1. Name Of The Medicinal Product
Cimzia 200 mg solution for injection
2. 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).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection in pre-filled syringe.
Clear to opalescent, colourless to yellow solution. The pH of the solution is approximately 4.7.
4. Clinical Particulars
4.1 Therapeutic Indications
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 methotrexate, has been inadequate.
Cimzia can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
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 methotrexate.
4.2 Posology And Method Of Administration
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis. Patients should be given the special alert card.
Posology
The recommended starting dose of Cimzia for adult patients with rheumatoid arthritis is 400 mg (as 2 injections of 200 mg each on one day) at weeks 0, 2 and 4, followed by a maintenance dose of 200 mg every 2 weeks. MTX should be continued during treatment with Cimzia where appropriate.
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 every 2 weeks as originally instructed.
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 (
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 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 if their physician determines that it is appropriate and with medical follow-up as necessary.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Active tuberculosis or other severe infections such as sepsis or opportunistic infections (see section 4.4).
Moderate to severe heart failure (NHYA classes III/IV) (see section 4.4).
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 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 HBV has occurred in patients who are chronic carriers of this virus receiving TNF antagonists. Some cases have had a fatal outcome. As HBV infection has also been reported with Cimzia, patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating Cimzia therapy. Adequate data on treating patients who are carriers of HBV with TNF antagonist therapy, in conjunction with anti-viral therapy, to prevent HBV reactivation are not available. Carriers of HBV who require treatment with TNF antagonists should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for 5 months following termination of therapy, especially if the patient is on concomitant corticosteroid therapy.
In patients who develop HBV reactivation, Cimzia should be discontinued and effective anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF antagonist therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of Cimzia therapy in this situation and monitor patients closely.
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
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
No data are available on the response to vaccinations or the transmission of infection by live vaccines in patients receiving Cimzia. Live vaccines or attenuated vaccines should not be administered concurrently with Cimzia.
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
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 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.
4.6 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 should not be used in pregnancy.
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). The clinical relevance of this finding is unknown.
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
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.
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 (
Table :1 . Adverse drug reactions in clinical trials and postmarketing
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*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.
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: 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-dependant manner. Incubation of monocytes with Cimzia resulted in a dose-dependant 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
The efficacy and safety of Cimzia have been assessed in 2 randomised, placebo-controlled, double-blind clinical trials in patients
Table :2. Clinical trial description
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ACR response
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 ACR20 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
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