-month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and/or high-density lipoprotein (HDL) cholesterol have been reported commonly. Approximately 24% of patients receiving ACTEMRA/RoACTEMRA in clinical trials experienced sustained elevations in total cholesterol ≥6.2 mmol/l, with 15% experiencing a sustained increase in LDL to ≥4.1 mmol/l. Elevations in lipid parameters responded to treatment with lipid-lowering agents.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled trials.
The clinical data are insufficient to assess the potential incidence of malignancy following exposure to ACTEMRA/RoACTEMRA. Long-term safety evaluations are ongoing.
There are limited data available on overdose with ACTEMRA/RoACTEMRA. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg. No adverse reactions were observed.
No serious adverse reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg, although dose-limiting neutropenia was observed.
RoACTEMRA® (tocilizumab) Summary of Product Characteristics. Roche Registration Limited. August 2011.