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Cimzia 200 mg solution for injection (2012)

Active ingredients: Certolizumab pegol

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).

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 Cimzia 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 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 (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.

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 Cimzia, 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.

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.

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 in trials. If severe reactions occur, administration of Cimzia should be discontinued immediately and appropriate therapy instituted.

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

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 Cimzia 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

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, and particular attention paid with respect to occurrence of infections.

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 Cimzia 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.

Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use adequate contraception to prevent pregnancy and continue its use for at least 5 months after the last Cimzia administration.

Pregnancy

There are no adequate data from the use of Cimzia in pregnant women.

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

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

Breast-feeding

There is insufficient information on the excretion of certolizumab pegol in human or animal breast milk. Since immunoglobulins are excreted into human breast milk, a risk to the breast-feeding child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Cimzia should be made taking into account the benefit of breast-feeding to the child and the benefit of Cimzia therapy to the woman.

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

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).

Undesirable effects

Cimzia was studied in 2,367 patients with rheumatoid arthritis in controlled and open label trials for up to 57 months. The data in Table 1 are based primarily on the pivotal controlled Studies involving 1,774 patients receiving Cimzia and 647 patients receiving placebo during the controlled period.

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

The proportion of patients who discontinued treatment due to adverse events during the controlled trials was 5% for patients treated with Cimzia and 2.5% for patients treated with placebo.

The most common adverse reactions belonged to the system organ classes Infections and infestations, reported in 15.5% of patients on Cimzia and 7.6% of patients on placebo, and General disorders and administration site conditions, reported in 10.0% of patients on Cimzia and 9.7% of patients on placebo.

Tabulated list of adverse reactions

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

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

Infections and infestations

Common: bacterial infections (including abscess), viral infections (including herpes, papillomavirus, influenza)

Uncommon: sepsis (including multi-organ failure, septic shock), tuberculosis, 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

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, autoantibody positive

Rare: angioneurotic oedema, sarcoidosis, serum sickness, panniculitis (including erythema nodosum)

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: vertigo

Rare: tinnitus

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

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 Cimzia is not known.

The additional following ADRs have been observed uncommonly with Cimzia in other indications: gastrointestinal stenosis and obstructions, general physical health deterioration, abortion spontaneous and azoospermia.

Infections

The incidence of new cases of infections in placebo-controlled clinical trials in rheumatoid arthritis was 0.91 per patient-year for all Cimzia-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections (see sections 4.3 and 4.4).

In the placebo-controlled clinical trials, there were more new cases of serious infection in the Cimzia treatment groups (0.06 per patient-year; all doses), compared with placebo (0.02 per patient-year). Serious infections included tuberculosis and invasive opportunistic infections (e.g. pneumocystosis, fungal oesophagitis, nocardiosis and herpes zoster disseminated). There is no evidence of an increased risk of infections with continued exposure over time (see section 4.4).

Malignancies and lymphoproliferative disorders

Excluding non-melanoma of the skin, 30 malignancies including 3 cases of lymphoma were observed in the Cimzia RA clinical trials in which a total of 2,367 patients were treated, representing 4,136 patient-years. Cases of lymphoma occurred at an incidence rate of 0.07 per 100 patient-years and melanoma at an incidence rate of 0.02 per 100 patient-years with Cimzia in rheumatoid arthritis clinical trials (see section 4.4).

Autoimmunity

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, 6.4% of patients treated with Cimzia developed injection site reactions (erythema, itching, haematoma, pain, swelling or bruising), compared to 6.5% of patients receiving placebo. Injection site pain was observed in 1.5% of patients treated with Cimzia with no cases leading to withdrawal.

Incompatibilities

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