Pharmacy & Therapeutics - October 2008 - (Page 579)

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 placebotreated 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, Serious Infections and Tuberculosis). 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, Tuberculosis). 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, Malignancies). 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, Autoimmunity). 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, Hypersensitivity Reactions). 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. DRUG INTERACTIONS 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, Use with Anakinra). Live Vaccines Do not give live (including attenuated) vaccines concurrently with CIMZIA (see WARNINGS AND PRECAUTIONS, Immunizations). 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. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B – Because certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab’ fragment (cTN3 PF) similar to certolizumab pegol. Reproduction studies have been performed in rats at doses up to 100 mg/kg and have revealed no evidence of impaired fertility or harm to the fetus due to cTN3 PF. There are, however, no adequate and well-controlled studies of CIMZIA in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CIMZIA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of CIMZIA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. A population pharmacokinetic analysis of all patients enrolled in CIMZIA clinical studies concluded that there was no apparent difference in drug concentration regardless of age. Because there is a higher incidence of infections in the elderly population in general, use caution when treating the elderly (see WARNINGS AND PRECAUTIONS, Serious Infections). OVERDOSAGE The maximum tolerated dose of certolizumab pegol has not been established. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have been administered without serious adverse reactions. In cases of overdosage, it is recommended that patients be monitored closely for any adverse reactions or effects, and appropriate symptomatic treatment instituted immediately. PATIENT COUNSELING INFORMATION See PATIENT COUNSELING INFORMATION, Medication Guide in Full Prescribing Information. Patient Counseling Advise patients of the potential risks and benefits of CIMZIA therapy. Give patients the Medication Guide and allow them time to read it prior to starting CIMZIA therapy and to review it periodically. Any questions resulting from the patient’s

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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