CIMZIA 200mg solution for injection in pre-filled syringe medication leaflet

Cimzia 200 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 200 mg certolizumab pegol in one ml.

Certolizumab pegol is a recombinant, humanised antibody Fab' fragment against tumour necrosisfactor alpha (TNFα) expressed in Escherichia coli and conjugated to polyethylene glycol (PEG).

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear to opalescent, colourless to yellow solution. The pH of the solution is approximately 4.7.

Cimzia, in combination with methotrexate (MTX), is indicated for:

* the treatment of moderate to severe, active rheumatoid arthritis (RA) in adult patients when theresponse to disease-modifying antirheumatic drugs (DMARDs) including MTX, has beeninadequate. Cimzia can be given as monotherapy in case of intolerance to MTX or whencontinued treatment with MTX is inappropriate

* the treatment of severe, active and progressive RA in adults not previously treated with MTX orother DMARDs.

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 MTX.

Cimzia is indicated for the treatment of adult patients with severe active axial spondyloarthritis,comprising:

Ankylosing spondylitis (AS) (also known as radiographic axial spondyloarthritis)

Adults with severe active ankylosing spondylitis who have had an inadequate response to, or areintolerant to nonsteroidal anti-inflammatory drugs (NSAIDs).

Axial spondyloarthritis without radiographic evidence of AS (also known as non-radiographic axialspondyloarthritis)

Adults with severe active axial spondyloarthritis without radiographic evidence of AS but withobjective signs of inflammation by elevated C-reactive protein (CRP) and /or magnetic resonanceimaging (MRI), who have had an inadequate response to, or are intolerant to NSAIDs.

Cimzia, in combination with MTX, is indicated for the treatment of active psoriatic arthritis in adultswhen the response to previous DMARD therapy has been inadequate.

Cimzia can be given as monotherapy in case of intolerance to methotrexate or when continuedtreatment with methotrexate is inappropriate.

Plaque psoriasis

Cimzia is indicated for the treatment of moderate to severe plaque psoriasis in adults who arecandidates for systemic therapy.

For details on therapeutic effects, see section 5.1.

Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis andtreatment of conditions for which Cimzia is indicated. Patients should be given the special remindercard.

Rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, plaque psoriasis

Loading dose

The recommended starting dose of Cimzia for adult patients is 400 mg (givenas 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. For rheumatoid arthritis andpsoriatic arthritis, MTX should be continued during treatment with Cimzia where appropriate.

After the starting dose, the recommended maintenance dose of Cimzia for adult patients withrheumatoid arthritis is 200 mg every 2 weeks. Once clinical response is confirmed, an alternativemaintenance dosing of 400 mg every 4 weeks can be considered. MTX should be continued duringtreatment with Cimzia where appropriate.

After the starting dose, the recommended maintenance dose of Cimzia for adult patients with axialspondyloarthritis is 200 mg every 2 weeks or 400 mg every 4 weeks. After at least 1 year of treatmentwith Cimzia, in patients with sustained remission, a reduced maintenance dose of 200 mg every 4weeks may be considered (see section 5.1).

After the starting dose, the recommended maintenance dose of Cimzia for adult patients with psoriaticarthritis is 200 mg every 2 weeks. Once clinical response is confirmed, an alternative maintenancedosing of 400 mg every 4 weeks can be considered. MTX should be continued during treatment with

Cimzia where appropriate.

For the above indications, available data suggest that clinical response is usually achievedwithin 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients whoshow no evidence of therapeutic benefit within the first 12 weeks of treatment.

Plaque psoriasis

After the starting dose, the maintenance dose of Cimzia for adult patients with plaque psoriasisis 200 mg every 2 weeks. A dose of 400 mg every 2 weeks can be considered in patients withinsufficient response (see section 5.1).

Available data in adults with plaque psoriasis suggest that a clinical response is usually achievedwithin 16 weeks of treatment. Continued therapy should be carefully reconsidered in patients whoshow no evidence of therapeutic benefit within the first 16 weeks of treatment. Some patients with aninitial partial response may subsequently improve with continued treatment beyond 16 weeks.

Patients who miss a dose should be advised to inject the next dose of Cimzia as soon as theyremember and then continue injecting subsequent doses as instructed.

Paediatric population (< 18 years old)

The safety and efficacy of Cimzia in children and adolescents below age 18 years have not yet beenestablished. No data are available.

Elderly patients (≥ 65 years old)

No dose adjustment is required. Population pharmacokinetic analyses showed no effect of age (seesection 5.2).

Cimzia has not been studied in these patient populations. No dose recommendations can be made (seesection 5.2).

The total content (1 ml) of the pre-filled syringe should be administered as a subcutaneous injectiononly. Suitable sites for injection would include the thigh or abdomen.

After proper training in injection technique, patients may self-inject using the pre-filled syringe if theirphysician determines that it is appropriate and with medical follow-up as necessary. The pre-filledsyringe with needle guard should only be used by healthcare professionals. The physician shoulddiscuss with the patient which injection presentation option is the most appropriate.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active tuberculosis or other severe infections such as sepsis or opportunistic infections (seesection 4.4).

Moderate to severe heart failure (NYHA classes III/IV) (see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Patients must be monitored closely for signs and symptoms of infections including tuberculosis before,during and after treatment with Cimzia. Because the elimination of certolizumab pegol may take upto 5 months, monitoring should be continued throughout this period (see section 4.3).

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 (see section 4.3).

Patients who develop a new infection while undergoing treatment with Cimzia should be monitoredclosely. Administration of Cimzia should be discontinued if a patient develops a new serious infectionuntil the infection is controlled. Physicians should exercise caution when considering the use of

Cimzia in patients with a history of recurring or opportunistic infection or with underlying conditionswhich may predispose patients to infections, including the use of concomitant immunosuppressivemedications.

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 indiagnosis and initiation of treatment.

Serious infections, including sepsis and tuberculosis (including miliary, disseminated andextrapulmonary disease), and opportunistic infections (e.g. histoplasmosis, nocardia, candidiasis) havebeen reported in patients receiving Cimzia. Some of these events have been fatal.

Before initiation of therapy with Cimzia, all patients must be evaluated for both active or inactive(latent) tuberculosis infection. This evaluation should include a detailed medical history for patientswith a personal history of tuberculosis, with possible previous exposure to others with activetuberculosis, and with previous and/or current use of immunosuppressive therapy. Appropriatescreening tests, e.g. tuberculin skin test and chest X-ray, should be performed in all patients (localrecommendations may apply). It is recommended that the conduct of these tests should be recorded inthe patient's reminder card. Prescribers are reminded of the risk of false negative tuberculin skin testresults, especially in patients who are severely ill or immunocompromised.

If active tuberculosis is diagnosed prior to or during treatment, Cimzia therapy must not be initiatedand must be discontinued (see section 4.3).

If inactive (‘latent’) tuberculosis is suspected, a physician with expertise in the treatment oftuberculosis should be consulted. In all situations described below, the benefit/risk balance of Cimziatherapy should be very carefully considered.

If latent tuberculosis is diagnosed, appropriate anti-tuberculosis therapy must be started beforeinitiating treatment with Cimzia and in accordance with local recommendations.

Use of anti-tuberculosis therapy should also be considered before the initiation of Cimzia in patientswith a past history of latent or active tuberculosis in whom an adequate course of treatment cannot beconfirmed, and in patients who have significant risk factors for tuberculosis despite a negative test forlatent 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.

Despite previous or concomitant prophylactic treatment for tuberculosis, cases of active tuberculosishave occurred in patients treated with TNF-antagonists including Cimzia. Some patients who havebeen successfully treated for active tuberculosis have redeveloped tuberculosis while being treatedwith Cimzia.

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 duringor after therapy with Cimzia.

Hepatitis B virus (HBV) reactivation

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including certolizumabpegol, who are chronic carriers of this virus (i.e., surface antigen positive). Some cases have had afatal outcome.

Patients should be tested for HBV infection before initiating treatment with Cimzia. For patients whotest positive for HBV infection, consultation with a physician with expertise in the treatment ofhepatitis B is recommended.

Carriers of HBV who require treatment with Cimzia should be closely monitored for signs andsymptoms of active HBV infection throughout therapy and for several months following terminationof therapy. Adequate data of treating patients who are carriers of HBV with anti-viral therapy inconjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patientswho develop HBV reactivation, Cimzia should be stopped and effective anti-viral therapy withappropriate supportive treatment should be initiated.

The 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 ofmalignancy or when considering continuing treatment in patients who develop malignancy.

With the current knowledge, a possible risk for the development of lymphomas, leukaemia or othermalignancies in patients treated with a TNF-antagonist cannot be excluded.

In clinical trials with Cimzia and other TNF-antagonists, more cases of lymphoma and othermalignancies have been reported among patients receiving TNF-antagonists than in control patientsreceiving placebo (see section 4.8). In the post marketing setting, cases of leukaemia have beenreported in patients treated with a TNF-antagonist. There is an increased background risk forlymphoma 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 continuetreatment in patients who develop malignancy, while receiving Cimzia.

Skin cancers

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-antagonistsincluding certolizumab pegol (see section 4.8). Periodic skin examination is recommended,particularly for patients with risk factors for skin cancer.

Paediatric malignancy

Malignancies, some fatal, have been reported among children, adolescents and young adults (upto 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age) in the postmarketing setting. Approximately half the cases were lymphomas. The other cases represented avariety of different malignancies and included rare malignancies usually associated withimmunosuppression. A risk for the development of malignancies in children and adolescents treatedwith TNF-antagonists cannot be excluded.

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), have been reported in patientstreated with TNF-antagonists. This rare type of T-cell lymphoma has a very aggressive disease courseand is usually fatal. The majority of reported TNF-antagonist cases occurred in adolescent and youngadult males with Crohn’s disease or ulcerative colitis. Almost all of these patients had receivedtreatment with the immunosuppressants azathioprine and/or 6-mercaptopurine concomitantly with a

TNF-antagonist at or prior to diagnosis. A risk for development of hepatosplenic T-cell lymphoma inpatients treated with Cimzia cannot be excluded.

Chronic obstructive pulmonary disease (COPD)

In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patientswith moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly inthe 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 toheavy smoking.

Cimzia is contraindicated in moderate or severe heart failure (see section 4.3). In a clinical trial withanother TNF-antagonist, worsening congestive heart failure and increased mortality due to congestiveheart failure have been observed. Cases of congestive heart failure have also been reported inrheumatoid arthritis patients receiving Cimzia. Cimzia should be used with caution in patients withmild heart failure (NYHA class I/II). Treatment with Cimzia must be discontinued in patients whodevelop new or worsening symptoms of congestive heart failure.

Reports of pancytopaenia, including aplastic anaemia, have been rare with TNF-antagonists. Adversereactions of the haematologic system, including medically significant cytopaenia (e.g. leukopaenia,pancytopaenia, thrombocytopaenia) have been reported with Cimzia (see section 4.8). All patientsshould be advised to seek immediate medical attention if they develop signs and symptoms suggestiveof 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 significanthaematological abnormalities.

Use of TNF-antagonists has been associated with rare cases of new onset or exacerbation of clinicalsymptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis. Inpatients 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. Rarecases of neurological disorders, including seizure disorder, neuritis and peripheral neuropathy, havebeen reported in patients treated with Cimzia.

Severe hypersensitivity reactions have been reported rarely following Cimzia administration. Some ofthese reactions occurred after the first administration of Cimzia. 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 hypersensitivityreaction towards another TNF-antagonist; in these patients caution is needed.

Latex-sensitivity

The needle shield inside the removable cap of the CIMZIA pre-filled syringe contains a derivative ofnatural rubber latex (see section 6.5). Contact with natural rubber latex may cause severe allergicreactions in individuals sensitive to latex. No antigenic latex protein has to date been detected in theremovable needle cap of the Cimzia pre-filled syringe. Nevertheless, a potential risk ofhypersensitivity reactions cannot be completely excluded in latex-sensitive individuals.

Since tumour necrosis factor (TNF) mediates inflammation and modulates cellular immune responses,the possibility exists for TNF-antagonists, including Cimzia, to cause immunosupression, affectinghost defences against infections and malignancies.

Autoimmunity

Treatment with Cimzia may result in the formation of antinuclear antibodies (ANA) and,uncommonly, in the development of a lupus-like syndrome (see section 4.8). The impact of long-termtreatment with Cimzia on the development of autoimmune diseases is unknown. If a patient developssymptoms suggestive of a lupus-like syndrome following treatment with Cimzia, treatment must bediscontinued. Cimzia has not been studied specifically in a lupus population (see section 4.8).

Patients treated with Cimzia may receive vaccinations, except for live vaccines. No data are availableon the response to live vaccinations or the secondary transmission of infection by live vaccines inpatients receiving Cimzia. Live vaccines should not be administered concurrently with Cimzia.

In a placebo-controlled clinical trial in patients with rheumatoid arthritis, similar antibody responsebetween Cimzia and placebo treatment were observed when the pneumococcal polysaccharide vaccineand influenza vaccine were administered concurrently with Cimzia. Patients receiving Cimzia andconcomitant methotrexate had a lower humoral response compared with patients receiving Cimziaalone. The clinical significance of this is unknown.

Concomitant use with other biologics

Severe infections and neutropaenia were reported in clinical trials with concurrent use of anakinra (aninterleukin-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 adverseevents 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 certolizumab pegol in combination with anakinra or abataceptis not recommended (see section 4.5).

There is limited safety experience with surgical procedures in patients treated with Cimzia. The 14-dayhalf-life of certolizumab pegol should be taken into consideration if a surgical procedure is planned. Apatient who requires surgery while on Cimzia should be closely monitored for infections, andappropriate actions should be taken.

Activated partial thromboplastin time (aPTT) assay

Interference with certain coagulation assays has been detected in patients treated with Cimzia. Cimziamay cause erroneously elevated aPTT assay results in patients without coagulation abnormalities. Thiseffect 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 aPTTassays may be affected as well. There is no evidence that Cimzia therapy has an effect on coagulationin vivo. After patients receive Cimzia, careful attention should be given to interpretation of abnormalcoagulation results. Interference with thrombin time (TT) and prothrombin time (PT) assays have notbeen observed.

In the clinical trials, there was an apparently higher incidence of infections among subjects ≥ 65 yearsof age, compared to younger subjects, although experience is limited. Caution should be exercisedwhen treating the elderly patients, and particular attention paid with respect to occurrence ofinfections.

Concomitant treatment with methotrexate, corticosteroids, nonsteroidal anti-inflammatory drugs(NSAIDs) and analgesics showed no effect on the pharmacokinetics of certolizumab pegol based on apopulation pharmacokinetics analysis.

The combination of certolizumab pegol and anakinra or abatacept is not recommended (seesection 4.4).

Co-administration of Cimzia with methotrexate had no significant effect on the pharmacokinetics ofmethotrexate. In study-to-study comparison, the pharmacokinetics of certolizumab pegol appearedsimilar to those observed previously in healthy subjects.

The use of adequate contraception should be considered for women of childbearing potential. Forwomen planning pregnancy, the clinical need for ongoing Cimzia treatment should be evaluated. If thedecision is made to clear Cimzia from the body prior to conception, contraception should be continuedfor 5 months after the last Cimzia dose (see section 5.2).

Human data

A large amount of data (more than 1500 pregnancies exposed to Cimzia during the first trimester)from prospectively reported pregnancies with known pregnancy outcomes, indicate no malformativenor feto/neonatal toxicity. Continuous data collection is ongoing with pharmacovigilance casesreporting and a pregnancy registry.

In a pregnancy register (the OTIS study) the proportion of major birth defects in live-born infants was15/132 (11.4%) in women treated with Cimzia at least during the first trimester, and 8/126 (6.3%) inwomen with the same indicated diseases but not treated with Cimzia (relative risk 1.85; 95% CI 0.74to 4.60). A similar association was seen when women treated with Cimzia were compared with womennot having a disease consistent with approved Cimzia indications (proportion 10/126 [7.9%] andrelative risk 1.65; 95% CI 0.75 to 3.64). No pattern of major or minor defects was identified.

There were no distinct differences between the Cimzia treated group and both comparison groups forspontaneous abortion, serious or opportunistic infections, hospitalization, adverse vaccine reactions, inthe children who were followed up for up to 5 years of age. No stillbirths or termination were reportedin the Cimzia arm while 2 stillbirths and 3 pregnancy terminations were reported in the diseaseunexposed arm. The interpretation of data may be impacted due to methodological limitations of thestudy, including small sample size and non-randomized design.

In a clinical study of 21 women receiving Cimzia during pregnancy, certolizumab pegol plasmaconcentrations were within the range of concentrations observed in non-pregnant adult patients (seesection 5.2).

In a clinical study 16 women were treated with certolizumab pegol (200 mg every 2 weeks or 400 mgevery 4 weeks) during pregnancy. Certolizumab pegol plasma concentrations measured in 14 infants atbirth were Below the Limit of Quantification (BLQ) in 13 samples; one was 0.042 µg/ml with aninfant/mother plasma ratio at birth of 0.09%. At Week 4 and Week 8, all infant concentrations were

BLQ. The clinical significance of low levels certolizumab pegol for infants is unknown. It isrecommended to wait a minimum of 5 months following the mother’s last Cimzia administrationduring pregnancy before administration of live or live-attenuated vaccines (e.g. BCG vaccine), unlessthe benefit of the vaccination clearly outweighs the theoretical risk of administration of live or live-attenuated vaccines to the infants.

Animal data

Animal studies using a rodent anti-rat TNFα did not reveal evidence of impaired fertility or harm tothe foetus. However, these are insufficient with respect to human reproductive toxicity (seesection 5.3). Due to its inhibition of TNFα, Cimzia administered during pregnancy could affect normalimmune response in the newborn.

Non-clinical studies suggest low or negligible level of placental transfer of a homologue Fab-fragmentof certolizumab pegol (no Fc region) (see section 5.3).

Cimzia should only be used during pregnancy if clinically needed. No dose adjustment is needed.

Cimzia can be used during breastfeeding.

In a clinical study in 17 lactating women treated with Cimzia, minimal transfer of certolizumab pegolfrom plasma to breast milk was observed. The percentage of the maternal certolizumab pegol dosereaching an infant during a 24 hour period was estimated to 0.04% to 0.30 %. In addition, sincecertolizumab pegol is a protein that is degraded in the gastrointestinal tract after oral administration,the absolute bioavailability is expected to be very low in a breastfed infant.

Effects on sperm motility measures and a trend of reduced sperm count in male rodents have beenobserved with no apparent effect on fertility (see section 5.3).

In a clinical trial to assess the effect of certolizumab pegol on semen quality parameters, 20 healthymale subjects were randomized to receive a single subcutaneous dose of 400 mg of certolizumab pegolor placebo. During the 14-week follow-up, no treatment effects of certolizumab pegol were seen onsemen quality parameters compared to placebo.

Cimzia may have a minor influence on the ability to drive and use machines. Dizziness (includingvertigo, vision disorder and fatigue) may occur following administration of Cimzia (see section 4.8).

Cimzia was studied in 4,049 patients with rheumatoid arthritis in controlled and open label trials forup to 92 months.

In the placebo-controlled studies, patients receiving Cimzia had an approximately 4 times greaterduration of exposure compared with the placebo group. This difference in exposure is primarily due topatients on placebo being more likely to withdraw early. In addition, Studies RA-I and RA-II had amandatory 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 controlledtrials was 4.4% for patients treated with Cimzia and 2.7% for patients treated with placebo.

The most common adverse reactions belonged to the system organ classes Infections and infestations,reported in 14.4% of patients on Cimzia and 8.0% of patients on placebo, General disorders andadministration site conditions, reported in 8.8% of patients on Cimzia and 7.4% of patients on placebo,and Skin and subcutaneous tissue disorders, reported in 7.0% of patients on Cimzia and 2.4% ofpatients on placebo.

Cimzia was initially studied in 325 patients with active axial spondyloarthritis (including ankylosingspondylitis and non-radiographic axial spondyloarthritis) in the AS001 clinical study for up to 4 years,which includes a 24-week placebo-controlled phase followed by a 24-week dose-blind period anda 156-week open-label treatment period. Cimzia was subsequently studied in 317 patients with non-radiographic axial spondyloarthritis in a placebo-controlled study for 52 weeks (AS0006). Cimzia wasalso studied in patients with axial spondyloarthritis (including ankylosing spondylitis and non-radiographic axial spondyloarthritis) in a clinical study for up to 96 weeks, which included a 48-weekopen-label run-in phase (N=736) followed by a 48-week placebo-controlled phase (N=313) forpatients in sustained remission (C-OPTIMISE). Cimzia was also studied in a 96-week open-labelstudy in 89 axSpA patients with a history of documented anterior uveitis flares. In all 4 studies, thesafety profile for these patients was consistent with the safety profile in rheumatoid arthritis andprevious experience with Cimzia.

Cimzia was studied in 409 patients with psoriatic arthritis in the PsA001 clinical study for upto 4 years which includes a 24-week placebo-controlled phase followed by a 24-week dose-blindperiod and a 168-week open-label treatment period. The safety profile for psoriatic arthritis patientstreated with Cimzia was consistent with the safety profile in rheumatoid arthritis and previousexperience with Cimzia.

Plaque psoriasis

Cimzia was studied in 1112 patients with psoriasis in controlled and open-label studies for up to 3years. In the Phase III program, the initial and maintenance periods were followed by a 96-week open-label treatment period (see section 5.1). The long-term safety profile of Cimzia 400 mg every 2 weeksand Cimzia 200 mg every 2 weeks was generally similar and consistent with previous experience with

Cimzia.

During controlled clinical trials through Week 16, the proportion of patients with serious adverseevents was 3.5% for Cimzia and 3.7% for placebo.

The proportion of patients who discontinued treatment due to adverse events in the controlled clinicalstudies was 1.5% for patients treated with Cimzia and 1.4% for patients treated with placebo.

The most common adverse reactions reported through Week 16 belonged to the system organ classes

Infections and infestations, reported in 6.1% of patients on Cimzia and 7% of patients on placebo,

General disorders and administration site conditions, reported in 4.1% of patients on Cimzia and 2.3%of patients on placebo, and Skin and subcutaneous tissue disorders, reported in 3.5% of patients on

Cimzia and 2.8% of patients on placebo.

Adverse reactions based primarily on experience from the placebo-controlled clinical trials andpostmarketing cases at least possibly related to Cimzia are listed in Table 1 below, according tofrequency 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 availabledata). Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness.

Table 1 Adverse reactions in clinical trials and postmarketing

System Organ Class Frequency Adverse reactions

Infections and Common bacterial infections (including abscess), viral infectionsinfestations (including herpes zoster, papillomavirus, influenza)

Uncommon sepsis (including multi-organ failure, septic shock),tuberculosis (including miliary, disseminated andextrapulmonary disease), fungal infections (includesopportunistic)

Neoplasms benign, Uncommon blood and lymphatic system malignancies (includingmalignant and lymphoma and leukaemia), solid organ tumours, non-unspecified (including melanoma skin cancers, pre-cancerous lesions (includingcysts and polyps) oral leukoplakia, melanocytic nevus), benign tumoursand cysts (including skin papilloma)

Rare gastrointestinal tumours, melanoma

Not known Merkel cell carcinoma*, Kaposi’s sarcoma

Blood and the lymphatic Common eosinophilic disorders, leukopaenia (includingsystem disorders neutropaenia, lymphopaenia)

Uncommon anaemia, lymphadenopathy, thrombocytopaenia,thrombocytosis

Rare pancytopaenia, splenomegaly, erythrocytosis, whiteblood cell morphology abnormal

Immune system disorders Uncommon vasculitides, lupus erythematosus, drug hypersensitivity(including anaphylactic shock), allergic disorders,auto-antibody positive

Rare angioneurotic oedema, sarcoidosis, serum sickness,panniculitis (including erythema nodosum), worsening ofsymptoms of dermatomyositis**

Endocrine disorders Rare thyroid disorders

Metabolism and nutrition Uncommon electrolyte imbalance, dyslipidaemia, appetite disorders,disorders weight change

Rare haemosiderosis

Psychiatric disorders Uncommon anxiety and mood disorders (including associatedsymptoms)

Rare suicide attempt, delirium, mental impairment

System Organ Class Frequency Adverse reactions

Nervous system disorders Common headaches (including migraine), sensory abnormalities

Uncommon peripheral neuropathies, dizziness, tremor

Rare seizure, cranial nerve inflammation, impairedcoordination or balance

Not known multiple sclerosis*, Guillain-Barré syndrome*

Eye disorders Uncommon visual disorder (including decreased vision), eye andeyelid inflammation, lacrimation disorder

Ear and labyrinth Uncommon tinnitus, vertigodisorders

Cardiac disorders Uncommon cardiomyopathies (including heart failure), ischaemiccoronary artery disorders, arrhythmias (including atrialfibrillation), palpitations

Rare pericarditis, atrioventricular block

Vascular disorders Common hypertension

Uncommon haemorrhage or bleeding (any site), hypercoagulation(including thrombophlebitis, pulmonary embolism),syncope, oedema (including peripheral, facial),ecchymoses (including haematoma, petechiae)

Rare cerebrovascular accident, arteriosclerosis, Raynaud’sphenomenon, livedo reticularis, telangiectasia

Respiratory, thoracic and Uncommon asthma and related symptoms, pleural effusion andmediastinal disorders symptoms, respiratory tract congestion andinflammation, cough

Rare interstitial lung disease, pneumonitis

Gastrointestinal disorders Common nausea

Uncommon ascites, gastrointestinal ulceration and perforation,gastrointestinal tract inflammation (any site), stomatitis,dyspepsia, abdominal distension, oropharyngeal dryness

Rare odynophagia, hypermotility

Hepatobiliary disorders Common hepatitis (including hepatic enzyme increased)

Uncommon hepatopathy (including cirrhosis), cholestasis, bloodbilirubin increased

Rare cholelithiasis

Skin and subcutaneous Common rashtissue disorders Uncommon alopecia, new onset or worsening of psoriasis (includingpalmoplantar pustular psoriasis) and related conditions,dermatitis and eczema, sweat gland disorder, skin ulcer,photosensitivity, acne, skin discolouration, dry skin, nailand nail bed disorders

Rare skin exfoliation and desquamation, bullous conditions,hair texture disorder, Stevens-Johnson syndrome**,erythema multiforme**, lichenoid reactions

Musculoskeletal, Uncommon muscle disorders, blood creatine phosphokinaseconnective tissue and increasedbone disorders

Renal and urinary Uncommon renal impairment, blood in urine, bladder and urethraldisorders symptoms

Rare nephropathy (including nephritis)

Reproductive system and Uncommon menstrual cycle and uterine bleeding disorders (includingbreast disorders amenorrhea), breast disorders

Rare sexual dysfunction

General disorders and Common pyrexia, pain (any site), asthaenia, pruritus (any site),administration site injection site reactionsconditions Uncommon chills, influenza-like illness, altered temperatureperception, night sweats, flushing

System Organ Class Frequency Adverse reactions

Rare fistula (any site)

Investigations Uncommon blood alkaline phosphatase increased, coagulation timeprolonged

Rare blood uric acid increased

Injury, poisoning and Uncommon skin injuries, impaired healingprocedural complications

*These events have been related to the class of TNF-antagonists, but incidence with certolizumabpegol is not known.

**These events have been related to the class of TNF-antagonists.

The additional following adverse reactions have been observed uncommonly with Cimzia in otherindications: gastrointestinal stenosis and obstructions, general physical health deterioration, abortionspontaneous and azoospermia.

The incidence rate of new cases of infections in placebo-controlled clinical trials in rheumatoidarthritis was 1.03 per patient-year for all Cimzia-treated patients and 0.92 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, urinary tractinfections, and lower respiratory tract infections and herpes viral infections (see sections 4.3 and 4.4).

In the placebo-controlled clinical trials in rheumatoid arthritis, there were more new cases of seriousinfection in the Cimzia treatment groups (0.07 per patient-year; all doses), compared with placebo(0.02 per patient-year). The most frequent serious infections included pneumonia, tuberculosisinfections. Serious infections also included invasive opportunistic infections (e.g. pneumocystosis,fungal oesophagitis, nocardiosis and herpes zoster disseminated). There is no evidence of an increasedrisk of infections with continued exposure over time (see section 4.4).

The incidence rate of new cases of infections in placebo-controlled clinical trials in psoriasiswas 1.37 per patient-year for all Cimzia-treated patients and 1.59 per patient-year for placebo-treatedpatients. The infections consisted primarily of upper respiratory tract infections and viral infections(including herpes infections). The incidence of serious infections was 0.02 per patient-year in Cimziatreated patients. No serious infections were reported in the placebo-treated patients. There is noevidence of an increased risk of infections with continued exposure over time.

Excluding non-melanoma of the skin, 121 malignancies including 5 cases of lymphoma were observedin the Cimzia RA clinical trials in which a total of 4,049 patients were treated,representing 9,277 patient-years. Cases of lymphoma occurred at an incidence rateof 0.05 per 100 patient-years and melanoma at an incidence rate of 0.08 per 100 patient-years with

Cimzia in rheumatoid arthritis clinical trials (see section 4.4). One case of lymphoma was alsoobserved in the Phase III psoriatic arthritis clinical trial.

Excluding non-melanoma skin cancer, 11 malignancies including 1 case of lymphoma were observedin the Cimzia psoriasis clinical trials in which a total of 1112 patients were treated, representing 2300patient-years.

Autoimmunity

In the rheumatoid arthritis pivotal studies, for subjects who were ANA negative at baseline, 16.7% ofthose treated with Cimzia developed positive ANA titers, compared with 12.0% of subjects in theplacebo group. For subjects who were anti-dsDNA antibody negative at baseline, 2.2% of those treatedwith Cimzia developed positive anti-dsDNA antibody titers, compared with 1.0% of subjects in theplacebo group. In both placebo-controlled and open-label follow-up clinical trials for rheumatoidarthritis, cases of lupus-like syndrome were reported uncommonly. There have been rare reports ofother immune-mediated conditions; the causal relationship to Cimzia is not known. The impact oflong-term treatment with Cimzia on the development of autoimmune diseases is unknown.

In the placebo-controlled rheumatoid arthritis clinical trials, 5.8% of patients treated with Cimziadeveloped injection site reactions such as erythema, itching, haematoma, pain, swelling or bruising,compared to 4.8% of patients receiving placebo. Injection site pain was observed in 1.5% of patientstreated with Cimzia with no cases leading to withdrawal.

Creatine phosphokinase elevations

The frequency of creatine phosphokinase (CPK) elevations was generally higher in patients withaxSpA as compared to the RA population. The frequency was increased both in patients treated withplacebo (2.8% vs 0.4% in axSpA and RA populations, respectively) as well as in patients treated with

Cimzia (4.7% vs 0.8% in axSpA and RA populations, respectively). The CPK elevations in the axSpAstudy were mostly mild to moderate, transient in nature and of unknown clinical significance with nocases leading to withdrawal.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No dose-limiting toxicity was observed during clinical trials. Multiple doses of up to 800 mgsubcutaneously and 20 mg/kg intravenously have been administered. In cases of overdose, it isrecommended that patients are monitored closely for any adverse reactions or effect, and appropriatesymptomatic treatment initiated immediately.

Pharmacotherapeutic group: immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors,

ATC code: L04AB05

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. Cimziaselectively 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-dependentmanner. Incubation of monocytes with Cimzia resulted in a dose-dependent inhibition oflipopolysaccharide (LPS)-induced TNFα and IL1β production in human monocytes.

Cimzia does not contain a fragment crystallisable (Fc) region, which is normally present in a completeantibody, and therefore does not fix complement or cause antibody-dependent cell-mediatedcytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derivedmonocytes or lymphocytes, or neutrophil degranulation.

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 accordingto American College of Rheumatology (ACR) criteria, RA-I (RAPID 1) and RA-II (RAPID 2).

Patients had ≥ 9 swollen and tender joints each and had active RA for at least 6 months prior tobaseline. Cimzia was administered subcutaneously in combination with oral MTX for a minimumof 6 months with stable doses of at least 10 mg weekly for 2 months in both trials. There is noexperience with Cimzia in combination with DMARDs other than MTX.

The efficacy and safety of Cimzia was assessed in DMARD-naïve adult patients with active RA in arandomized, placebo-controlled, double-blind clinical trial (C-EARLY). In the C-EARLY trial patientswere ≥ 18 years of age and had ≥ 4 swollen and tender joints each and must have been diagnosed withmoderate to severe active and progressive RA within 1 year (as defined by the 2010 ACR/European

League Against Rheumatism (EULAR) classification criteria). Patients had a mean time sincediagnosis at baseline of 2.9 months and were DMARD naïve (including MTX). For both the Cimziaand placebo arms, MTX was initiated as of Week 0 (10 mg/week), titrated up to maximum tolerateddose by Week 8 (min 15 mg/week, max 25 mg/week allowed), and maintained throughout the study(average dose of MTX after Week 8 for placebo and Cimzia was 22.3 mg/week and 21.1 mg/weekrespectively).

Table 2 Clinical trial description

Study Patient Active dose regimen Study objectivesnumber numbers

RA-I 982 400 mg (0,2,4 weeks) Evaluation for treatment of signs and(52 weeks) with MTX symptoms and inhibition of structural damage.

200 mg or 400 mg Co-primary endpoints: ACR 20 at Week 24 andevery 2 weeks with MTX change from baseline in mTSS at Week 52

RA-II 619 400 mg (0,2,4 weeks) Evaluation for treatment of signs and(24 weeks) with MTX symptoms and inhibition of structural damage.

200 mg or 400 mg Primary endpoint: ACR 20 at Week 24.every 2 weeks with

MTX

C-EARLY 879 400 mg (0,2,4 weeks) Evaluation for treatment of signs and(to 52 wee with MTX symptoms and inhibition of structural damageks) 200 mg every 2 weeks in DMARD naïve patients.with MTX Primary endpoint: proportion of subjects insustained remission* at Week 52mTSS: modified Total Sharp Score

*Sustained remission at Week 52 is defined as DAS28[ESR] <2.6 at both Week 40 and Week 52.

Signs and symptoms

The results of clinical trials RA-I and RA-II are shown in Table 3. Statistically significantly greater

ACR 20 and ACR 50 responses were achieved from Week 1 and Week 2, respectively, in both clinicaltrials compared to placebo. Responses were maintained through Weeks 52 (RA-I) and 24 (RA-II). Ofthe 783 patients initially randomised to active treatment in RA-I, 508 completed 52 weeks of placebo-controlled treatment and entered the open-label extension study. Of these, 427 completed 2 years ofopen-label follow-up and thus had a total exposure to Cimzia of 148 weeks overall. The observed

ACR 20 response rate at this timepoint was 91%.The reduction (RA-I) from Baseline in DAS28 (ESR)also was significantly greater (p<0.001) at Week 52 (RA-I) and Week 24 (RA-II) compared to placeboand maintained through 2 years in the open-label extension trial to RA-I.

Table 3 ACR response in clinical trials RA-I and RA-II

Study RA-I Study RA-II

Methotrexate combination Methotrexate combination(24 and 52 weeks) (24 weeks)

Response Placebo + MTX Cimzia Placebo + MTX Cimzia200 mg + MTX 200 mg + MTX

N=199 every 2 weeks N=127 every 2 weeks

N=393 N=246

ACR 20

Week 24 14% 59%** 9% 57%**

Week 52 13% 53%** N/A N/A

ACR 50

Week 24 8% 37%** 3% 33%**

Week 52 8% 38%** N/A N/A

ACR 70

Week 24 3% 21%** 1% 16%*

Week 52 4% 21%** N/A N/A

Major 1% 13%**

Clinical

Responsea.

Cimzia vs. placebo: *p≤0.01, ** p<0.001

a. Major clinical response is defined as achieving ACR 70 response at every assessment over acontinuous 6-month period

Wald p-values are quoted for the comparison of treatments using logistic regression with factors fortreatment and region.

Percentage response based upon number of subjects contributing data (n) to that endpoint and timepoint which may differ from N

The C-EARLY trial met its primary and key secondary endpoints. The key results from the study arepresented in table 4.

Table 4: C-EARLY trial: percent of patients in sustained remission and sustained low diseaseactivity at Week 52

Response Placebo+MTX Cimzia 200 mg + MTX

N= 213 N= 655

Sustained remission* 15.0 % 28.9%**(DAS28(ESR) <2.6 at both Week 40 and Week 52)

Sustained low disease activity 28.6 % 43.8%**(DAS28(ESR) ≤3.2 at both Week 40 and Week 52)

*Primary endpoint of C-EARLY trial (to Week 52)

Full analysis set, non-responder imputation for missing values.

**Cimzia+MTX vs placebo+MTX: p<0.001p value was estimated from a logistic regression model with factors for treatment, region, and timesince RA diagnosis at Baseline (≤4 months vs >4 months)

Patients in the Cimzia+MTX group had a greater reduction from baseline in DAS 28 (ESR) comparedwith the placebo+MTX group observed as early as Week 2 and continued through

Week 52 (p<0.001 at each visit). Assessments on remission (DAS28(ESR) <2.6), Low Disease

Activity (DAS28(ESR) ≤3.2) status, ACR50 and ACR 70 by visit demonstrated that Cimzia+MTXtreatment led to faster and greater responses than PBO+MTX treatment. These results were maintainedover 52 weeks of treatment in DMARD-naïve subjects.

In RA-I, structural joint damage was assessed radiographically and expressed as change in mTSS andits components, the erosion score and joint space narrowing (JSN) score, at Week 52, compared tobaseline. Cimzia patients demonstrated significantly less radiographic progression than patientsreceiving placebo at Week 24 and Week 52 (see Table 5). In the placebo group, 52% of patientsexperienced no radiographic progression (mTSS ≤ 0.0) at Week 52 compared to 69% in the

Cimzia 200 mg treatment group.

Table 5 Changes over 12 months in RA-I

Placebo + MTX Cimzia 200 mg + MTX Cimzia 200 mg + MTX -

N=199 N=393 Placebo + MTX

Mean (SD) Mean (SD) Mean DifferencemTSS

Week 52 2.8 (7.8) 0.4 (5.7) -2.4

Erosion Score

Week 52 1.5 (4.3) 0.1 (2.5) -1.4

JSN Score

Week 52 1.4 (5.0) 0.4 (4.2) -1.0p-values were < 0.001 for both mTSS and erosion score and ≤ 0.01 for JSN score. An ANCOVAwas fitted to the ranked change from baseline for each measure with region and treatment as factorsand rank baseline as a covariate.

Of the 783 patients initially randomised to active treatment in RA-I, 508 completed 52 weeks ofplacebo-controlled treatment and entered the open-label extension study. Sustained inhibition ofprogression of structural damage was demonstrated in a subset of 449 of these patients who completedat least 2 years of treatment with Cimzia (RA-I and open-label extension study) and had evaluable dataat the 2-year timepoint.

In C-EARLY, Cimzia+ MTX inhibited the radiographic progression compared to placebo+MTX at

Week 52 (see Table 6). In the placebo+MTX group, 49.7% of patients experienced no radiographicprogression (change in mTSS ≤0.5) at Week 52 compared to 70.3% in the Cimzia+MTX group(p<0.001).

Table 6 Radiographic change at Week 52 in trial C-EARLY

Placebo +MTX Cimzia 200 mg + MTX Cimzia 200 mg + MTX -

N= 163 N = 528 Placebo +MTX

Mean (SD) Mean (SD) Difference*mTSS 1.8 (4.3) 0.2 (3.2)** -0.978 (-1.005, -0.500)

Week 52

Erosion score 1.1 (3.0) 0.1 (2.1)** -0.500 (-0.508, -0.366)

Week 52

JSN score 0.7 (2.3) 0.1 (1.7)** 0.000 (0.000, 0.000)

Week 52

Radiographic set with linear extrapolation.

* Hodges-Lehmann point estimate of shift and 95% asymptotic (Moses) confidence interval.

**Cimzia+MTX vs placebo+MTX p<0.001. p value was estimated from an ANCOVA model on theranks with treatment, region, time since RA diagnosis at Baseline (≤4 months vs >4 months) asfactors and Baseline rank as a covariate.

Physical function response and health-related outcomes

In RA-I and RA-II, Cimzia-treated patients reported significant improvements in physical function asassessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and in tiredness(fatigue) as reported by the Fatigue Assessment Scale (FAS) from Week 1 through to the end of thestudies compared to placebo. In both clinical trials, Cimzia-treated patients reported significantlygreater improvements in the SF-36 Physical and Mental Component Summaries and all domain scores.

Improvements in physical function and HRQoL were maintained through 2 years in the open-labelextension to RA-I. Cimzia-treated patients reported statistically significant improvements in the Work

Productivity Survey compared to placebo.

In C-EARLY, Cimzia+MTX-treated patients reported significant improvements at Week 52 comparedto placebo+MTX in pain as assessed by the Patient Assessment of Arthritis Pain (PAAP) - 48,5 vs

- 44,0 (least square mean) (p<0.05).

DoseFlex clinical trial

The efficacy and safety of 2 dose regimens (200 mg every 2 weeks and 400 mg every 4 weeks) of

Cimzia versus placebo were assessed in an 18-week, open-label, run-in, and 16-week randomised,double-blind, placebo-controlled clinical trial in adult patients with active rheumatoid arthritisdiagnosed according to the ACR criteria who had inadequate response to MTX.

Patients received loading doses of Cimzia 400 mg at weeks 0, 2, and 4 followed by Cimzia 200 mgevery 2 weeks during the initial open label period. Responders (achieved ACR 20) at week 16 wererandomised at week 18 to Cimzia 200 mg every 2 weeks, Cimzia 400 mg every 4 weeks, or placebo incombination with MTX for an additional 16 weeks (total trial length: 34 weeks). These 3 groups werewell balanced with regards to clinical response following the active run-in period (ACR 20: 83-84% atweek 18).

The primary endpoint of the study was the ACR 20 responder rate at week 34. The results atweek 34 are shown in Table 7. Both Cimzia regimens showed sustained clinical response and werestatistically significant compared to placebo at week 34. The ACR 20 endpoint was achieved for both

Cimzia 200 mg every 2 weeks and 400 mg every 4 weeks.

Table 7 ACR response in DoseFlex clinical trial at week 34

Treatment regimen week 0 to 16 Cimzia 400 mg + MTX at week 0, 2 and 4, followed by

Cimzia 200 mg + MTX every 2 weeks

Randomised, double-blind Placebo + MTX Cimzia Cimziatreatment regimen 200 mg + MTX 400 mg + MTXweek 18 to 34 every 2 weeks every 4 weeks

N=69 N=70 N=69

ACR 20 45% 67% 65%p-value* N/A 0.009 0.017

ACR 50 30% 50% 52%p-value* N/A 0.020 0.010

ACR 70 16% 30% 38%p-value* N/A 0.052 0.005

N/A: Not Applicable

*Wald p-values for Cimzia 200 mg vs. placebo and Cimzia 400 mg vs. placebo comparisons areestimated from a logistic regression model with factors for treatment

Axial spondyloarthritis (non-radiographic axial spondyloarthritis and ankylosing spondylitissubpopulations)

AS001

The efficacy and safety of Cimzia were assessed in one multicenter, randomized, double-blind,placebo-controlled trial (AS001) in 325 patients ≥18 years of age with adult-onset active axialspondyloarthritis for at least 3 months as defined by the Assessment of Spondyloarthritis International

Society (ASAS) Classification Criteria for axial spondyloarthritis. The axial spondyloarthritis overallpopulation included subpopulations with and without (non-radiographic axial spondyloarthritis [nr-axSpA]) radiographic evidence for ankylosing spondylitis (AS) (also known as radiographic axialspondyloarthritis). Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease

Activity Index (BASDAI) ≥ 4, spinal pain ≥ 4 on a 0 to 10 Numerical Rating Scale (NRS) andincreased CRP or current evidence of sacroiliitis on Magnetic Resonance Imaging (MRI). Patientsmust have been intolerant to or had an inadequate response to at least one NSAID. Overall, 16% ofpatients had prior TNF-antagonist exposure. Patients were treated with a loading dose of

Cimzia 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either 200 mg of

Cimzia every 2 weeks or 400 mg of Cimzia every 4 weeks or placebo. 87.7% of patients receivedconcomitant NSAIDs. The primary efficacy endpoint was the ASAS20 response rate at Week 12.

The 24-week double-blind, placebo-controlled treatment period of the study was followed by a 24-week dose-blind treatment period, and a 156-week open-label treatment period. The maximumduration of the study was 204 weeks. All patients received Cimzia in both the dose-blind and open-label follow-up periods. A total of 199 subjects (61.2% of randomized subjects) completed the studythrough Week 204.

Key efficacy outcomes

In AS001 clinical trial, at Week 12 ASAS20 responses were achieved by 58% of patients receiving

Cimzia 200 mg every 2 weeks and 64% of patients receiving Cimzia 400 mg every 4 weeks ascompared to 38% of patients receiving placebo (p<0.01). In the overall population, the percentage of

ASAS20 responders was clinically relevant and significantly higher for the Cimzia 200 mgevery 2 weeks and Cimzia 400 mg every 4 weeks treatment groups compared to placebo group atevery visit from Week 1 through Week 24 (p≤0.001 at each visit). At Weeks 12 and 24, the percentageof subjects with an ASAS40 response was greater in the Cimzia-treated groups compared to placebo.

Similar results were achieved in both the ankylosing spondylitis and non-radiographic axialspondyloarthritis subpopulations. In women, ASAS20 responses were not statistically significantlydifferent from placebo until after the Week 12 time point.

Improvements in ASAS5/6, Partial Remission and BASDAI-50 were statistically signficant at

Week 12 and Week 24 and were sustained up to Week 48 in the overall popualtion as well as in thesubpopulations. Key efficacy outcomes from the AS001 clinical trial are shown in Table -8. Amongpatients remaining in the study, improvements in all afore-mentioned key efficacy outcomes weremaintained through Week 204 in the overall population as well as in the subpopulations.

Table 8 Key efficacy outcomes in AS001 clinical trial (percent of patients)

Ankylosing spondylitis Non-radiographic Axial spondyloarthritisaxial Overall Population

Parameters spondyloarthritits

Placebo Cimzia Placeb Cimzia all Placebo Cimzia all dosing

N=57 all dosing o dosing N=107 regimens(a)regimens(a) N=50 regimens(a) N=218

N=121 N=97

ASAS20(b,c)

Week 12 37% 60%* 40% 61%* 38% 61%**

Week 24 33% 69%** 24% 68%** 29% 68%**

ASAS40(c,d)

Week 12 19% 45%** 16% 47%** 18% 46%**

Week 24 16% 53%** 14% 51%** 15% 52%**

ASAS 5/6(c,d)

Week 12 9% 42%** 8% 44%** 8% 43%**

Week 24 5% 40%** 4% 45%** 5% 42%**

Partialremission(c,d) 2% 20%** 6% 29%** 4% 24%**

Week 12 7% 28%** 10% 33%** 9% 30%**

Week 24

BASDAI 50(c,d)

Week 12 11% 41%** 16% 49%** 13% 45%**

Week 24 16% 49%** 20% 57%** 18% 52%**(a) Cimzia all dosing regimen = data from Cimzia 200 mg administered every 2 weeks preceded by aloading dose of 400 mg at Weeks 0, 2 and 4 plus Cimzia 400 mg administered every 4 weekspreceded by a loading dose of 400 mg at Weeks 0, 2 and 4(b) Results are from the randomized set(c) Wald p-values are quoted for the comparison of treatments using logistic regression with factorsfor treatment and region.(d) Full Analysis Set

NA = not available

*p≤0.05, Cimzia vs placebo

**p<0.001, Cimzia vs placebo

Spinal mobility

Spinal mobility was assessed in the double-blind, placebo-controlled period by using BASMI atseveral time points including Baseline, Week 12 and Week 24. Clinically meaningful and statisticallysignificant differences in Cimzia-treated patients compared with placebo-treated patients weredemonstrated at each post-baseline visit. The difference from placebo tended to be greater in nr-axSpAthan in the AS subpopulation which may be due to less chronic structural damage in nr-axSpApatients.

The improvement in BASMI linear score achieved at Week 24 was maintained through Week 204 forpatients who remained in the study.

Physical function response and health-related outcomes

In the AS001 clinical trial, Cimzia-treated patients reported significant improvements in physicalfunction as assessed by the BASFI and in pain as assessed by the Total and Nocturnal Back Pain NRSscales as compared to placebo. Cimzia-treated patients reported significant improvements in tiredness(fatigue) as reported by the BASDAI-fatigue item and in health-related quality of life as measured bythe ankylosing spondylitis QoL (ASQoL) and the SF-36 Physical and Mental Component Summariesand all domain scores as compared to placebo. Cimzia-treated patients reported significantimprovements in axial spondyloarthritis-related productivity at work and within household, as reportedby the Work Productivity Survey as compared to placebo. For patients remaining in the study,improvements in all afore-mentioned outcomes were largely maintained through Week 204.

Inhibition of inflammation in Magnetic Resonance Imaging (MRI)

In an imaging sub-study including 153 patients, signs of inflammation were assessed by MRI atweek 12 and expressed as change from baseline in SPARCC (Spondyloarthritis Research Consortiumof Canada) score for sacroiliac joints and ASspiMRI-a score in the Berlin modifications for the spine.

At week 12, significant inhibition of inflammatory signs in both sacroiliac joints and the spine wasobserved in the Cimzia-treated patients (all dose group), in the overall axial spondyloarthritispopulation as well as in the sub-populations of ankylosing spondylitis and non-radiographic axialspondyloarthritis.

Among patients remaining in the study, who had both baseline values and week 204 values, inhibitionof inflammatory signs in both the sacroiliac joints (n=72) and spine (n=82) was largely maintainedthrough Week 204 in the overall axial spondyloarthritis population as well as in both the AS and thenr-axSpA subpopulations.

C-OPTIMISE

The efficacy and safety of dose reduction and treatment withdrawal in patients in sustained remissionwere assessed in adult patients (18-45 years of age) with early active axSpA (symptom duration of lessthan 5 years), an ASDAS score ≥2.1 (and similar disease inclusion criteria as in the AS001 study), andwho had inadequate response to at least 2 NSAIDs or an intolerance to or contraindication for

NSAIDs. Patients included both the AS and nr-axSpA subpopulations of axSpA, and were enrolledinto an open-label run-in 48-Week period (Part A) during which they all received 3 loading doses of

Cimzia 400 mg at Weeks 0, 2, and 4 followed by Cimzia 200 mg every 2 weeks from Week 6 to Week46.

Patients who achieved sustained remission (defined as having inactive disease [ASDAS<1.3] over aperiod of at least 12 weeks) and remained in remission at week 48, were randomized into Part B andreceived either Cimzia 200 mg every 2 weeks (N=104), Cimzia 200 mg every 4 weeks (dosereduction, N=105), or placebo (treatment withdrawal, N=104) for 48 Weeks.

The primary efficacy variable was the percentage of patients who did not experience a flare during

Part B.

Patients who experienced a flare in Part B, ie, had an ASDAS ≥2.1 at 2 consecutive visits or

ASDAS >3.5 at any visit during Part B, received escape treatment of Cimzia 200 mg every 2 weeks forat least 12 weeks (with a loading dose of Cimzia 400 mg at Week 0, 2 and 4 in placebo-treated patients).

The percentage of patients who achieved sustained remission at Week 48 in Part A was 43.9% for theoverall axSpA population, and was similar in the nr-axSpA (45.3%) and AS (42.8%) subpopulations.

Among the patients who were randomized in Part B (N=313), a statistically significant (p <0.001,

NRI) greater proportion of patients did not experience a flare when continuing treatment with

Cimzia 200 mg every 2 weeks (83.7%) or Cimzia 200 mg every 4 weeks (79.0%) compared withtreatment withdrawal (20.2%).

The difference in time to flare between the treatment withdrawal group and either of the Cimziatreatment groups, was statistically significant (p<0.001 for each comparison) and clinicallymeaningful. In the placebo group, flares started approximately 8 weeks after Cimzia was withdrawn,with the majority of flares occurring within 24 weeks of treatment withdrawal (Figure 1).

Figure 1 Kaplan-Meier curve of time to flare

Non responder imputation (NRI) was used; Results are for the Randomized Set

Note: Time to flare was defined as the time from the date of randomization to the date of the flare. For study participants who did not have aflare, the time to flare was censored at the date of Week 96 Visit.

The Kaplan-Meier plot was truncated to 97 weeks when <5% of participants were still remaining in the study.

Results for Part B are presented in Table 9.

Table 9 Maintenance of clinical response in Part B at Week 96

Placebo(treatment CIMZIA 200 mg CIMZIA 200 mgwithdrawal) every 2 weeks every 4 weeks

Endpoints N=104 N=104 N=105

ASDAS-MI, n (%)1

Part B Baseline (Week 48) 84 (80.8) 90 (86.5) 89 (84.8)

Week 96 11 (10.6) 70 (67.3)* 61 (58.1)*

ASAS40, n (%)1

Part B Baseline (Week 48) 101 (97.1) 103 (99.0) 101 (96.2)

Week 96 22 (21.2) 88 (84.6)* 77 (73.3)*

BASDAI change from Part

B baseline (Week 48), LSmean (SE)2

Week 96 3.02 (0.226) 0.56 (0.176)* 0.78 (0.176)*

ASDAS change from Part Bbaseline (Week 48), LSmean (SE)2

Week 96 1.66 (0.110) 0.24 (0.077)* 0.45 (0.077)*1 Non responder imputation (NRI) was used; Results are for the Randomized Set2 mixed model with repeated measures (MMRM) was used; Results are for the Randomized Set

ASDAS-MI = Ankylosing Spondylitis Disease Activity Score-Major Improvement; ASAS: Assessment of Sponyloarthritis international

Society; ASAS40= ASAS40% response criteria; SE = Standard error;

Note: ASDAS major improvement is defined as a reduction from Baseline ≥2.0.

Note: Part A Baseline was used as a reference to define ASDAS clinical improvement variables and ASAS variables

* Nominal p<0.001, CIMZIA vs. placebo

Inhibition of inflammation in Magnetic Resonance imaging (MRI)

In Part B, signs of inflammation were assessed by MRI at Week 48 and at Week 96 and expressed aschange from baseline in SIJ SPARCC and ASspiMRI-a score in the Berlin modifications. Patients whowere in sustained remission at Week 48 had no or very low inflammation, and no meaningful increasein inflammation was observed at Week 96 irrespective of their treatment group.

Retreatment in patients that experience a flare

In Part B, 70% (73/104) placebo-treated patients, 14% (15/105) patients treated with Cimzia 200 mgevery 4 weeks and 6.7% (7/104) patients treated with Cimzia 200 mg every 2 weeks experienced a flareand were subsequently treated with Cimzia 200 mg every 2 weeks.

Among the 15 patients who flared in the group allocated to Cimzia 200 mg every 4 weeks, all patientscompleted 12 weeks of rescue therapy with Cimzia and had available ASDAS data, out of which 12(80%) had ASDAS Low or Inactive disease (i.e. all ASDAS <2.1) after 12 weeks of restarting the open-label treatment.

Among the 73 patients who flared in the group allocated to treatment withdrawal, 71 patients completed12 weeks of rescue therapy with Cimzia and had available ASDAS data, out of which 64 (90%) had

ASDAS Low or Inactive disease (i.e. all ASDAS < 2.1) after 12 weeks of restarting the open-labeltreatment.

Based on the results from C-OPTIMISE, a dose reduction in patients in sustained remission after oneyear of treatment with Cimzia may be considered (see section 4.2). Withdrawal of Cimzia treatment isassociated with a high risk of flare.

Non-radiographic axial spondyloarthritis (nr-axSpA)

The efficacy and safety of Cimzia were assessed in a 52 weeks multicenter, randomized, double-blind,placebo-controlled study (AS0006) in 317 patients ≥18 years of age with adult-onset axialspondyloarthritis and back pain for at least 12 months. Patients had to fulfil ASAS criteria for nr-axSpA (not including family history and good response to NSAIDs), and have had objective signs ofinflammation indicated by C-reactive protein (CRP) levels above the upper limit of normal and/orsacroiliitis on magnetic resonance imaging (MRI), indicative of inflammatory disease [positive CRP(> ULN) and/or positive MRI], but without definitive radiographic evidence of structural damage onsacroiliac joints. Patients had active disease as defined by the BASDAI ≥4, and spinal pain ≥4 ona 0 to 10 NRS. Patients must have been intolerant to or had an inadequate response to at least two

NSAIDs. Patients were treated with placebo or a loading dose of Cimzia 400 mg at

Weeks 0, 2 and 4 followed by 200 mg of Cimzia every 2 weeks. Utilization and dose adjustment ofstandard of care medication (SC) (e.g., NSAIDs, DMARDs, corticosteroids, analgesics) werepermitted at any time. The primary efficacy variable was the Ankylosing Spondylitis Disease Activity

Score major improvement (ASDAS-MI) response at Week 52. ASDAS-MI response was defined as an

ASDAS reduction (improvement) ≥ 2.0 relative to baseline or as reaching the lowest possible score.

ASAS 40 was a secondary endpoint.

At baseline, 37 % and 41% of patients had high disease activity (ASDAS ≥2.1, ≤3.5) and 62% and58% of patient had very high disease activity (ASDAS >3.5) in the CIMZIA group and placebo grouprespectively.

Study AS0006, performed in subjects without radiographic signs of inflammation in the SI joints,confirmed the effect previously demonstrated in this subgroup in the AS001 study.

At Week 52, a statistically significant greater proportion of patients treated with Cimzia achieved

ASDAS-MI response compared to patients treated with placebo. Cimzia-treated patients also hadimprovements compared to placebo in multiple components of axial spondyloarthritis disease activity,including CRP. At both Week 12 and 52, ASAS 40 responses were significantly greater than placebo.

Key results are presented in Table 10.

Table 10: ASDAS-MI and ASAS 40 responses in AS0006 (percent of patients)

Parameters Placebo

N=158 Cimziaa 200 mg every 2 weeks N=159

ASDAS-MI

Week 52 7% 47%*

ASAS 40

Week 12 11% 48%*

Week 52 16% 57%*a Cimzia administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4

* p<0.001

All percents reflect the proportion of patients who responded in the full analysis set.

At Week 52, the percentage of patients achieving ASDAS inactive disease (ASDAS < 1.3) was 36.4 %for the Cimzia group compared to 11.8 % for the placebo group.

At Week 52, patients treated with Cimzia showed a clinical meaningful improvement in the MASEScompared to placebo (LS mean change from baseline -2.4; -0.2 respectively).

The efficacy and safety of Cimzia were assessed in a multicentre, randomised, double-blind, placebocontrolled clinical trial (PsA001) in 409 patients ≥ 18 years of age with adult-onset active psoriaticarthritis for at least 6 months as defined by the Classification Criteria for Psoriatic Arthritis(CASPAR) criteria. Patients had ≥ 3 swollen and tender joints and increased acute phase reactants.

Patients also had active psoriatic skin lesions or a documented history of psoriasis and had failed 1 ormore DMARDs. Previous treatment with one TNF-antagonist was allowed and 20% of patients hadprior TNF-antagonist exposure. Patients received a loading dose of Cimzia 400 mg at

Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either Cimzia 200 mgevery 2 weeks or 400 mg every 4 weeks or placebo every 2 weeks. Patients receiving concomitant

NSAIDs and conventional DMARDs were 72.6% and 70.2% respectively. The two primary endpointswere the percentage of patients achieving ACR 20 response at Week 12 and change from baseline inmodified Total Sharp Score (mTSS) at Week 24. Efficacy and safety of Cimzia in patients with PsAwhose predominant symptoms were sacroiliitis or axial spondyloarthritis have not been separatelyanalysed.

The 24-week double-blind placebo controlled treatment period of the study was followed bya 24-week dose-blind treatment period and an 168-week open-label treatment period. The maximumduration of the study was 216 weeks. All patients received Cimzia in both the dose-blind and open-label follow-up periods. A total of 264 subjects (64.5%) completed the study through Week 216.

Cimzia-treated patients had a statistically significant higher ACR 20 response rate at Week 12 and

Week 24 compared with placebo-treated patients (p<0.001). The percentage of ACR 20 responderswas clinically relevant for the Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 4 weekstreatment groups compared to placebo group at every visit after baseline through Week 24 (nominalp≤0.001 at each visit). Cimzia treated patients also had significant improvements in

ACR 50 and 70 response rates. At week 12 and 24 improvements in parameters of peripheral activitycharacteristic of psoriatic arthritis (e.g. number of swollen joints, number of painful/tender joints,dactylitis and enthesitis) were seen in the Cimzia-treated patients (nominal p-value p<0.01).

Key efficacy outcomes from the PsA001 clinical trial are shown in Table 11.

Table 11: Key efficacy outcomes in PsA001 clinical trial (percent of patients)

Response Placebo Cimzia(a)200 mg Cimzia(b) 400 mg

Q2W Q4W

N=136 N=138 N=135

ACR20

Week 12 24% 58%** 52%**

Week 24 24% 64%** 56%**

ACR50

Week 12 11% 36%** 33%**

Week 24 13% 44%** 40%**

ACR70

Week 12 3% 25%** 13%*

Week 24 4% 28%** 24%**

Response Placebo Cimzia(a)200 mg Cimzia(b) 400 mg

Q2W Q4W

N=86 N=90 N=76

PASI 75 (c)

Week 12 14% 47%*** 47%***

Week 24 15% 62%*** 61%***

Week 48 N/A 67% 62%(a) Cimzia administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4(b) Cimzia administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4(c) In subjects with at least 3% psoriasis BSA at Baseline

*p<0.01, Cimzia vs placebo

**p<0.001, Cimzia vs placebo

***p<0.001(nominal), Cimzia vs placebo

Results are from the randomized set.Treatment Difference: Cimzia 200 mg-placebo, Cimzia 400 mg-placebo (and corresponding 95% CI and p-value) are estimated using a standard two-sided Waldasymptotic standard errors test. Non-responder Imputation (NRI) is used for patients who escapedtherapy or had missing data.

Among 273 patients initially randomised to Cimzia 200 mg every 2 weeks and Cimzia 400 mgevery 4 weeks, 237 (86.8%) were still on this treatment at Week 48. Of the 138 patients randomised to

Cimzia 200 mg every 2 weeks, 92, 68 and 48 had an ACR 20/50/70 response, at Week 48,respectively. Of the 135 patients randomised to Cimzia 400 mg every 4 weeks, 89, 62 and 41 patientshad an ACR 20/50/70 response, respectively.

Among patients remaining in the study, ACR 20, 50 and 70 response rates were maintained through

Week 216. This was also the case for the other parameters of peripheral activity (e.g. number ofswollen joints, number of painful/tender joints, dactylitis and enthesitis).

In PsA001 clinical trial, inhibition of progression of structural damage was assessed radiographicallyand expressed as the change in modified total Sharp score (mTSS) and its components, the Erosion

Score (ES) and Joint Space Narrowing score (JSN) at Week 24, compared to baseline. The mTSS

Score was modified for psoriatic arthritis by addition of hand distal interphalangeal joints. Cimziatreatment inhibited the radiographic progression compared with placebo treatment at Week 24 asmeasured by change from baseline in total mTSS Score (LS mean [±SE] score was 0.28 [±0.07] in theplacebo group compared with 0.06 [±0.06] in the Cimzia all doses group; p=0.007). Inhibition ofradiographic progression was maintained with Cimzia treatment up to Week 48 in the subset ofpatients at higher risk of radiographic progression (patients with a Baseline mTSS score of > 6).

Inhibition of radiographic progression was further maintained up to Week 216 for the patients whoremained in the study.

Physical function response and health-related outcomes

In PsA001 clinical trial, Cimzia-treated patients reported significant improvements in physicalfunction as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI), in pain asassessed by the PAAP and in tiredness (fatigue) as reported by the Fatigue Assessment Scale (FAS) ascompared to placebo. Cimzia-treated patients reported significant improvements in health-relatedquality of life as measured by the psoriatic arthritis QoL (PsAQoL) and the SF-36 Physical and Mental

Components and in psoriatic arthritis-related productivity at work and within household, as reportedby the Work Productivity Survey compared to placebo. Improvements in all afore-mentionedoutcomes were maintained through Week 216.

Plaque psoriasis

The efficacy and safety of Cimzia were assessed in two placebo-controlled studies (CIMPASI-1 and

CIMPASI-2) and one placebo- and active-controlled study (CIMPACT) in patients ≥18 years of agewith moderate to severe chronic plaque psoriasis for at least 6 months. Patients had a Psoriasis Areaand Severity Index (PASI) score ≥ 12, body surface area (BSA) involvement of ≥ 10%, Physician

Global Assessment (PGA) of ≥ 3, and were candidates for systemic therapy and/or phototherapyand/or chemophototherapy. Patients who were ‘primary’ non-responders on any prior biologic therapy(defined as no response within the first 12 weeks of treatment) were excluded from the phase IIIstudies (CIMPASI-1, CIMPASI-2 and CIMPACT). The efficacy and safety of Cimzia were evaluatedversus etanercept in the CIMPACT study.

In studies CIMPASI-1 and CIMPASI-2 the co-primary efficacy endpoints were the proportion ofpatients achieving PASI 75 and PGA “clear” or “almost clear” (with at least a 2-point reduction frombaseline) at Week 16. In the CIMPACT study, the primary efficacy endpoint was the proportion ofpatients achieving PASI 75 at Week 12. PASI75 and PGA at Week 16 were key secondary endpoints.

PASI 90 at Week 16 was a key secondary endpoint in all 3 studies.

CIMPASI-1 and CIMPASI-2 evaluated 234 patients and 227 patients respectively. In both studiespatients were randomized to receive placebo or Cimzia 200 mg every 2 weeks (following a loadingdose of Cimzia 400 mg at Weeks 0, 2 and 4) or Cimzia 400 mg every 2 weeks. At week 16, patientsrandomized to Cimzia who achieved a PASI 50 response continued to receive Cimzia up to

Week 48 at the same randomized dose. Patients originally randomized to placebo that achieved a

PASI 50 response but not a PASI 75 response at Week 16 received Cimzia 200 mg every 2 weeks(with a loading dose of Cimzia 400 mg at Weeks 16, 18, and 20). Patients with an inadequate responseat Week 16 (PASI 50 non-responders) were eligible to receive Cimzia 400 mg every 2 weeks in anopen-label manner for a maximum of 128 weeks.

The CIMPACT study evaluated 559 patients. Patients were randomized to receive placebo, or

Cimzia 200 mg every 2 weeks (following a loading dose of Cimzia 400 mg at Weeks 0, 2 and 4), or

Cimzia 400 mg every 2 weeks up to Week 16, or etanercept 50 mg twice weekly, up to Week 12.

Patients originally randomized to Cimzia who achieved a PASI75 response at Week 16 were re-randomized based on their original dosing schedule. Patients on Cimzia 200 mg every 2 weeks werere-randomized to Cimzia 200 mg every 2 weeks, Cimzia 400 mg every 4 weeks or placebo. Patient on

Cimzia 400 mg every 2 weeks were re-randomized to Cimzia 400 mg every 2 weeks, Cimzia 200 mgevery 2 weeks, or placebo. Patients were evaluated in a double-blind placebo-controlled mannerthrough Week 48. All subjects who did not achieve a PASI 75 response at Week 16 entered an escapearm and received Cimzia 400 mg every 2 weeks in an open-label manner for a maximum of 128weeks.

In all three studies, the blinded 48-week maintenance period was followed by a 96-week open-labeltreatment period for the patients who were PASI 50 responders at Week 48. All these patients,including those receiving Cimzia 400 mg every 2 weeks, started the open-label period at Cimzia 200mg every 2 weeks.

Patients were predominantly men (64%) and Caucasian (94%), with a mean age of 45.7 years(18 to 80 years); of these, 7.2% were ≥ 65 years of age. Of the 850 patients randomized to receiveplacebo or Cimzia in these placebo-controlled studies, 29% of patients were naïve to prior systemictherapy for the treatment of psoriasis. 47% had received prior phototherapy or chemophototherapy,and 30% had received prior biologic therapy for the treatment of psoriasis. Of the 850 patients, 14%had received at least one TNF-antagonist, 13% had received an anti-IL-17, and 5% had received ananti-IL 12/ 23. Eighteen percent of patients reported a history of psoriatic arthritis at baseline. Themean PASI score at baseline was 20 and ranged from 12 to 69. The baseline PGA score ranged frommoderate (70%) to severe (30%). Mean baseline BSA was 25% and ranged from 10% to 96%.

Clinical response at Week 16 and 48

The key results of CIMPASI-1 and CIMPASI-2 studies are presented in Table 12.

Table 12 Clinical response in studies CIMPASI-1 and CIMPASI-2 at Week 16 and Week 48

Week 16 Week 48

CIMPASI-1

Placebo Cimzia 200 mg Cimzia 400 mg Cimzia 200 mg Cimzia 400 mg

Q2W a) Q2W Q2W Q2W

N=51 N=95 N=88 N=95 N=88

PGA clear or 4.2% 47.0%* 57.9%* 52.7% 69.5%almost clearb)

PASI 75 6.5% 66.5%* 75.8%* 67.2% 87.1%

PASI 90 0.4% 35.8%* 43.6%* 42.8% 60.2%

CIMPASI-2

Placebo Cimzia 200 mg Cimzia 400 mg Cimzia 200 mg Cimzia 400 mg

Q2W a) Q2W Q2W Q2W

N=49 N=91 N=87 N= 91 N= 87

PGA clear or 2.0% 66.8%* 71.6%* 72.6% 66.6%almost clearb)

PASI 75 11.6% 81.4%* 82.6%* 78.7% 81.3%

PASI 90 4.5% 52.6%* 55.4%* 59.6% 62.0%a) Cimzia 200 mg administered every 2 weeks preceded by a loading dose of 400 mg at Week 0, 2, 4.b) PGA 5 category scale. Treatment success of “clear” (0) or “almost clear”(1) consisted of no signs ofpsoriasis or normal to pink coloration of lesions, no thickening of the plaque, and none to minimalfocal scaling.

* Cimzia vs placebo: p< 0.0001.

Response rates and p-values for PASI and PGA were estimated based on a logistic regression modelwhere missing data were imputed using multiple imputation based on the MCMC method. Subjectwho escaped or withdrew (based on not achieving PASI 50 response) were treated as non-respondersat Week 48.

Results are from the Randomized Set.

The key results of the CIMPACT trial are presented in Table 13.

Table 13 Clinical response in CIMPACT study at Week 12 and Week 16

Week 12 Week 16

Placebo Cimzia Cimzia 400 mg Etanercept Placebo Cimzia 200 mg Cimzia 400

N=57 200 mg Q2W 50 mg N=57 Q2W mg

Q2W a) N=167 BiW N=165 Q2W

N=165 N=170 N=167

PASI 7 5% 61.3%*,66.7%*,§§ 53.3%5 § 3.8% 68.2%* 74.7%*

PASI 90 0.2% 31.2%* 34.0%* 27.1% 0.3% 39.8%* 49.1%*

PGAclear oralmost 1.9% 39.8%*b) * 50.3%* 39.2% 3.4% 48.3%* 58.4%*cleara) Cimzia 200 mg administered every 2 weeks preceded by a loading dose of 400 mg at Week 0, 2, 4.b) PGA 5 category scale. Treatment success of “clear” (0) or “almost clear”(1) consisted of no signs ofpsoriasis or normal to pink coloration of lesions, no thickening of the plaque, and none to minimalfocal scaling.

* Cimzia vs placebo: p< 0.0001.§ Cimzia 200 mg every 2 weeks versus etanercept 50 mg twice weekly demonstrated non-inferiority(difference between etanercept and Cimzia 200 mg every 2 weeks was 8.0%, 95% CI -2.9, 18.9, basedon a pre-specified non-inferiority margin of 10%).§§ Cimzia 400 mg every 2 weeks versus etanercept 50 mg twice weekly demonstrated superiority(p<0.05)

** Cimzia vs Placebo p < 0.001. Response rates and p-values based on a logistic regression model.

Missing data were imputed using multiple imputation based on the MCMC method. Results are fromthe Randomized Set.

In all 3 studies, the PASI 75 response rate was significantly greater for Cimzia compared to placebostarting at Week 4.

Both doses of Cimzia demonstrated efficacy compared to placebo regardless of age, gender, bodyweight, BMI, psoriasis disease duration, previous treatment with systemic therapies and previoustreatment with biologics.

In an integrated analysis of CIMPASI-1 and CIMPASI-2, among patients who were PASI 75responders at Week 16 and received Cimzia 400 mg every 2 weeks (N=134 of 175 randomisedsubjects) or Cimzia 200 mg every 2 weeks (N=132 of 186 randomised subjects), the maintenance ofresponse at Week 48 was 98.0% and 87.5%, respectively. Among patients who were PGA clear oralmost clear at Week 16 and received Cimzia 400 mg every 2 weeks (N=103 of 175) or Cimzia 200mg every 2 weeks (N=95 of 186), the maintenance of response at Week 48 was 85.9% and 84.3%respectively.

After an additional 96 weeks of open-label treatment (Week 144) the maintenance of response wasevaluated. Twenty-one percent of all randomised subjects were lost to follow-up before Week 144.

Approximately 27% of completer study subjects who entered the open-label treatment between weeks48 to 144 on Cimzia 200 mg every 2 weeks had their dose increased to Cimzia 400 mg every 2 weeksfor maintenance of response. In an analysis in which all patients with treatment failures wereconsidered non-responders, the maintenance of response of the Cimzia 200 mg every 2 weekstreatment group for the respective endpoint, after an additional 96 weeks of open-label therapy, was84.5% for PASI 75 for study subjects who were responders at Week 16 and 78.4% for PGA clear oralmost clear. The maintenance of response of the Cimzia 400 mg every 2 weeks treatment group, whoentered the open-label period at Cimzia 200 mg every 2 weeks, was 84.7% for PASI 75 for studysubjects who were responders at Week 16 and 73.1% for PGA clear or almost clear.

These response rates were based on a logistic regression model where missing data were imputed over48 or 144 weeks using multiple imputation (MCMC method) combined with NRI for treatmentfailures.

In the CIMPACT study, among PASI 75 responders at Week 16 who received Cimzia 400 mg every 2weeks and were re-randomized to either Cimzia 400 mg every 2 weeks, Cimzia 200 mg every 2weeks, or placebo, there was a higher percentage of PASI 75 responders at Week 48 in the Cimziagroups as compared to placebo (98.0%, 80.0%, and 36.0%, respectively). Among PASI75 respondersat Week 16 who received Cimzia 200 mg every 2 weeks and were re-randomized to either Cimzia 400mg every 4 weeks, Cimzia 200 mg every 2 weeks, or placebo, there was also a higher percentage of

PASI 75 responders at Week 48 in the Cimzia groups as compared to placebo (88.6%, 79.5%, and45.5%, respectively). Non-responder imputation was used for missing data.

Quality of life/Patient reported outcomes

Statistically significant improvements at Week 16 (CIMPASI-1 and CIMPASI-2) from baselinecompared to placebo were demonstrated in the DLQI (Dermatology Life Quality Index). Meandecreases (improvements) in DLQI from baseline ranged from -8.9 to -11.1 with Cimzia 200 mg every2 weeks, from -9.6 to -10.0 with Cimzia 400 mg every 2 weeks, versus -2.9 to -3.3 for placebo at

Week 16.

In addition, at Week 16, Cimzia treatment was associated with a greater proportion of patientsachieving a DLQI score of 0 or 1 (Cimzia 400 mg every 2 weeks, 45.5% and 50.6% respectively;

Cimzia 200 mg every 2 weeks, 47.4% and 46.2% respectively, versus placebo, 5.9% and 8.2%respectively).

Improvements in DLQI score were sustained or slightly decreased through Week 144.

Cimzia-treated patients reported greater improvements compared to placebo in the Hospital Anxietyand Depression Scale (HADS)-D.

The data below reflect the percentage of patients whose test results were considered positive forantibodies to certolizumab pegol in an ELISA and later in a more sensitive method, and are highlydependent 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 samplecollection, concomitant medications, and underlying disease. For these reasons, comparison of theincidence of antibodies to certolizumab pegol in the studies described below with the incidence ofantibodies in other studies or to other products may be misleading.

The overall percentage of patients with antibodies to Cimzia detectable on at least 1 occasionwas 9.6% in RA placebo-controlled trials. Approximately one-third of antibody-positive patients hadantibodies with neutralising activity in vitro. Patients treated with concomitant immunosuppressants(MTX) had a lower rate of antibody development than patients not taking immunosuppressants atbaseline. Antibody formation was associated with lowered drug plasma concentration and in somepatients, reduced efficacy.

In 2 long-term (up to 5 years of exposure) open-label studies, the overall percentage of patients withantibodies to Cimzia detectable on at least one occasion was 13% (8.4% of the overall patients hadtransient formation of antibodies and an additional 4.7% had persistent formation of antibodies to

Cimzia). The overall percentage of patients that were antibody positive with a persistent reduction ofdrug plasma concentration was estimated to be 9.1%. Similar to the placebo-controlled studies,antibody positivity was associated with reduced efficacy in some patients.

A pharmacodynamic model based on the Phase III trial data predicts that around 15% of the patientsdevelop antibodies in 6 months at the recommended dose regimen (200 mg every 2 weeks following aloading dose) without MTX co-treatment. This number decreases with increasing doses ofconcomitant MTX treatment. These data are reasonably in agreement with observed data.

The overall percentage of patients with antibodies to Cimzia detectable on at least one occasion up to

Week 24 was 11.7% in the Phase III placebo-controlled trial in patients with psoriatic arthritis.

Antibody formation was associated with lowered drug plasma concentration.

Over the course of the entire study (up to 4 years of exposure), the overall percentage of patients withantibodies to Cimzia detectable on at least one occasion was 17.3% (8.7% had transient formation andan additional 8.7% had persistent formation of antibodies to Cimzia). The overall percentage ofpatients that were antibody positive with a persistent reduction of drug plasma concentration wasestimated to be 11.5%.

Plaque psoriasis

In the Phase III placebo- and active-controlled studies, the percentages of patients who were positivefor antibodies to Cimzia on at least one occasion during treatment up to Week 48 were 8.3 % (22/265)and 19.2% (54/281) for the Cimzia 400 mg every 2 weeks and Cimzia 200 mg every 2 weeksrespectively. In CIMPASI-1 and CIMPASI-2, sixty patients were antibody positive, 27 of thesepatients were evaluable for neutralizing antibodies and tested positive. First occurrences of antibodypositivity in the open-label treatment period were observed in 2.8% (19/668) of patients. Antibodypositivity was associated with lowered drug plasma concentration and in some patients with reducedefficacy.

AS001

The overall percentage of patients with antibodies to Cimzia detectable on at least one occasion up to

Week 24 was 4.4% in the AS001 phase III placebo-controlled trial in patients with axialspondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritissubpopulations). Antibody formation was associated with lowered drug plasma concentration.

Over the course of the entire study (up to 192 weeks), the overall percentage of patients withantibodies to Cimzia detectable on at least one occasion was 9.6% (4.8% had transient formation andan additional 4.8% had persistent formation of antibodies to Cimzia). The overall percentage ofpatients that were antibody positive with a persistent reduction of drug plasma concentration wasestimated to be 6.8%.

AS0006 and C-OPTIMISE

A more sensitive and drug tolerant assay was used for the first time in the AS0006 study (and lateralso in the C-OPTIMISE study), resulting in a greater proportion of samples having measurableantibodies to Cimzia and thus a greater incidence of patients being classed as antibody positive. In

AS0006, the overall incidence of patients who were antibody positive to Cimzia was 97%(248/255 patients) after up to 52 weeks of treatment. Only the highest titers were associated withreduced Cimzia plasma levels, however, no impact on efficacy was observed. Similar results inrelation to antibodies to Cimzia were seen in C-OPTIMISE. Results from C-OPTIMISE also indicatedthat a reduction of the dose to Cimzia 200 mg every 4 weeks did not change immunogenicityoutcomes.

About 22% (54/248) of the patients in AS0006 who were anti-Cimzia antibody positive at any time,had antibodies that were classified as neutralizing. The neutralizing status of antibodies in C-

OPTIMISE was not assessed.

Certolizumab pegol plasma concentrations were broadly dose-proportional. Pharmacokineticsobserved in patients with rheumatoid arthritis and psoriasis were consistent with those seen in healthysubjects.

Following subcutaneous administration, peak plasma concentrations of certolizumab pegol wereattained between 54 and 171 hours post-injection. Certolizumab pegol has a bioavailability (F) ofapproximately 80% (range 76% to 88%) following subcutaneous administration compared tointravenous administration.

The apparent volume of distribution (V/F) was estimated at 8.01 l in a population pharmacokineticanalysis of patients with rheumatoid arthritis and at 4.71 l in a population pharmacokinetic analysis ofpatients with plaque psoriasis.

PEGylation, the covalent attachment of PEG polymers to peptides, delays the elimination of theseentities from the circulation by a variety of mechanisms, including decreased renal clearance,decreased proteolysis, and decreased immunogenicity. Accordingly, certolizumab pegol is an antibody

Fab' fragment conjugated with PEG in order to extend the terminal plasma elimination half-life of the

Fab' to a value comparable with a whole antibody product. The terminal elimination phase half-life(t1/2) was approximately 14 days for all doses tested.

Clearance following subcutaneous dosing was estimated to be 21.0 ml/h in a rheumatoid arthritispopulation pharmacokinetic analysis, with an inter-subject variability of 30.8% (CV) and an inter-occasion variability of 22.0%. When assessed using the previous ELISA method, the presence ofantibodies to certolizumab pegol resulted in an approximately three-fold increase in clearance.

Compared with a 70 kg person, clearance is 29% lower and 38% higher, respectively, in individual RApatients weighing 40 kg and 120 kg. The clearance following subcutaneous dosing in patients withpsoriasis was 14 ml/h with an inter-subject variability of 22.2% (CV).

The Fab' fragment comprises protein compounds and is expected to be degraded to peptides and aminoacids by proteolysis. The de-conjugated PEG component is rapidly eliminated from plasma and is toan unknown extent excreted renally.

Specific clinical trials have not been performed to assess the effect of renal impairment on thepharmacokinetics of certolizumab pegol or its PEG fraction. However, population pharmacokineticanalysis based on subjects with mild renal impairment showed no effect of creatinine clearance. Thereare insufficient data to provide a dosing recommendation in moderate and severe renal impairment.

The pharmacokinetics of the PEG fraction of certolizumab pegol are expected to be dependent onrenal function but have not been assessed in patients with renal impairment.

Specific clinical trials have not been performed to assess the effect of hepatic impairment on thepharmacokinetics of certolizumab pegol.

Elderly patients (≥ 65 years old)

Specific clinical trials have not been performed in elderly patients subjects. However, no effect of agewas observed in a population pharmacokinetic analysis in patients with rheumatoid arthritis inwhich 78 subjects (13.2% of the population) were aged 65 or greater and the oldest subject wasaged 83 years. No effect of age was observed in a population pharmacokinetic analysis in adultpatients with plaque psoriasis.

In a clinical study, 21 women received Cimzia at a maintenance dose of 200 mg or 400 mg every 2weeks or 400 mg every 4 weeks, during pregnancy and at least 13 weeks post-partum (see section4.6).

Based on population PK modeling, median systemic Cimzia exposure for the dosing regimens studiedwere estimated to be 22% (AUC) and 36% (Cmin) lower during pregnancy (with the greatestreduction observed during the third trimester) relative to post-partum or in non-pregnant individuals.

Although certolizumab pegol plasma concentrations were lower during pregnancy compared withpost-partum, they were still within the range of concentrations observed in non-pregnant adult patientswith psoriasis, axSpA, and rheumatoid arthritis.

There was no effect of gender on the pharmacokinetics of certolizumab pegol. As clearance decreaseswith decreasing body weight, females may generally obtain somewhat higher systemic exposure ofcertolizumab pegol.

On the basis of Phase II and Phase III clinical trial data in patients with rheumatoid arthritis, apopulation exposure-response relationship was established between average plasma concentration ofcertolizumab pegol during a dosing interval (Cavg) and efficacy (ACR 20 responder definition). Thetypical Cavg that produces half the maximum probability of ACR 20 response (EC50) was 17 µg/ml(95% CI: 10-23 µg/ml). Similarly, on the basis of Phase III clinical trial data in patients with psoriasis,a population exposure-response relationship was established between plasma concentration ofcertolizumab pegol and PASI with an EC90 of 11.1 µg/ml.

The pivotal non-clinical safety studies were conducted in the cynomolgus monkey. In rats andmonkeys, at doses higher than those given to humans, histopathology revealed cellular vacuolation,present mainly in macrophages, in a number of organs (lymph nodes, injection sites, spleen, adrenal,uterine, cervix, choroid plexus of the brain, and in the epithelial cells of the choroid plexus). It is likelythat this finding was caused by cellular uptake of the PEG moiety. In vitro functional studies of humanvacuolated macrophages indicated all functions tested were retained. Studies in rats indicated that> 90% of the administered PEG was eliminated in 3 months following a single dose, with the urinebeing the main route of excretion.

Certolizumab pegol does not cross-react with rodent TNF. Therefore, reproductive toxicology studieshave been performed with a homologous reagent recognising rat TNF. The value of these data to theevaluation of human risk may be limited. No adverse effects were seen on maternal well-being orfemale fertility, embryo-foetal and peri- and post-natal reproductive indices in rats using a rodent anti-rat TNFα PEGylated Fab' (cTN3 PF) following sustained TNFα suppression. In male rats, reducedsperm motility and a trend of reduced sperm count were observed.

Distribution studies have demonstrated that placental and milk transfer of cTN3 PF to the foetal andneonatal circulation is negligible. Certolizumab pegol does not bind to the human neonatal Fc receptor(FcRn). Data from a human closed-circuit placental transfer model ex vivo suggest low or negligibletransfer to the foetal compartment. In addition, experiments of FcRn-mediated transcytosis in cellstransfected with human FcRn showed negligible transfer (see section 4.6).

No mutagenic or clastogenic effects were demonstrated in preclinical studies. Carcinogenicity studieshave not been performed with certolizumab pegol.

Sodium acetate

Sodium chloride

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years.

See also section 6.4 for shelf-life related to storage at room temperature up to a maximum of 25°C.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

The pre-filled syringes may be stored at room temperature (up to 25°C) for a single period ofmaximum 10 days with protection from light. At the end of this period the pre-filled syringes must beused or discarded.

One ml pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber),containing 200 mg of certolizumab pegol. The needle shield is styrene butadiene rubber whichcontains a derivative of natural rubber latex (see section 4.4).

Pack size of 2 pre-filled syringes and 2 alcohol wipes.

Multipack containing 6 (3 packs of 2) pre-filled syringes and 6 (3 packs of 2) alcohol wipes.

Multipack containing 10 (5 packs of 2) pre-filled syringes and 10 (5 packs of 2) alcohol wipes.

Pack size of 2 pre-filled syringes with needle guard and 2 alcohol wipes (for use by healthcareprofessionals only).

Not all pack sizes may be marketed.

Comprehensive instructions for the preparation and administration of Cimzia in a pre-filled syringe aregiven in the package leaflet.

This medicinal product is for single use only. Any unused product or waste material should bedisposed of in accordance with local requirements.

UCB Pharma S.A.

Allée de la Recherche 60

B-1070 Bruxelles

Belgium

EU/1/09/544/001

EU/1/09/544/002

EU/1/09/544/003

EU/1/09/544/004

Date of first authorisation: 01 October 2009

Date of latest renewal: 16 May 2014

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu