4.1. 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) (also known as radiographic axial spondyloarthritis)

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 (also known as non-radiographic axial spondyloarthritis)

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.

Plaque psoriasis

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

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 reminder card.

Posology

Rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, plaque psoriasis

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. 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).

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.

Plaque psoriasis

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

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

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 been established. Cimzia should not be used in children and adolescents below 18 years of age.

Elderly patients (≥ 65 years old)

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

Renal and hepatic impairment

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

Method of administration

The total content (1 ml) of the pre-filled pen 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 pen if their physician determines that it is appropriate and with medical follow-up as necessary. The physician should discuss with the patient which injection presentation option is the most appropriate.

4.3. Contraindications

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

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

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

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.

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 (see section 4.3).

Treatment with Cimzia must not be initiated in patients with a clinically important active infection, including chronic or localised infections, until the infection is controlled (see section 4.3).

Patients who develop a new infection while undergoing treatment with Cimzia should be 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 reminder 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 (see section 4.3).

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 (see section 4.8). 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 (see section 4.8). Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.

Paediatric malignancy

Malignancies, some fatal, have been reported among children, adolescents and young adults (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 (see section 4.3). 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 (see section 4.8). 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.

Latex-sensitivity

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

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 (see section 4.8). 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 (see section 4.8).

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 (see section 4.5).

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.

4.5. 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 (see section 4.4).

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.

4.6. 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, the clinical need for ongoing Cimzia treatment should be evaluated. If the decision is made to clear Cimzia from the body prior to conception, contraception should be continued for 5 months after the last Cimzia dose (see section 5.2).

Pregnancy

Human data

A large amount of data (more than 1500 pregnancies exposed to Cimzia during the first trimester) from prospectively reported pregnancies with known pregnancy outcomes, indicate no malformative nor feto/neonatal toxicity. Continuous data collection is ongoing with pharmacovigilance cases reporting and a pregnancy registry.

In a pregnancy register (the OTIS study) the proportion of major birth defects in live-born infants was 15/132 (11.4%) in women treated with Cimzia at least during the first trimester, and 8/126 (6.3%) in women with the same indicated diseases but not treated with Cimzia (relative risk 1.85; 95% CI 0.74 to 4.60). A similar association was seen when women treated with Cimzia were compared with women not having a disease consistent with approved Cimzia indications (proportion 10/126 [7.9%] and relative risk 1.65; 95% CI 0.75 to 3.64). No pattern of major or minor defects was identified.

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

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

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.

Animal data

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.

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).

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

Breastfeeding

Cimzia can be used during 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.

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 (see section 5.3).

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.

4.7. 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 (see section 4.8).

4.8. 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.

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 initially studied in 325 patients with active axial spondyloarthritis (including ankylosing spondylitis and non-radiographic axial spondyloarthritis) in the AS001 clinical study for up to 4 years, which includes a 24-week placebo-controlled phase followed by a 24-week dose-blind period and a 156-week open-label treatment period. Cimzia was subsequently studied in 317 patients with non-radiographic axial spondyloarthritis in a placebo-controlled study for 52 weeks (AS0006). Cimzia 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). Cimzia was also studied in a 96-week open-label study in 89 axSpA patients with a history of documented anterior uveitis flares. In all 4 studies, the safety profile for these patients 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.

Plaque psoriasis

Cimzia was studied in 1112 patients with psoriasis in controlled and open-label studies for up to 3 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 was generally similar and consistent with previous experience with Cimzia.

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

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

The most common adverse reactions reported through Week 16 belonged to the system organ classes Infections and infestations, reported in 6.1% of patients on Cimzia and 7% of patients on placebo, General disorders and administration site conditions, reported in 4.1% of patients on Cimzia and 2.3% of patients on placebo, and Skin and subcutaneous tissue disorders, reported in 3.5% of patients on Cimzia and 2.8% of patients on placebo.

Tabulated list of adverse reactions

Adverse reactions reactions based primarily on experience from the placebo-controlled 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*, Kaposi's sarcoma

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**, lichenoid reactions

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 (see sections 4.3 and 4.4).

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). 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).

The incidence rate of new cases of infections in placebo-controlled clinical trials in psoriasis was 1.37 per patient-year for all Cimzia-treated patients and 1.59 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections and viral infections (including herpes infections). The incidence of serious infections was 0.02 per patient-year in Cimzia treated patients. No serious infections were reported in the placebo-treated patients. 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 (see section 4.4). One case of lymphoma was also observed in the Phase III psoriatic arthritis clinical trial.

Excluding non-melanoma skin cancer, 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 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. 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. 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.