Excluding non-melanoma of the skin, 30 malignancies including 3 cases of lymphoma were observed in the Cimzia RA clinical trials in which a total of 2,367 patients were treated, representing 4,136 patient-years. Cases of lymphoma occurred at an incidence rate of 0.07 per 100 patient-years and melanoma at an incidence rate of 0.02 per 100 patient-years with Cimzia in rheumatoid arthritis clinical trials (see section 4.4).
Autoimmunity
For subjects who were ANA negative at baseline, 16.7% of those treated with Cimzia developed positive ANA titers, compared with 12.0% of subjects in the placebo group. For subjects who were anti-dsDNA antibody negative at baseline, 2.2% of those treated with Cimzia developed positive anti-dsDNA antibody titers, compared with 1.0% of subjects in the placebo group. In both placebo-controlled and open-label follow-up clinical trials for rheumatoid arthritis, cases of lupus-like syndrome were reported uncommonly. There have been rare reports of other immune-mediated conditions; the causal relationship to Cimzia is not known. The impact of long-term treatment with Cimzia on the development of autoimmune diseases is unknown.
Injection site reactions
In the placebo-controlled rheumatoid arthritis clinical trials, 6.4% of patients treated with Cimzia developed injection site reactions (erythema, itching, haematoma, pain, swelling or bruising), compared to 6.5% of patients receiving placebo. Injection site pain was observed in 1.5% of patients treated with Cimzia with no cases leading to withdrawal.
4.9 Overdose
No dose-limiting toxicity was observed during clinical trials. Multiple doses of up to 800 mg subcutaneously and 20 mg/kg intravenously have been administered. In cases of overdose, it is recommended that patients are monitored closely for any adverse reactions or effect, and appropriate symptomatic treatment initiated immediately.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Tumour necrosis factor alpha (TNFα) inhibitors, ATC code: L04AB05
Mechanism of action
Cimzia has a high affinity for human TNFα and binds with a dissociation constant (KD) of 90 pM. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Cimzia selectively neutralises TNFα (IC90 of 4 ng/ml for inhibition of human TNFα in the in vitro L929 murine fibrosarcoma cytotoxicity assay) but does not neutralise lymphotoxin α (TNFβ).
Cimzia was shown to neutralise membrane associated and soluble human TNFα in a dose-dependant manner. Incubation of monocytes with Cimzia resulted in a dose-dependant inhibition of lipopolysaccharide (LPS)-induced TNFα and IL1β production in human monocytes.
Cimzia does not contain a fragment crystallisable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, or neutrophil degranulation.
Clinical efficacy
The efficacy and safety of Cimzia have been assessed in 2 randomised, placebo-controlled, double-blind clinical trials in patients 18 years of age with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria, RA-I (RAPID 1) and RA-II (RAPID 2). Patients had 9 swollen a |
