Drug Description
Each pre-filled syringe contains 200 mg certolizumab pegol in one ml.Certolizumab pegol is a recombinant, humanised antibody Fab' fragment against tumour necrosis factor alpha (TNF?) expressed in Escherichia coli and conjugated to polyethylene glycol (PEG).

Presentation
Solution for injection in pre-filled syringe.Clear to opalescent, colourless to yellow solution. The pH of the solution is approximately 4.7.

Indications
Cimzia, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe, active rheumatoid arthritis (RA) in adult patients when the response to disease-modifying antirheumatic drugs (DMARDs) including methotrexate, has been inadequate.Cimzia can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.Cimzia has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.

Adult Dosage
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis. Patients should be given the special alert card.PosologyThe recommended starting dose of Cimzia for adult patients with rheumatoid arthritis is 400 mg (as 2 injections of 200 mg each on one day) at weeks 0, 2 and 4, followed by a maintenance dose of 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia where appropriate.Available data suggest that clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment.Missed dosePatients who miss a dose should be advised to inject the next dose of Cimzia as soon as they remember and then continue injecting subsequent doses every 2 weeks as originally instructed.Paediatric population (< 18 years old)The safety and efficacy of Cimzia in children and adolescents below age 18 years have not yet been established. No data are available.Elderly (65 years old)No dose adjustment is required. Population pharmacokinetic analyses showed no effect of age.Renal and hepatic impairmentCimzia has not been studied in these patient populations. No dose recommendations can be made.Method of administrationThe total content (1 ml) of the pre-filled syringe should be administered as a subcutaneous injection only. Suitable sites for injection would include the thigh or abdomen.After proper training in injection technique, patients may self-inject if their physician determines that it is appropriate and with medical follow-up as necessary.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Active tuberculosis or other severe infections such as sepsis or opportunistic infections.Moderate to severe heart failure (NHYA classes III/IV)

Special Precautions
InfectionsPatients must be monitored closely for signs and symptoms of infections including tuberculosis before, during and after treatment with Cimzia. Because the elimination of Cimzia may take up to 5 months, monitoring should be continued throughout this period.Treatment with Cimzia must not be initiated in patients with a clinically important active infection, including chronic or localised infections, until the infection is controlled.Patients who develop a new infection while undergoing treatment with Cimzia should be monitored closely. Administration of Cimzia should be discontinued if a patient develops a new serious infection until the infection is controlled. Physicians should exercise caution when considering the use of Cimzia in patients with a history of recurring infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications.Patients with rheumatoid arthritis may not manifest typical symptoms of infection, including fever, due to their disease and concomitant medicinal products. Therefore, early detection of any infection, particularly atypical clinical presentations of a serious infection, is critical to minimise delays in diagnosis and initiation of treatment.Serious infections, including sepsis and tuberculosis (including miliary, disseminated and extrapulmonary disease), and opportunistic infections (e.g. histoplasmosis, nocardia, candidiasis) have been reported in patients receiving Cimzia. Some of these events have been fatal.TuberculosisBefore initiation of therapy with Cimzia, all patients must be eva luated for both active or inactive (latent) tuberculosis infection. This eva luation should include a detailed medical history for patients with a personal history of tuberculosis, with possible previous exposure to others with active tuberculosis, and with previous and/or current use of immunosuppressive therapy. Appropriate screening tests, e.g. tuberculin skin test and chest X -ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient's alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.If active tuberculosis is diagnosed prior to or during treatment, Cimzia therapy must not be initiated and must be discontinued.If inactive ('latent') tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. In all situations described below, the benefit/risk balance of Cimzia therapy should be very carefully considered.If latent tuberculosis is diagnosed, appropriate anti-tuberculosis therapy must be started before initiating treatment with Cimzia and in accordance with local recommendations.Use of anti-tuberculosis therapy should also be considered before the initiation of Cimzia in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and in patients who have significant risk factors for tuberculosis despite a negative test for latent tuberculosis. Biological tests for tuberculosis screening should be considered before starting Cimzia treatment if there is any potential latent tuberculosis infection, regardless of BCG vaccination.Patients should be instructed to seek medical advice if signs/symptoms (e.g. persistent cough, wasting/weight loss, low grade fever, listlessness) suggestive of a tuberculosis infection occur during or after therapy with Cimzia.Hepatitis B Virus (HBV) reactivationReactivation of HBV has occurred in patients who are chronic carriers of this virus receiving TNF antagonists. Some cases have had a fatal outcome. As HBV infection has also been reported with Cimzia, patients at risk for HBV infection should be eva luated for prior evidence of HBV infection before initiating Cimzia therapy. Adequate data on treating patients who are carriers of HBV with TNF antagonist therapy, in conjunction with anti-viral therapy, to prevent HBV reactivation are not available. Carriers of HBV who require treatment with TNF antagonists should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for 5 months following termination of therapy, especially if the patient is on concomitant corticosteroid therapy.In patients who develop HBV reactivation, Cimzia should be discontinued and effective anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF antagonist therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of Cimzia therapy in this situation and monitor patients closely.Malignancies and lymphoproliferative disordersThe potential role of TNF antagonist therapy in the development of malignancies is not known. Caution should be exercised when considering TNF antagonist therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy.With the current knowledge, a possible risk for the development of lymphomas, leukaemia or other malignancies in patients treated with a TNF antagonist cannot be excluded.In clinical trials with Cimzia and other TNF antagonists, more cases of lymphoma and other malignancies have been reported among patients receiving TNF antagonists than in control patients receiving placebo. In the post marketing setting, cases of leukaemia have been reported in patients treated with a TNF antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation.No trials have been conducted that include patients with a history of malignancy, or that continue treatment in patients who develop malignancy, while receiving Cimzia.Paediatric malignancyMalignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF antagonists (initiation of therapy 18 years of age) in the post marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF antagonists cannot be excluded.Chronic obstructive pulmonary disease (COPD)In an exploratory clinical trial eva luating the use of another TNF antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF antagonist in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking.Congestive heart failureCimzia is contraindicated in moderate or severe heart failure. In a clinical trial with another TNF antagonist, worsening congestive heart failure and increased mortality due to congestive heart failure have been observed. Cases of congestive heart failure have also been reported in rheumatoid arthritis patients receiving Cimzia. Cimzia should be used with caution in patients with mild heart failure (NYHA class I/II). Treatment with Cimzia must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.Haematological reactionsReports of pancytopaenia, including aplastic anaemia, have been rare with TNF antagonists. Adverse reactions of the haematologic system, including medically significant cytopaenia (e.g. leukopaenia, pancytopaenia, thrombocytopaenia) have been reported with Cimzia. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on Cimzia. Discontinuation of Cimzia therapy should be considered in patients with confirmed significant haematological abnormalities.Neurological eventsUse of TNF antagonists has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of TNF antagonist treatment should be carefully considered before initiation of Cimzia therapy. Rare cases of neurological disorders, including seizure disorder, neuritis and peripheral neuropathy, have been reported in patients treated with Cimzia.HypersensitivitySevere hypersensitivity reactions have been reported rarely following Cimzia administration in trials. If severe reactions occur, administration of Cimzia should be discontinued immediately and appropriate therapy instituted.There are limited data on the use of Cimzia in patients who have experienced a severe hypersensitivity reaction towards another TNF antagonist; in these patients caution is needed.ImmunosuppressionSince tumour necrosis factor (TNF) mediates inflammation and modulates cellular immune responses, the possibility exists for TNF antagonists, including Cimzia, to cause immunosupression, affecting host defences against infections and malignancies.AutoimmunityTreatment with Cimzia may result in the formation of antinuclear antibodies (ANA) and, uncommonly, in the development of a lupus-like syndrome. The impact of long-term treatment with Cimzia on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Cimzia, treatment must be discontinued. Cimzia has not been studied specifically in a lupus population.VaccinationsNo data are available on the response to vaccinations or the transmission of infection by live vaccines in patients receiving Cimzia. Live vaccines or attenuated vaccines should not be administered concurrently with Cimzia.Concomitant use with other biologicsSevere infections and neutropaenia were reported in clinical trials with concurrent use of anakinra (an interleukin-1 antagonist) or abatacept (a CD28 modulator) and another TNF antagonist, etanercept, with no added benefit compared to TNF antagonist therapy alone. Because of the nature of the adverse events seen with the combination of another TNF antagonist with either abatacept or anakinra therapy, similar toxicities may also result from the combination of anakinra or abatacept and other TNF antagonists. Therefore the use of Cimzia in combination with anakinra or abatacept is not recommended.SurgeryThere is limited safety experience with surgical procedures in patients treated with Cimzia. The 14-day half-life of certolizumab pegol should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Cimzia should be closely monitored for infections, and appropriate actions should be taken.Activated partial thromboplastin time (aPTT) assayInterference with certain coagulation assays has been detected in patients treated with Cimzia. Cimzia may cause erroneously elevated aPTT assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilised silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. There is no evidence that Cimzia therapy has an effect on coagulation in vivo. After patients receive Cimzia, careful attention should be given to interpretation of abnormal coagulation results. Interference with thrombin time (TT) and prothrombin time (PT) assays have not been observed.ElderlyIn the clinical trials, there was an apparently higher incidence of infections among subjects 65 years of age, compared to younger subjects, although experience is limited. Caution should be exercised when treating the elderly, and particular attention paid with respect to occurrence of infections.

Interactions
Concomitant treatment with methotrexate, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics showed no effect on the pharmacokinetics of certolizumab pegol based on a population pharmacokinetics analysis.The combination of Cimzia and anakinra or abatacept is not recommended.Co-administration of Cimzia with methotrexate had no significant effect on the pharmacokinetics of methotrexate. In study-to-study comparison, the pharmacokinetics of certolizumab pegol appeared similar to those observed previously in healthy subjects.

Adverse Reactions
Cimzia was studied in 2,367 patients with rheumatoid arthritis in controlled and open label trials for up to 57 months. The data in Table 1 is based on the pivotal controlled Studies involving 1,774 patients receiving Cimzia and 647 patients receiving placebo during the controlled period.In the placebo-controlled studies, patients receiving Cimzia had an approximately 4 times greater duration of exposure compared with the placebo group. This difference in exposure is primarily due to patients on placebo being more likely to withdraw early. In addition, Studies RA-I and RA-II had a mandatory withdrawal for non-responders at Week 16, the majority of whom were on placebo.The proportion of patients who discontinued treatment due to adverse events during the controlled trials was 5% for patients treated with Cimzia and 2.5% for patients treated with placebo.The most common adverse reactions belonged to the system organ classes Infections and infestations, reported in 15.5% of patients on Cimzia and 7.6% of patients on placebo, and General disorders and administration site conditions, reported in 10.0% of patients on Cimzia and 9.7% of patients on placebo.Adverse reactions reported in rheumatoid arthritis clinical trials and at least possibly related to Cimzia are listed in Table 1 below, according to frequency and system organ class. Frequency categories are defined as follows: Very common ( 1/10); Common ( 1/100 to < 1/10); Uncommon ( 1/1000 to <1/100); Rare ( 1/10,000 to <1/1000); Very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Table : 1. Adverse drug reactions in clinical trialsSystem Organ ClassFrequencyAdverse Drug ReactionsInfections and infestationsCommonbacterial infections (including abscess), viral infections (including herpes, papillomavirus, influenza)Uncommonsepsis (including multi-organ failure, septic shock), tuberculosis, fungal infections (including candidiasis, histoplasmosis, pneumocystosis),Neoplasms benign, malignant and unspecified (including cysts and polyps)Uncommonsolid organ tumours, non-melanoma skin cancers, pre-cancerous lesions (including oral leukoplakia, melanocytic nevus), benign tumours and cysts (including skin papilloma)Rarelymphoma, gastrointestinal tumours, melanomaUnknownleukaemiaBlood and the lymphatic system disordersCommoneosinophilic disorders, leukopaenia (including neutropaenia, lymphopaenia)Uncommonanaemia, lymphadenopathy, thrombocytopaenia, thrombocytosisRarepancytopaenia, splenomegaly, erythrocytosis, white blood cell morphology abnormalImmune system disordersUncommonvasculitides, lupus erythematosus, drug hypersensitivity, allergic disorders, autoantibody positiveRareangioneurotic oedema, sarcoidosis, serum sickness, panniculitis (including erythema nodosum)Endocrine disordersRarethyroid disordersMetabolism and nutrition disordersUncommonelectrolyte imbalance, dyslipidaemia, appetite disorders, weight changeRarehaemosiderosisPsychiatric disordersUncommonanxiety (including restlessness), mood disordersRaresuicide attempt, delirium, mental impairmentNervous system disordersCommonheadaches (including migraine), sensory abnormalitiesUncommonperipheral neuropathies, dizziness, tremorRareacoustic neuritis, trigeminal neuralgia, impaired coordination or balanceNot knownmultiple sclerosis*Eye disordersUncommonvisual disorder (including decreased vision), eye and eyelid inflammation, lacrimation disorderEar and labyrinth disordersUncommonvertigoRaretinnitusCardiac disordersUncommoncardiomyopathies (including heart failure), ischaemic coronary artery disorders , arrhythmias (including atrial fibrillation), palpitationsRarepericarditis, atrioventricular blockVascular disordersCommonhypertensionUncommonhaemorrhage or bleeding (any site), hypercoagulation (including thrombophlebitis, pulmonary embolism), syncope, oedema (including peripheral, facial), ecchymoses (including haematoma, petechiae)Rarecerebrovascular accident, arteriosclerosis, Raynaud's phenomenon, livedo reticularis, telangiectasiaRespiratory, thoracic and mediastinal disordersUncommonasthma and related symptoms, pleural effusion and symptoms, respiratory tract congestion and inflammation, coughRareinterstitial lung disease, pneumonitisGastrointestinal disordersUncommonascites, gastrointestinal ulceration and perforation, gastrointestinal tract inflammation (any site), stomatitis, dyspepsia, abdominal distension, oropharyngeal drynessRaregastrointestinal fistula, odynophagia, hypermotilityHepatobiliary disordersCommonhepatitis (including hepatic enzyme increased)Uncommonhepatopathy (including cirrhosis), cholestasis, blood bilirubin increasedRarecholelithiasisSkin and subcutaneous tissue disordersCommonrashUncommonalopecia, new onset or worsening of psoriasis (including palmoplantar pustular psoriasis) and related conditions, dermatitis and eczema, sweat gland disorder, skin ulcer, photosensitivity, acne, skin discolouration, dry skin, nail and nail bed disordersRareskin exfoliation and desquamation, bullous conditions, hair texture disorderMusculoskeletal, connective tissue and bone disordersUncommonmuscle disorders, blood creatine phosphokinase increasedRenal and urinary disordersUncommonrenal impairment, blood in urine, bladder and urethral symptomsRarenephropathy (including nephritis)Reproductive system and breast disordersUncommonmenstrual cycle and uterine bleeding disorders (including amenorrhea), breast disordersRaresexual dysfunctionGeneral disorders and administration site conditionsCommonpyrexia, pain (any site), asthaenia, pruritis (any site), injection site reactionsUncommonchills, influenza-like illness, altered temperature perception, night sweats, flushingInvestigationsUncommonblood alkaline phosphatase increased, coagulation time prolongedRareblood uric acid increasedInjury, poisoning and procedural complicationsUncommonskin injuries, impaired healing*These events have been related to the class of TNF-antagonists, but incidence with Cimzia is not known.The additional following ADRs have been observed uncommonly with Cimzia in other indications: gastrointestinal stenosis and obstructions, general physical health deterioration, grand mal convulsion, optic neuritis, abortion spontaneous and azoospermia.InfectionsThe incidence of new cases of infections in placebo-controlled clinical trials in rheumatoid arthritis was 0.91 per patient-year for all Cimzia-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections.In the placebo-controlled clinical trials, there were more new cases of serious infection in the Cimzia treatment groups (0.06 per patient-year; all doses), compared with placebo (0.02 per patient-year). Serious infections included tuberculosis and invasive opportunistic infections (e.g. pneumocystosis, fungal oesophagitis, nocardiosis and herpes zoster disseminated). There is no evidence of an increased risk of infections with continued exposure over time.Malignancies and lymphoproliferative disordersExcluding 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.AutoimmunityFor 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 reactionsIn 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.

Manufacturer
UCB Pharma Limited

Drug Availability
POM – Prescription Only Medicine

Updated
24 September 2010