Clinical Trials Experience

The most serious adverse reactions were:

• Serious Infections [see WARNINGS and PRECAUTIONS]
• Malignancies [see WARNINGS and PRECAUTIONS]

The data described below reflect exposure to CIMZIA at 400 mg subcutaneous dosing in studies of patients with Crohn's disease. In the safety population in controlled studies, a total of 620 subjects with Crohn's disease received CIMZIA at a dose of 400 mg, and 614 subjects received placebo (including subjects randomized to placebo in Study CD2 following open label dosing of CIMZIA at Week 0, 2, 4). In controlled and uncontrolled studies, 1,564 subjects received CIMZIA at some dose level, of whom 1,350 subjects received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% were male, and 94% were Caucasian. The majority of patients in the active group were between the ages of 18 and 64.

During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for CIMZIA and 9% for placebo. The most common adverse reactions (occurring in ≥ 5% of Cimzia-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with CIMZIA was upper respiratory infection (20% CIMZIA, 13% placebo), urinary tract infection (7% CIMZIA, 6% placebo), and arthralgia (6% CIMZIA, 4% placebo).

The proportion of patients who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for CIMZIA and 7% for placebo. The most common adverse reactions leading to the discontinuation of CIMZIA (for at least 2 patients and with a higher incidence than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo), diarrhea (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0% placebo).

Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.

Infections

The incidence of infections in controlled clinical studies was 38% for CIMZIA-treated patients and 30% for placebo-treated patients. The infections consisted primarily of upper respiratory infection (20% CIMZIA, 13% placebo). The incidence of serious infections during the controlled clinical studies was 3% for CIMZIA-treated patients and 1% for placebo-treated patients. Serious infections observed included bacterial and viral infections, pneumonia, and pyelonephritis [see WARNINGS and PRECAUTIONS].

Tuberculosis and Opportunistic Infections

In completed and ongoing clinical studies that include over 4,650 patients, the overall rate of tuberculosis is approximately 0.5 per 100 patient-years. The rate in Crohn's disease studies was 0.3 cases per 100 patient-years. The reports include cases of pulmonary and disseminated tuberculosis. Cases of opportunistic infection have also been reported in clinical trials. Some cases of opportunistic infections and tuberculosis have been fatal [see WARNINGS and PRECAUTIONS].

Malignancies

In clinical studies of CIMZIA, the overall incidence rate of malignancies was similar for CIMZIA-treated and control patients. For some TNF blockers, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients [see WARNINGS and PRECAUTIONS].

Autoantibodies

In clinical studies in Crohn's disease, 4% of patients treated with CIMZIA and 2% of patients treated with placebo that had negative baseline ANA titers developed positive titers during the studies. One of the 1,564 Crohn's disease patients treated with CIMZIA developed symptoms of a lupus-like syndrome. The impact of long-term treatment with CIMZIA on the development of autoimmune diseases is unknown [see WARNINGS and PRECAUTIONS].

Immunogenicity

Patients were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. The overall percentage of antibody positive patients was 8% in patients continuously exposed to CIMZIA, of which approximately 80% were neutralizing in vitro. No apparent correlation of antibody development to adverse events or efficacy was observed. Patients treated with concomitant immunosuppressants had a lower rate of antibody development than patients not taking immunosuppressants at baseline (3% and 11%, respectively).

The following adverse events were reported in antibody-positive patients (N = 100) at an incidence at least 3% higher compared to antibody-negative patients (N = 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site erythema, injection site pain, pain in extremity, and upper respiratory tract infection.

The data reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing 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 medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to certolizumab pegol with the incidence of antibodies to other products may be misleading.

Hypersensitivity Reactions

The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, dermatitis allergic, dizziness (postural), dyspnea, hot flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum sickness, and (vasovagal) syncope [see WARNINGS and PRECAUTIONS].

Other Adverse Reactions

The most commonly occurring adverse reactions in controlled trials of Crohn's disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn's disease and other diseases under investigation, occurring in patients receiving CIMZIA at doses of 400 mg or other doses include:

Blood and lymphatic system disorders: Anemia, leukopenia, lymphadenopathy, pancytopenia, and thrombophilia.

Cardiac disorders: Angina pectoris, arrhythmias, cardiac failure, hypertensive heart disease, myocardial infarction, myocardial ischemia, pericardial effusion, and pericarditis.

Eye disorders: Optic neuritis, retinal hemorrhage, and uveitis.

General disorders and administration site conditions: Bleeding and injection site reactions.

Hepatobiliary disorders: Elevated liver enzymes and hepatitis.

Immune system disorders: Alopecia totalis.

Psychiatric disorders: Anxiety, bipolar disorder, and suicide attempt.

Renal and urinary disorders: Nephrotic syndrome and renal failure.

Reproductive system and breast disorders: Menstrual disorder.

Skin and subcutaneous tissue disorders: Dermatitis, erythema nodosum, and urticaria.

Vascular disorders: Vasculitis.

Adverse Reaction Information from Other Sources

Cases of severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have been identified during post-approval use of other TNF blockers. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

Anakinra

Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF blocker has shown an increased risk of serious infections, an increased risk of neutropenia, and no added benefit compared to these medicinal products alone. Therefore, the combination of anakinra with other TNF blockers, including CIMZIA, may also result in similar toxicities [see WARNINGS and PRECAUTIONS].

Live Vaccines

Do not give live (including attenuated) vaccines concurrently with CIMZIA [see WARNINGS and PRECAUTIONS].

Laboratory Tests

Interference with certain coagulation assays has been detected in patients treated with CIMZIA. Certolizumab pegol may cause erroneously elevated aPTT assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-LA test from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilized silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. Interference with thrombin time (TT) and prothrombin time (PT) assays has not been observed. There is no evidence that CIMZIA therapy has an effect on in vivo coagulation.

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