Cimzia

Overdose

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

Shelf life

18 months.

Contraindications

Active tuberculosis or other severe infections such as sepsis or opportunistic infections.

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

Incompatibilities

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

List of excipients

Sodium acetate

Sodium chloride

Water for injections

Pharmaceutical form

Solution for injection (injection).

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

Undesirable effects

Summary of the safety profile

Rheumatoid arthritis

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.

In the placebo-controlled studies, patients receiving Cimzia had an approximately 4 times greater duration of exposure compared with the placebo group. This difference in exposure is primarily due to patients on placebo being more likely to withdraw early. In addition, Studies RA-I and RA-II had a mandatory withdrawal for non-responders at Week 16, the majority of whom were on placebo.

The proportion of patients who discontinued treatment due to adverse events during the controlled trials was 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.

Axial spondyloarthritis

Cimzia was studied in 325 patients with active 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 and a 156-week open-label treatment period. 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 the PsA001 clinical study for up to 4 years which includes a 24-week placebo-controlled phase followed by a 24-week dose-blind period and a 168-week open-label treatment period. The safety profile for psoriatic arthritis patients treated with Cimzia was consistent with the safety profile in rheumatoid arthritis and previous experience with Cimzia.

Tabulated list of adverse reactions

Adverse reactions reported in rheumatoid arthritis clinical trials and postmarketing cases at least possibly related to Cimzia are listed in Table 1 below, according to frequency and system organ class. Frequency categories are defined as follows: Very common (> 1/10); Common (> 1/100 to < 1/10); Uncommon (> 1/1000 to < 1/100); Rare (> 1/10,000 to < 1/1000); Very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions in clinical trials and postmarketing

System Organ Class	Frequency	Adverse reactions
Infections and infestations	Common	bacterial infections (including abscess), viral infections (including herpes zoster, papillomavirus, influenza)
	Uncommon	sepsis (including multi-organ failure, septic shock), tuberculosis (including miliary, disseminated and extrapulmonary disease), fungal infections (includes opportunistic)
Neoplasms benign, malignant and unspecified (including cysts and polyps)	Uncommon	blood and lymphatic system malignancies (including lymphoma and leukaemia), solid organ tumours, non-melanoma skin cancers, pre-cancerous lesions (including oral leukoplakia, melanocytic nevus), benign tumours and cysts (including skin papilloma)
	Rare	gastrointestinal tumours, melanoma
	Not known	Merkel cell carcinoma*
Blood and the lymphatic system disorders	Common	eosinophilic disorders, leukopaenia (including neutropaenia, lymphopaenia)
	Uncommon	anaemia, lymphadenopathy, thrombocytopaenia, thrombocytosis
	Rare	pancytopaenia, splenomegaly, erythrocytosis, white blood 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 of symptoms of dermatomyositis**
Endocrine disorders	Rare	thyroid disorders
Metabolism and nutrition disorders	Uncommon	electrolyte imbalance, dyslipidaemia, appetite disorders, weight change
	Rare	haemosiderosis
Psychiatric disorders	Uncommon	anxiety and mood disorders (including associated symptoms)
	Rare	suicide attempt, delirium, mental impairment
Nervous system disorders	Common	headaches (including migraine), sensory abnormalities
	Uncommon	peripheral neuropathies, dizziness, tremor
	Rare	seizure, cranial nerve inflammation, impaired coordination or balance
	Not known	multiple sclerosis*, Guillain-Barré syndrome*
Eye disorders	Uncommon	visual disorder (including decreased vision), eye and eyelid inflammation, lacrimation disorder
Ear and labyrinth disorders	Uncommon	tinnitus, vertigo
Cardiac disorders	Uncommon	cardiomyopathies (including heart failure), ischaemic coronary artery disorders , arrhythmias (including atrial fibrillation), 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's phenomenon, livedo reticularis, telangiectasia
Respiratory, thoracic and mediastinal disorders	Uncommon	asthma and related symptoms, pleural effusion and symptoms, respiratory tract congestion and inflammation, 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, blood bilirubin increased
	Rare	cholelithiasis
Skin and subcutaneous tissue disorders	Common	rash
	Uncommon	alopecia, new onset or worsening of psoriasis (including palmoplantar pustular psoriasis) and related conditions, dermatitis and eczema, sweat gland disorder, skin ulcer, photosensitivity, acne, skin discolouration, dry skin, nail and nail bed disorders
	Rare	skin exfoliation and desquamation, bullous conditions, hair texture disorder, Stevens-Johnson syndrome**, erythema multiforme**
Musculoskeletal, connective tissue and bone disorders	Uncommon	muscle disorders, blood creatine phosphokinase increased
Renal and urinary disorders	Uncommon	renal impairment, blood in urine, bladder and urethral symptoms
	Rare	nephropathy (including nephritis)
Reproductive system and breast disorders	Uncommon	menstrual cycle and uterine bleeding disorders (including amenorrhea), breast disorders
	Rare	sexual dysfunction
General disorders and administration site conditions	Common	pyrexia, pain (any site), asthaenia, pruritus (any site), injection site reactions
	Uncommon	chills, influenza-like illness, altered temperature perception, night sweats, flushing
	Rare	fistula (any site)
Investigations	Uncommon	blood alkaline phosphatase increased, coagulation time prolonged
	Rare	blood uric acid increased
Injury, poisoning and procedural complications	Uncommon	skin injuries, impaired healing

*These events have been related to the class of TNF-antagonists, but incidence with certolizumab pegol 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 other indications: gastrointestinal stenosis and obstructions, general physical health deterioration, abortion spontaneous and azoospermia.

Description of selected adverse reactions

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.

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.

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

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.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

UK

The Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharamcovogilance

EArlsfort Terrace

IRL - Dublin 2

Tel: +353 1 676 4971

Fax: +353 1 676 2517

Website: www.hpra.ie

e-mail: [email protected]

Preclinical safety data

The pivotal non-clinical safety studies were conducted in the cynomolgus monkey. In rats and monkeys, 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 likely that this finding was caused by cellular uptake of the PEG moiety. In vitro functional studies of human vacuolated 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 urine being the main route of excretion.

Certolizumab pegol does not cross-react with rodent TNF. Therefore, reproductive toxicology studies have been performed with a homologous reagent recognising rat TNF. The value of these data to the evaluation of human risk may be limited. No adverse effects were seen on maternal well-being or female 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, reduced sperm 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 and neonatal 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 negligible transfer to the foetal compartment. In addition, experiments of FcRn-mediated transcytosis in cells transfected with human FcRn showed negligible transfer.

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

Therapeutic indications

Rheumatoid arthritis

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

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

- the treatment of severe, active and progressive RA in adults not previously treated with MTX or other 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.

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 C-reactive protein (CRP) and /or magnetic resonance imaging (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.

Pharmacotherapeutic group

immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors, ATC code: L04AB05

Pharmacodynamic properties

Pharmacotherapeutic group: immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors, ATC code: L04AB05

Mechanism of action

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. Cimzia selectively 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-dependent manner. Incubation of monocytes with Cimzia resulted in a dose-dependent inhibition of lipopolysaccharide (LPS)-induced TNFα and IL1β production in human monocytes.

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

Clinical efficacy

Rheumatoid arthritis

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 according to 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 to baseline. Cimzia was administered subcutaneously in combination with oral MTX for a minimum of 6 months with stable doses of at least 10 mg weekly for 2 months in both trials. There is no experience 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 a randomized, placebo-controlled, double-blind clinical trial (C-EARLY). In the C-EARLY trial patients were > 18 years of age and had > 4 swollen and tender joints each and must have been diagnosed with moderate 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 since diagnosis at baseline of 2.9 months and were DMARD naïve (including MTX). For both the Cimzia and placebo arms, MTX was initiated as of Week 0 (10 mg/week), titrated up to maximum tolerated dose 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/week respectively).

Table 2 Clinical trial description

Study number	Patient numbers	Active dose regimen	Study objectives
RA-I (52 weeks)	982	400 mg (0,2,4 weeks) with MTX 200 mg or 400 mg every 2 weeks with MTX	Evaluation for treatment of signs and symptoms and inhibition of structural damage. Co-primary endpoints: ACR 20 at Week 24 and change from baseline in mTSS at Week 52
RA-II (24 weeks)	619	400 mg (0,2,4 weeks) with MTX 200 mg or 400 mg every 2 weeks with MTX	Evaluation for treatment of signs and symptoms and inhibition of structural damage. Primary endpoint: ACR 20 at Week 24.
C-EARLY (to 52 weeks)	879	400 mg (0,2,4 weeks) with MTX 200 mg every 2 weeks with MTX	Evaluation for treatment of signs and symptoms and inhibition of structural damage in DMARD naïve patients. Primary endpoint: proportion of subjects in sustained remission* at Week 52
mTSS: 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 clinical trials compared to placebo. Responses were maintained through Weeks 52 (RA-I) and 24 (RA-II). Of the 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 of open-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 placebo and 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 Methotrexate combination (24 and 52 weeks)		Study RA-II Methotrexate combination (24 weeks)
Response	Placebo + MTX N=199	Cimzia 200 mg + MTX every 2 weeks N=393	Placebo + MTX N=127	Cimzia 200 mg + MTX every 2 weeks 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 Clinical Responsea.	1%	13%**
Cimzia vs. placebo: *p≤0.01, ** p<0.001 a. Major clinical response is defined as achieving ACR 70 response at every assessment over a continuous 6-month period Wald p-values are quoted for the comparison of treatments using logistic regression with factors for treatment and region. Percentage response based upon number of subjects contributing data (n) to that endpoint and time point which may differ from N

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

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

Response	Placebo+MTX N= 213	Cimzia 200 mg + MTX N= 655
Sustained remission* (DAS28(ESR) <2.6 at both Week 40 and Week 52)	15.0 %	28.9%**
Sustained low disease activity (DAS28(ESR) ≤3.2 at both Week 40 and Week 52)	28.6 %	43.8%**
*Primary endpoint of C-EARLY trial (to Week 52) Full analysis set, non-responder imputation for missing values. **Cimzia+MTX vs placebo+MTX: p<0.001 p value was estimated from a logistic regression model with factors for treatment, region, and time since 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) compared with 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+MTX treatment led to faster and greater responses than PBO+MTX treatment. These results were maintained over 52 weeks of treatment in DMARD-naïve subjects.

Radiographic response

In RA-I, structural joint damage was assessed radiographically and expressed as change in mTSS and its components, the erosion score and joint space narrowing (JSN) score, at Week 52, compared to baseline. Cimzia patients demonstrated significantly less radiographic progression than patients receiving placebo at Week 24 and Week 52 (see Table 5). In the placebo group, 52% of patients experienced 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 N=199 Mean (SD)	Cimzia 200 mg + MTX N=393 Mean (SD)	Cimzia 200 mg + MTX - Placebo + MTX Mean Difference
mTSS
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)	-1.0
p-values were < 0.001 for both mTSS and erosion score and ≤ 0.01 for JSN score. An ANCOVA was fitted to the ranked change from baseline for each measure with region and treatment as factors and rank baseline as a covariate.

Of the 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. Sustained inhibition of progression of structural damage was demonstrated in a subset of 449 of these patients who completed at least 2 years of treatment with Cimzia (RA-I and open-label extension study) and had evaluable data at 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 radiographic progression (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 N= 163 Mean (SD)	Cimzia 200 mg + MTX N = 528 Mean (SD)	Cimzia 200 mg + MTX - Placebo +MTX Difference*
mTSS Week 52	1.8 (4.3)	0.2 (3.2)**	-0.978 (-1.005, -0.500)
Erosion score Week 52	1.1 (3.0)	0.1 (2.1)**	-0.500 (-0.508, -0.366)
JSN score Week 52	0.7 (2.3)	0.1 (1.7)**	0.000 (0.000, 0.000)
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 the ranks with treatment, region, time since RA diagnosis at Baseline (≤4 months vs >4 months) as factors 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 as assessed 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 the studies compared to placebo. In both clinical trials, Cimzia-treated patients reported significantly greater 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-label extension 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 compared to 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 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 7. 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 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 treatment regimen week 18 to 34	Placebo + MTX     N=69	Cimzia 200 mg + MTX every 2 weeks N=70	Cimzia 400 mg + MTX every 4 weeks N=69
ACR 20 p-value*	45% N/A	67% 0.009	65% 0.017
ACR 50 p-value*	30% N/A	50% 0.020	52% 0.010
ACR 70 p-value*	16% N/A	30% 0.052	38% 0.005
N/A: Not Applicable *Wald p-values for Cimzia 200 mg vs. placebo and Cimzia 400 mg vs. placebo comparisons are estimated from a logistic regression model with factors for treatment

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. 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 maximum duration 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 study through 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 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 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 the subpopulations. Key efficacy outcomes from the AS001 clinical trial are shown in Table -8. Among patients remaining in the study, improvements in all afore-mentioned key efficacy outcomes were maintained 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)

Parameters	Ankylosing spondylitis		Non-radiographic axial spondyloarthritits		Axial spondyloarthritis Overall Population
	Placebo N=57	Cimzia all dosing regimens(a) N=121	Placebo N=50	Cimzia all dosing regimens(a) N=97	Placebo N=107	Cimzia all dosing regimens(a) N=218
ASAS20(b,c) Week 12 Week 24	37% 33%	60%* 69%**	40% 24%	61%* 68%**	38% 29%	61%** 68%**
ASAS40(c,d) Week 12 Week 24	19% 16%	45%** 53%**	16% 14%	47%** 51%**	18% 15%	46%** 52%**
ASAS 5/6(c,d) Week 12 Week 24	9% 5%	42%** 40%**	8% 4%	44%** 45%**	8% 5%	43%** 42%**
Partial remission(c,d) Week 12 Week 24	2% 7%	20%** 28%**	6% 10%	29%** 33%**	4% 9%	24%** 30%**
BASDAI 50(c,d) Week 12 Week 24	11% 16%	41%** 49%**	16% 20%	49%** 57%**	13% 18%	45%** 52%**
(a) Cimzia all dosing regimen = data from Cimzia 200 mg administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 plus Cimzia 400 mg administered every 4 weeks preceded 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 factors for 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 at several time points including 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.

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

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

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

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 ACR 20 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.

The 24-week double-blind placebo controlled treatment period of the study was followed by a 24-week dose-blind treatment period and an 168-week open-label treatment period. The maximum duratio

Pharmacokinetic properties

Certolizumab pegol plasma concentrations were broadly dose-proportional. Pharmacokinetics observed in patients with rheumatoid arthritis were consistent with those seen in healthy subjects.

Absorption

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

Distribution

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

Biotransformation and elimination

PEGylation, the covalent attachment of PEG polymers to peptides, delays the elimination of these entities 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 arthritis population pharmacokinetic analysis, with an inter-subject variability of 30.8% (CV) and an inter-occasion variability of 22.0%. The presence of antibodies 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 RA patients weighing 40 kg and 120 kg.

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

Special populations

Renal impairment

Specific clinical trials have not been performed to assess the effect of renal impairment on the pharmacokinetics of certolizumab pegol or its PEG fraction. However, population pharmacokinetic analysis based on subjects with mild renal impairment showed no effect of creatinine clearance. There are 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 on renal function but have not been assessed in patients with renal impairment.

Hepatic impairment

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

Elderly patients (> 65 years old)

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

Gender

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

Pharmacokinetic/pharmacodynamic relationship

On the basis of Phase II and Phase III clinical trial data, a population exposure-response relationship was established between average plasma concentration of certolizumab pegol during a dosing interval (Cavg) and efficacy (ACR 20 responder definition). The typical Cavg that produces half the maximum probability of ACR 20 response (EC50) was 17 µg/ml (95% CI: 10-23 µg/ml).

Date of revision of the text

12/2017

Name of the medicinal product

Cimzia 200 mg solution for injection in pre-filled syringe

Marketing authorisation holder

UCB Pharma S.A.

Allée de la Recherche 60

B-1070 Bruxelles

Belgium

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.

Nature and contents of container

One ml pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber), containing 200 mg of certolizumab pegol.

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 healthcare professionals only).

Not all pack sizes may be marketed.

Marketing authorisation number(s)

EU/1/09/544/001

EU/1/09/544/002

EU/1/09/544/003

EU/1/09/544/004

Fertility, pregnancy and lactation

Women of childbearing potential

The use of adequate contraception should be considered for women of childbearing potential. For women planning pregnancy, continued contraception may be considered for 5 months after the last Cimzia dose due to its elimination rate , but the need for treatment of the woman should also be taken into account (see below).

Pregnancy

Data from more than 500 prospectively collected pregnancies exposed to Cimzia with known pregnancy outcomes, including more than 400 pregnancies exposed during the first trimester, does not indicate a malformative effect of Cimzia. However, the available clinical experience is too limited to, with a reasonable certainty, conclude that there is no increased risk associated with Cimzia administration during 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. Due to its inhibition of TNFα, Cimzia administered during pregnancy could affect normal immune response in the newborn.

Cimzia should only be used during pregnancy if clinically needed.

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

In a clinical study 16 women were treated with certolizumab pegol (200 mg every 2 weeks or 400 mg every 4 weeks) during pregnancy. Certolizumab pegol plasma concentrations measured in 14 infants at birth were Below the Limit of Quantification (BLQ) in 13 samples; one was 0.042 µg/ml with an infant/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 is recommended to wait a minimum of 5 months following the mother's last Cimzia administration during pregnancy before administration of live or live-attenuated vaccines (e.g. BCG vaccine), unless the benefit of the vaccination clearly outweighs the theoretical risk of administration of live or live-attenuated vaccines to the infants.

Breastfeeding

In a clinical study in 17 lactating women treated with Cimzia, minimal transfer of certolizumab pegol from plasma to breast milk was observed. The percentage of the maternal certolizumab pegol dose reaching an infant during a 24 hour period was estimated to 0.04% to 0.30 %. In addition, since certolizumab 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.

Consequently, Cimzia can be used during breastfeeding.

Fertility

Effects on sperm motility measures and a trend of reduced sperm count in male rodents have been observed with no apparent effect on fertility.

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

Qualitative and quantitative composition

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

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

Special warnings and precautions for use

Infections

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 up to 5 months, monitoring should be continued throughout this period.

Treatment with Cimzia must not be initiated in patients with a clinically important active infection, including chronic or localised infections, until the infection is controlled.

Patients who develop a new infection while undergoing treatment with Cimzia should be monitored closely. Administration of Cimzia should be discontinued if a patient develops a new serious infection until the infection is controlled. Physicians should exercise caution when considering the use of Cimzia in patients with a history of recurring or opportunistic infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications.

Patients with rheumatoid arthritis may not manifest typical symptoms of infection, including fever, due to their disease and concomitant medicinal products. Therefore, early detection of any infection, particularly atypical clinical presentations of a serious infection, is critical to minimise delays in diagnosis and initiation of treatment.

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

Tuberculosis

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 patients with a personal history of tuberculosis, with possible previous exposure to others with active tuberculosis, and with previous and/or current use of immunosuppressive therapy. Appropriate screening tests, e.g. tuberculin skin test and chest X-ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient's alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

If active tuberculosis is diagnosed prior to or during treatment, Cimzia therapy must not be initiated and must be discontinued.

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

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

Use of anti-tuberculosis therapy should also be considered before the initiation of Cimzia in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and in patients who have significant risk factors for tuberculosis despite a negative test for latent tuberculosis. Biological tests for tuberculosis screening should be considered before starting Cimzia treatment if there is any potential latent tuberculosis infection, regardless of BCG vaccination.

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

Hepatitis B virus (HBV) reactivation

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including certolizumab pegol, who are chronic carriers of this virus (i.e., surface antigen positive). 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.

Carriers of HBV who require treatment with Cimzia should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of 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.

Malignancies and lymphoproliferative disorders

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 of malignancy or when considering continuing treatment in patients who develop malignancy.

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

In clinical trials with Cimzia and other TNF-antagonists, more cases of lymphoma and other malignancies have been reported among patients receiving TNF-antagonists than in control patients receiving placebo. In the post marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation.

No trials have been conducted that include patients with a history of malignancy, or that continue treatment in patients who develop malignancy, while receiving Cimzia.

Skin cancers

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-antagonists including certolizumab pegol. 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 (up to 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age) in the post marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.

Post-marketing 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.

Chronic obstructive pulmonary disease (COPD)

In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking.

Congestive heart failure

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

Haematological reactions

Reports of pancytopaenia, including aplastic anaemia, have been rare with TNF-antagonists. Adverse reactions of the haematologic system, including medically significant cytopaenia (e.g. leukopaenia, pancytopaenia, thrombocytopaenia) have been reported with Cimzia. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on Cimzia. Discontinuation of Cimzia therapy should be considered in patients with confirmed significant haematological abnormalities.

Neurological events

Use of TNF-antagonists has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of TNF-antagonist treatment should be carefully considered before initiation of Cimzia therapy. Rare cases of neurological disorders, including seizure disorder, neuritis and peripheral neuropathy, have been reported in patients treated with Cimzia.

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.

There are limited data on the use of Cimzia in patients who have experienced a severe hypersensitivity reaction towards another TNF-antagonist; in these patients caution is needed.

Immunosuppression

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

Autoimmunity

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

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.

Concomitant use with other biologics

Severe infections and neutropaenia were reported in clinical trials with concurrent use of anakinra (an interleukin-1 antagonist) or abatacept (a CD28 modulator) and another TNF-antagonist, etanercept, with no added benefit compared to TNF-antagonist therapy alone. Because of the nature of the adverse events seen with the combination of another TNF-antagonist with either abatacept or anakinra therapy, similar toxicities may also result from the combination of anakinra or abatacept and other TNF-antagonists. Therefore the use of certolizumab pegol in combination with anakinra or abatacept is not recommended.

Surgery

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

Activated partial thromboplastin time (aPTT) assay

Interference with certain coagulation assays has been detected in patients treated with Cimzia. Cimzia may cause erroneously elevated aPTT assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilised silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. There is no evidence that Cimzia therapy has an effect on coagulation in vivo. After patients receive Cimzia, careful attention should be given to interpretation of abnormal coagulation results. Interference with thrombin time (TT) and prothrombin time (PT) assays have not been observed.

Elderly patients

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

Effects on ability to drive and use machines

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

Dosage (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 adult 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 instructed.

Special populations

Paediatric population (< 18 years old)

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

Elderly patients (> 65 years old)

No dose adjustment is required. Population pharmacokinetic analyses showed no effect of age.

Renal and hepatic impairment

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

Method of administration

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

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

Special precautions for disposal and other handling

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

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

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 01 October 2009

Date of latest renewal: 16 May 2014

Interaction with other medicinal products and other forms of interaction

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

The combination of certolizumab pegol and anakinra or abatacept is not recommended.

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