Cimzia 200 mg solution for injection in pre-filled syringe

II - CCDS v5.0 - Prospective pregnancy outcomes 

II - CCDS v5.0 - Prospective pregnancy outcomes 

Update to Section 4.8 of the SPC with information relating to C-VIEW Clinical Study Report

PRAC Recommendation - Addition of Kaposi’s sarcoma as an adverse event of unknown frequency

PRAC Recommendation - Addition of Kaposi’s sarcoma as an adverse event of unknown frequency

section 4.2: additional sentence "After at least 1 year of treatment with Cimzia, in patients with sustained remission, a reduced maintenance dose of 200 mg every 4 weeks may be considered (see section 5.1)" in Axial Spondylorthritis

section 4.8: additional text "Cimzia was also 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-week open-label run-in phase (N=736) followed by a 48-week placebo-controlled phase (N=313) for patients in sustained remission (C-OPTIMISE)." in Axial spondylorathritis

section 5.1: additional section "C-Optimise", additional figure (Graph), additional table of data; additional section under "immunogenicity". Section "Axial spondyloarthritis" moved to the end with additional study data related to ASooo6 and C-OPTIMISE; deletion of section "for all indication".

section 10: revision date changed to 07/2020

    Axial spondyloarthritis
•    The starting dose for adults with axial spondyloarthritis is 400 mg given at weeks 0, 2 and 4. 
•    This is followed by a maintenance dose of 200 mg every 2 weeks (from week 6) or 400 mg every 4 weeks (from week 8) as instructed by your physician. If you have received Cimzia for at least 1 year and respond to the medicine, your physician may prescribe a reduced maintenance dose of 200 mg every 4 weeks.
 

4.4       Special warnings and precautions for use

Traceability

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

4.8       Undesireable effects      

Plaque psoriasis

Cimzia was studied in 1112 patients with psoriasis in controlled and open-label studies for up to 18 months3 years. 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 weeks and Cimzia 200 mg every 2 weeks were was generally similar and consistent with previous experience with Cimzia.

Description of selected adverse reactions

Infections

In the placebo-controlled clinical trials in rheumatoid arthritis, there were more new cases of serious infection in the Cimzia treatment groups (0.07 per patient-year; all doses), compared with placebo (0.02 per patient-year).

Malignancies and lymphoproliferative disorders

Excluding non-melanoma skin cancer, 9 11 malignancies including 1 case of lymphoma were observed in the Cimzia psoriasis clinical trials in which a total of 1112 patients were treated, representing 1481 2300 patient-years.

Autoimmunity

In the rheumatoid arthritis pivotal studies, for subjects who were ANA negative at baseline, 16.7% of those treated with Cimzia developed positive ANA titers, compared with 12.0% of subjects in the placebo group.

5.1      Pharmacodynamic properties

Plaque psoriasis

Patients with an inadequate response at Week 16 (PASI 50 non-responders) were eligible to receive Cimzia 400 mg every 2 weeks until Week 48 in an open-label manner for a maximum of 128 weeks.

All subjects who did not achieve a PASI 75 response at Week 16 entered an escape arm and received Cimzia 400 mg every 2 weeks in an open-label manner for a maximum of 128 weeks.

In all three studies, the blinded 48-week maintenance period was followed by a 96-week open-label treatment 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 200 mg every 2 weeks.

Maintenance of response

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

After an additional 96 weeks of open-label treatment (Week 144) the maintenance of response was evaluated. 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 weeks 48 to 144 on Cimzia 200 mg every 2 weeks had their dose increased to Cimzia 400 mg every 2 weeks for maintenance of response. In an analysis in which all patients with treatment failures were considered non-responders, the maintenance of response of the Cimzia 200 mg every 2 weeks treatment group, for the respective endpoint, after an additional 96 weeks of open-label therapy, was 84.5% for PASI 75 for study subjects who were responders at Week 16 (N=132/186) and 78.4% for PGA clear or almost clear (N=95/186). The maintenance of response of the Cimzia 400 mg every 2 weeks treatment group, who entered the open-label period at Cimzia 200 mg every 2 weeks, was 84.7% for PASI 75 for study subjects who were responders at Week 16 (N=134/175) and 73.1% for PGA clear or almost clear(N=103/175).

These response rates were based on a logistic regression model where missing data were imputed over 48 or 144 weeks using multiple imputation (MCMC method) combined with NRI for treatment failures.

In the CIMPACT study, among PASI 75 responders at Week 16 who received Cimzia 400 mg every 2 weeks and were re-randomized to either Cimzia 400 mg every 2 weeks (48 patients), Cimzia 200 mg every 2 weeks, or placebo, there was a higher percentage of PASI 75 responders at Week 48 in the Cimzia groups as compared to placebo (98.0%, 80.0%, and 36.0%, respectively). Among PASI75 responders at Week 16 who received Cimzia 200 mg every 2 weeks and were re-randomized to either Cimzia 400 mg every 4 weeks, Cimzia 200 mg every 2 weeks (36 patients), 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%, and 45.5%, respectively). After an additional 96 weeks of open-label treatment (Week 144), the maintenance of PASI 75 response in patients re-randomized to Cimzia 400 mg every 2 weeks or Cimzia 200 mg every 2 week, who entered the open-label period at Cimzia 200 mg every two weeks, was 83.3% in both groups. Non-responder imputation was used for missing data.

Quality of life / Patient reported outcomes

In addition, at Week 16, Cimzia treatment was associated with a greater proportion of patients achieving 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 Anxiety and Depression Scale (HADS)-D.

Improvements in all afore mentioned outcomes were maintained through Week 48.

Plaque psoriasis

In the Phase III placebo- and active-controlled studies, the percentages of patients who were positive for  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 weeks respectively. In CIMPASI-1 and CIMPASI-2, sixty patients were antibody positive, 27 of these patients were evaluable for neutralizing antibodies and tested positive. First occurrences of antibody positivity in the open-label treatment period were observed in 2.8% (19/668) of patients. Antibody positivity was associated with lowered drug plasma concentration and in some patients with reduced efficacy.

10.      DATE OF REVISION OF THE TEXT

{MM/YYYY}April 2020

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

In section 4.1 & 5.1: 

- additional description added

In section 4.8:

- additional clinical study data added

- additional description added

In section 5.2:

- additional clinical study data added

6.3     Shelf life

18 months.2 years.

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

6.4     Special precautions for storage

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 of maximum 10 days with protection from light. At the end of this period the pre-filled syringes must be used or discarded.

-‘’Plaque psoriasis” information has been added in the following sections ‘’ 4.1 Therapeutic indications’’,’’ 4.2 Posology and method of administration’’, ‘’ 4.8 Undesirable effects”, 5.1 Pharmacodynamic properties’’;
-‘’Posology’’ and ‘’Latex-sensitivity’’ information has also been updated in section ’’ 4.2 Posology and method of administration’’;
-‘’Rheumatoid arthritis”, ‘’Tabulated list of adverse reactions”, ‘’Description of selected adverse reactions-Infections, Malignancies and lymphoproliferative disorders” has been updated in section ‘’4.8 Undesirable effects”;
-‘’Maintenance of response”, ‘’Quality of life / Patient reported outcomes”,’’Immunogenicity” has been updated in section ‘’5.1 Pharmacodynamic properties’’;
-‘’Distribution’’, ’’Pharmacokinetic/pharmacodynamic relationship” has been updated in section’’ 5.2 Pharmacokinetic properties’’;
- The section “6.5 Nature and contents of container’’ has been updated;
-‘’Section 10. DATE OF REVISION OF THE TEXT’’ has been updated {MM/YYYY} 06/2018.

SmPC changes: in sections 4.8 and 5.1: to add information about the long-term data, following the submission of two final study reports.

The following sections have been updated: 

Section 4.1: to add a new indication.

Section 5.1. to add new results of clinical trials.

 The following are the main changes, all other changes are minor.

3.       PHARMACEUTICAL form

 4.1 Therapeutic indications 
Axial spondyloarthritis

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

Ankylosing spondylitis (AS)

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

Axial spondyloarthritis without radiographic evidence of AS

Adults with severe active axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated CRP and /or MRI, who have had an inadequate response to, or are intolerant to NSAIDs.

Psoriatic arthritis

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

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

For details on therapeutic effects, see section 5.1.

 
4.2 Posology and method of administration

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

Posology

Loading dose

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

Maintenance dose

Rheumatoid arthritis

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

Axial spondyloarthritis

After the starting dose, the recommended maintenance dose of Cimzia for adults patients with axial spondyloarthritis is 200 mg every 2 weeks or 400 mg every 4 weeks.

Psoriatic arthritis

After the starting dose, the recommended maintenance dose of Cimzia for adult patients with psoriatic arthritis is 200 mg every 2 weeks. Once clinical response is confirmed, an alternative maintenance dosing 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 achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment.

Missed dose

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

 4.8 Undesirable effects

Axial spondyloarthritis

Cimzia was studied in 325 patients with active axial spondyloarthritis in a placebo-controlled clinical trial (AS001) for up to 30 months. The safety profile for axial spondyloarthritis patients treated with Cimzia was consistent with the safety profile in rheumatoid arthritis and previous experience with Cimzia.

Psoriatic arthritis

Cimzia was studied in 409 patients with psoriatic arthritis in a placebo-controlled clinical trial (PsA001) for up to 30 months. The safety profile for psoriatic arthritis patients treated with Cimzia was consistent with the safety profile in rheumatoid arthritis and previous experience with Cimzia.

Malignancies and lymphoproliferative disorders

One case of lymphoma was also observed in the Phase III psoriatic arthritis clinical trial.

Creatine phosphokinase elevations

The frequency of creatine phosphokinase (CPK) elevations was generally higher in patients with axSpA as compared to the RA population. The frequency was increased both in patients treated with placebo (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 axSpA study were mostly mild to moderate, transient in nature and of unknown clinical significance with no cases leading to withdrawal.

Reporting of suspected adverse reactions

Healthcare professionals are asked to report any suspected adverse reactions via IMB and MHRA (refer to SmPC for further details)

 
5.1 Pharmacodynamic properties

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 arthritis diagnosed 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 mg every 2 weeks during the initial open label period. Responders (achieved ACR 20) at week 16 were randomised at week 18 to Cimzia 200 mg every 2 weeks, Cimzia 400 mg every 4 weeks, or placebo in combination with MTX for an additional 16 weeks (total trial length: 34 weeks). These 3 groups were well balanced with regards to clinical response following the active run-in period (ACR 20: 83-84% at week 18).

The primary endpoint of the study was the ACR 20 responder rate at week 34. The results at week 34 are shown in Table 5. Both Cimzia regimens showed sustained clinical response and were statistically 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: 5 ACR response in DoseFlex clinical trial at week 34 (refer to SmPC for further details)

Axial spondyloarthritis

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 axial spondyloarthritis for at least 3 months as defined by the Assessment of Spondyloarthritis International Society (ASAS) Classification Criteria for axial spondyloarthritis. The axial spondyloarthritis overall population included subpopulations with and without (non-radiographic axial spondyloarthritis (nr-axSpA)) radiographic evidence for ankylosing spondylitis (AS).  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) and increased CRP or current evidence of sacroiliitis on Magnetic Resonance Imaging (MRI).Patients must have been intolerant to or had an inadequate response to at least one NSAID. Overall 16% of patients 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 received concomitant NSAIDs.The primary efficacy endpoint was the ASAS20 response rate at Week 12.

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 as compared 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 mg every 2 weeks and Cimzia 400 mg every 4 weeks treatment groups compared to placebo group at every visit from Week 1 through Week 24 (p≤0.001 at each visit). At Weeks 12 and 24, the percentage of 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 axial spondyloarthritis subpopulations. In women, ASAS20 responses were not statistically significantly different from placebo until after the Week 12 time point.

Improvements in ASAS 5/6, 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 the subpopulations.  Key efficacy outcomes from the AS001 clinical trial are shown in Table 5.

Table: 5 Key efficacy outcomes in AS001 clinical trial (percent of patients) (refer to SmPC for further details)

Spinal Mobility

Spinal mobility was assessed by BASMI at Baseline, Week 12 and Week 24. Clinically meaningful and statistically significant differences in Cimzia-treated patients compared with placebo-treated patients were demonstrated at each post-baseline visit.  The difference from placebo tended to be greater in nr-axSpA than in the AS subpopulation which  may be due to less chronic structural damage in nr-axSpA patients.

Physical function response and health-related outcomes

In the AS001 clinical trial, Cimzia-treated patients reported significant improvements in physical function as assessed by the BASFI and in pain as assessed by the Total and Nocturnal Back Pain NRS scales 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 by the ankylosing spondylitis QOL (ASQoL) and the SF-36 Physical and Mental Component Summaries and all domain scores as compared to placebo. Cimzia-treated patients reported significant improvements in axial spondyloarthritis-related productivity at work and within household, as reported by the Work Productivity Survey as compared to placebo. These improvements were sustained up to Week 48.

Inhibition of inflammation in Magnetic Resonance imaging (MRI)

In an imaging sub-study including 153 patients, signs of inflammation were assessed by MRI at week 12 and expressed as change from baseline in SPARCC (Spondyloarthritis Research Consortium of Canada) score for sacroiliac joints and ASspiMRI-a score in the Berlin modifications for the spine. Significant inhibition of inflammatory signs in both sacroiliac joints and the spine was observed in the Cimzia-treated patient (all doses group), in the overall axial spondyloarthritis population as well as in the sub-populations of ankylosing spondylitis and non-radiographic axial spondyloarthritis.

Psoriatic arthritis

The efficacy and safety of Cimzia were assessed in a multicentre, randomised, double-blind, placebo controlled clinical trial (PsA001) in 409 patients ≥18 years of age with adult-onset active psoriatic arthritis 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 or more DMARDs. Previous treatment with one TNF-antagonist was allowed and 20% of patients had prior 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 mg every 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 endpoints were the percentage of patients achieving ACR20 response at Week 12 and change from baseline in modified Total Sharp Score (mTSS) at Week 24. Efficacy and safety of Cimzia in patients with PsA whose predominant symptoms were sacroiliitis or axial spondyloarthritis have not been separately analysed.

ACR response

Cimzia-treated patients had a statistically significant higher ACR20 response rate at Week 12 and Week 24 compared with placebo-treated patients (p<0.001). The percentage of ACR20 responders was clinically relevant for the Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 4 weeks treatment groups compared to placebo group at every visit after baseline through Week 24 (nominal p≤0.001 at each visit). At week 12 and 24 improvements in parameters of peripheral activity characteristic 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). Among 273 patients initially randomised to Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 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, respectively. Of the 135 patients randomised to Cimzia 400 mg every 4 weeks, 89, 62 and 41 patients had an ACR 20/50/70 response, respectively. Cimzia treated patients also had significant improvements in ACR50 and 70 response rates.  Key efficacy outcomes from the PsA001 clinical trial are shown in Table 7.

Table: 7 Key efficacy outcomes in PsA001 clinical trial (percent of patients) (refer to SmPC for further details)

Radiographic response

In PsA001 clinical trial, inhibition of progression of structural damage was assessed radiographically and 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. Cimzia treatment inhibited the radiographic progression compared with placebo treatment at Week 24 as measured by change from baseline in total mTSS Score (LS mean [±SE] score was 0.28 [±0.07] in the placebo group compared with 0.06 [± 0.06] in the Cimzia all doses group; p=0.007). Inhibition of radiographic progression was maintained with Cimzia treatment up to Week  48 in the subset of patients at higher risk of radiographic progression (patients with a Baseline mTSS score of > 6).

Physical function response and health-related outcomes

In PsA001 clinical trial, Cimzia-treated patients reported significant improvements in physical function as assessed by the Health Assessment Questionnaire – Disability Index (HAQ-DI), in pain as assessed by the Patient Assessment of Arthritis Pain (PAAP) and in tiredness (fatigue) as reported by the Fatigue Assessment Scale (FAS) as compared to placebo. Cimzia-treated patients reported significant improvements in health-related quality 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 reported by the Work Productivity Survey compared to placebo. These improvements were sustained up to Week 48.

Immunogenicity

Axial spondyloarthritis

The overall percentage of patients with antibodies to Cimzia detectable on at least one occasion up to Week 24 was 4.4% in the phase III placebo controlled trial in patients with axial spondyloarthritis. Antibody formation was associated with lowered drug plasma concentration.

Psoriatic arthritis

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. The number of patients with antibodies to Cimzia in this trial was insufficient to make valid assessment of the impact of the antibody formation on efficacy.

 4.2       Posology and method of administration

Method of administration

4.4     Special warnings and precautions for use

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), have been reported in patients treated with TNF-antagonists. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. The majority of reported TNF-antagonist cases occurred in adolescent and young adult males with Crohn’s disease or ulcerative colitis. Almost all of these patients had received treatment 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 in patients treated with Cimzia cannot be excluded.

4.8         Undesirable effects

Cimzia was studied in 4,049 patients with rheumatoid arthritis in controlled and open label trials for up to 92 months. The data in Table 1 are based primarily on the placebo controlled Studies involving 2,965 patients receiving Cimzia and 1,137 patients receiving placebo during the controlled period.

The proportion of patients who discontinued treatment due to adverse events during the controlled trials 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 and administration 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% of patients on placebo.

Table :1.          Adverse drug reactions in clinical trials and postmarketing

System Organ Class                 Frequency        Adverse Drug Reactions

Ear and labyrinth disorders          Uncommon      tinnitus, vertigo

Infections

The incidence rate of new cases of infections in placebo-controlled clinical trials in rheumatoid arthritis 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 tract infections, and lower respiratory tract infections and herpes viral infections (see sections 4.3 and 4.4).

In the placebo-controlled clinical trials, there were more new cases of serious infection 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, tuberculosis infections. Serious infections also included invasive opportunistic infections (e.g. pneumocystosis, fungal oesophagitis, nocardiosis and herpes zoster disseminated). There is no evidence of an increased risk of infections with continued exposure over time (see section 4.4).

Malignancies and lymphoproliferative disorders

Excluding non-melanoma of the skin, 121 malignancies including 5 cases of lymphoma were observed in 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 rate of 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).

Autoimmunity

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

Injection site reactions

In the placebo-controlled rheumatoid arthritis clinical trials, 5.8% of patients treated with Cimzia developed 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 patients treated with Cimzia with no cases leading to withdrawal.

5.1     Pharmacodynamic properties

Immunogenicity

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

4.4     Special warnings and precautions for use

Hypersensitivity

Severe hypersensitivity reactions have been reported rarely following Cimzia administration. Some of these reactions occurred after the first administration of Cimzia. If severe reactions occur, administration of Cimzia should be discontinued immediately and appropriate therapy instituted.

4.4     Special warnings and precautions for use

Infections

Physicians should exercise caution when considering the use of Cimzia in patients with a history of recurring or opportunistic infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications.

Vaccinations

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

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

Pregnancy

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

Non-clinical studies suggest low or negligible level of placental transfer of a homologue Fab-fragment of certolizumab pegol (no Fc region) (see section 5.3). Limited clinical data show low levels of certolizumab pegol in plasma of an infant born by a treated woman. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to certolizumab pegol in utero is not recommended for a minimum of 5 months following the mother’s last Cimzia administration during pregnancy (see section 4.4).

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

4.8         Undesirable effects

Gastrointestinal disorders Common nausea

5.3     Preclinical safety data

Distribution studies have demonstrated that placental and milk transfer of cTN3 PF to the foetal and neonatal circulation is negligible. Data from a human closed-circuit placental transfer model in vitro suggest low or negligible transfer to the foetal compartment (see section 4.6).

Hepatitis B Virus (HBV) reactivation

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

Patients should be tested for HBV infection before initiating treatment with Cimzia. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.As HBV infection has also been reported with Cimzia, patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating Cimzia therapy. Adequate data on treating patients who are carriers of HBV with TNF antagonist therapy, in conjunction with anti-viral therapy, to prevent HBV reactivation are not available.

Carriers of HBV who require treatment with TNF antagonistsCimzia should be closely monitored for signs and symptomsclinical and laboratory signs of active HBV infection throughout therapy and for 5 several months following termination of therapy, especially if the patient is on concomitant corticosteroid therapy. Adequate data of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, Cimzia should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.