ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Cimzia 200 mg solution for injection
2.
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.
Solution for injection in pre-filled syringe.
Clear to opalescent, colourless to yellow solution. The pH of the solution is approximately 4.7.
4.
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.
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.
2
Elderly (≥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 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.
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).
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
3
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
4
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
5
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 ≥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.
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.
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.
6
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.
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).
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 (≥ 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
System Organ Class
Frequency
Adverse Drug Reactions
Infections and infestations
Common
bacterial infections (including abscess), viral
infections (including herpes, papillomavirus,
influenza)
7
System Organ Class
Frequency Adverse Drug Reactions
Uncommon sepsis (including multi-organ failure, septic shock),
tuberculosis, fungal infections (includes
opportunistic)
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)
Neoplasms benign, malignant
and unspecified (including
cysts and polyps)
Rare gastrointestinal tumours, melanoma
Common eosinophilic disorders, leukopaenia (including
neutropaenia, lymphopaenia)
Uncommon anaemia, lymphadenopathy, thrombocytopaenia,
thrombocytosis
Blood and the lymphatic
system disorders
Rare pancytopaenia, splenomegaly, erythrocytosis, white
blood cell morphology abnormal
Uncommon vasculitides, lupus erythematosus, drug
hypersensitivity (including anaphylactic shock),
allergic disorders, autoantibody positive
Immune system disorders
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
Psychiatric disorders
Rare haemosiderosis
Uncommon anxiety and mood disorders (including associated
symptoms)
Rare suicide attempt, delirium, mental impairment
Common headaches (including migraine), sensory
abnormalities
Uncommon peripheral neuropathies, dizziness, tremor
Rare
Nervous system disorders
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
Uncommon vertigo
Ear and labyrinth disorders
Rare tinnitus
Uncommon cardiomyopathies (including heart failure), ischaemic
coronary artery disorders , arrhythmias (including
atrial fibrillation), palpitations
Cardiac disorders
Rare pericarditis, atrioventricular block
Common hypertension
Uncommon haemorrhage or bleeding (any site), hypercoagulation
(including thrombophlebitis, pulmonary embolism),
syncope, oedema (including peripheral, facial),
ecchymoses (including haematoma, petechiae)
Vascular disorders
Rare cerebrovascular accident, arteriosclerosis, Raynaud’s
phenomenon, livedo reticularis, telangiectasia
Uncommon asthma and related symptoms, pleural effusion and
symptoms, respiratory tract congestion and
inflammation, cough
Respiratory, thoracic and
mediastinal disorders
Rare
interstitial lung disease, pneumonitis
8
System Organ Class
Frequency Adverse Drug Reactions
Uncommon ascites, gastrointestinal ulceration and perforation,
gastrointestinal tract inflammation (any site),
stomatitis, dyspepsia, abdominal distension,
oropharyngeal dryness
Gastrointestinal disorders
Hepatobiliary disorders
Rare odynophagia, hypermotility
Common hepatitis (including hepatic enzyme increased)
Uncommon hepatopathy (including cirrhosis), cholestasis, blood
bilirubin increased
Rare cholelithiasis
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
Skin and subcutaneous tissue
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)
Uncommon menstrual cycle and uterine bleeding disorders
(including amenorrhea), breast disorders
Reproductive system and
breast disorders
Rare sexual dysfunction
Common pyrexia, pain (any site), asthaenia, pruritis (any site),
injection site reactions
Uncommon chills, influenza-like illness, altered temperature
perception, night sweats, flushing
General disorders and
administration site conditions
Rare fistula (any site)
Uncommon blood alkaline phosphatase increased, coagulation
time prolonged
Investigations
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,
9
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.
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.
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
10
The efficacy and safety of Cimzia have been assessed in 2 randomised, placebo-controlled, double-
blind clinical trials in patients ≥ 18 years of age with active rheumatoid arthritis diagnosed according
to American College of Rheumatology (ACR) criteria, RA-I (RAPID 1) and RA-II (RAPID 2).
Patients had ≥ 9 swollen and tender joints each and had active RA for at least 6 months prior to
baseline. Cimzia was administered subcutaneously in combination with oral MTX for a minimum of 6
months with stable doses of at least 10 mg weekly for 2 months in both trials. There is no experience
with Cimzia in combination with DMARDs other than MTX.
Table :2. Clinical trial description
Study
number
Patient
numbers
Dose regimen
Study objectives
RA-I
(52 weeks)
982
400 mg (0,2,4 weeks)
with MTX
200 mg or 400 mg every
2 weeks
with MTX
Evaluation for treatment of signs and
symptoms and inhibition of structural damage.
Co-primary endpoints: ACR 20 at Week 24 and
change from baseline in mTSS at Week 52
RA-II
(24 weeks)
619
400 mg (0,2,4 weeks)
with MTX
200 mg or 400 mg every
2 weeks with MTX
Evaluation for treatment of signs and
symptoms and inhibition of structural damage.
Primary endpoint: ACR 20 at Week 24.
mTSS: modified Total Sharp Score
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
Study RA-I
Methotrexate combination
(24 and 52 weeks)
Study RA-II
Methotrexate combination
(24 weeks)
Response
Placebo + MTX
N=199
Cimzia
200 mg + MTX
every 2 weeks
N=393
Placebo + MTX
N=127
Cimzia
200 mg + MTX
every 2 weeks
N=246
Week 24
14%
59%**
9%
57%**
Week 52
13%
53%**
N/A
N/A
ACR 50
Week 24
8%
37%**
3%
33%**
Week 52
8%
38%**
N/A
N/A
ACR 70
Week 24
3%
21%**
1%
16%*
Week 52
4%
21%**
N/A
N/A
Major
Clinical
Response
a.
1%
13%**
Cimzia vs. placebo: *p≤0.01, ** p<0.001
a.
Major clinical response is defined as achieving ACR 70 response at every assessment over a
continuous 6-month period
11
ACR 20
Wald p-values are quoted for the comparison of treatments using logistic regression with factors for
treatment and region.
Percentage response based upon number of subjects contributing data (n) to that endpoint and time
point which may differ from N
Radiographic response
In RA-I, structural joint damage was assessed radiographically and expressed as change in mTSS and
its components, the erosion score and joint space narrowing (JSN) score, at Week 52, compared to
baseline. Cimzia patients demonstrated significantly less radiographic progression than patients
receiving placebo at Week 24 and Week 52 (see Table 4). In the placebo group, 52% of patients
experienced no radiographic progression (mTSS ≤0.0) at Week 52 compared to 69% in the Cimzia
200 mg treatment group.
Table :4. Changes over 12 months in RA-I
Cimzia 200 mg + MTX –
Placebo + MTX
Mean Difference
mTSS
Week 52 2.8 (7.8) 0.4 (5.7) -2.4
Erosion Score
Week 52 1.5 (4.3) 0.1 (2.5) -1.4
JSN Score
Week 52 1.4 (5.0) 0.4 (4.2) -1.0
p-values were < 0.001 for both mTSS and erosion score and ≤0.01 for JSN score. An ANCOVA was
fitted to the ranked change from baseline for each measure with region and treatment as factors and
rank baseline as a covariate.
Cimzia 200 mg + MTX
N=393
Mean (SD)
Of the 783 patients initially randomised to active treatment in RA-I, 508 completed 52 weeks of
placebo-controlled treatment and entered the open-label extension study. Sustained inhibition of
progression of structural damage was demonstrated in a subset of 449 of these patients who completed
at least 2 years of treatment with Cimzia (RA-I and open-label extension study) and had evaluable data
at the 2-year timepoint.
Physical function response and health-related outcomes
In RA-I and RA-II , Cimzia-treated patients reported significant improvements in physical function as
assessed by the Health Assessment Questionnaire – Disability Index (HAQ-DI) and in tiredness
(fatigue) as reported by the Fatigue Assessment Scale (FAS) from Week 1 through to the end of the
studies compared to placebo. In both clinical trials, Cimzia-treated patients reported significantly
greater improvements in the SF-36 Physical and Mental Component Summaries and all domain scores.
Improvements in physical function and HRQoL were maintained through 2 years in the open-label
extension to RA-I. Cimzia-treated patients reported statistically significant improvements in the Work
Productivity Survey compared to placebo.
Immunogenicity
The overall percentage of patients with antibodies to Cimzia detectable on at least 1 occasion was
7.7% in the Phase III RA placebo-controlled trials. Approximately one-third of antibody-positive
patients (2.6% of the total population) had antibodies with neutralising activity
in vitro
. Patients
treated with concomitant immunosuppressants (MTX) had a lower rate of antibody development than
patients not taking immunosuppressants at baseline. Antibody formation was associated with lowered
drug plasma concentration and in some patients, reduced efficacy.
A pharmacodynamic model based on the Phase III trial data predicts that around 15% of the patients
develop antibodies in 6 months at the recommended dose regimen (200 mg every 2 weeks following a
loading dose) without MTX co-treatment. This number decreases with increasing doses of
concomitant MTX treatment. These data are reasonably in agreement with observed data.
12
Placebo + MTX
N=199
Mean (SD)
The data reflect the percentage of patients whose test results were considered positive for antibodies to
Cimzia in an ELISA, and are highly dependant on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibodies in an assay may be influenced by several factors
including sample handling, timing of sample collection, concomitant medicinal products, and
underlying disease. For these reasons, comparison of the incidence of antibodies to Cimzia with the
incidence of antibodies to other TNF antagonists is not appropriate.
5.2 Pharmacokinetic properties
Certolizumab pegol plasma concentrations were broadly dose-proportional. Pharmacokinetics
observed in patients with rheumatoid arthritis were consistent with those seen in healthy subjects.
Absorption
Following subcutaneous administration, peak plasma concentrations of certolizumab pegol were
attained between 54 and 171 hours post-injection. Certolizumab pegol has a bioavailability (F) of
approximately 80% (range 76% to 88%) following subcutaneous administration compared to
intravenous administration.
Distribution
The apparent volume of distribution (V/F) was estimated at 8.01 l in a population pharmacokinetic
analysis of patients with rheumatoid arthritis.
Biotransformation and elimination
PEGylation, the covalent attachment of PEG polymers to peptides, delays the elimination of these
entities from the circulation by a variety of mechanisms, including decreased renal clearance,
decreased proteolysis, and decreased immunogenicity. Accordingly, certolizumab pegol is an antibody
Fab' fragment conjugated with PEG in order to extend the terminal plasma elimination half-life of the
Fab' to a value comparable with a whole antibody product. The terminal elimination phase half-life
(t
1/2
) was approximately 14 days for all doses tested.
Clearance following subcutaneous dosing was estimated to be 21.0 ml/h in a rheumatoid arthritis
population pharmacokinetic analysis, with an inter-subject variability of 30.8% (CV) and an inter-
occasion variability of 22.0%. The presence of antibodies to certolizumab pegol resulted in an
approximately three-fold increase in clearance. Compared with a 70 kg person, clearance is 29% lower
and 38% higher, respectively, in individual RA patients weighing 40 kg and 120 kg.
The Fab' fragment comprises protein compounds and is expected to be degraded to peptides and amino
acids by proteolysis. The de-conjugated PEG component is rapidly eliminated from plasma and is to
an unknown extent excreted renally.
Special populations
Renal impairment
Specific clinical trials have not been performed to assess the effect of renal impairment on the
pharmacokinetics of certolizumab pegol or its PEG fraction. However, population pharmacokinetic
analysis based on subjects with mild renal impairment showed no effect of creatinine clearance. There
are insufficient data to provide a dosing recommendation in moderate and severe renal impairment.
The pharmacokinetics of the PEG fraction of certolizumab pegol are expected to be dependent on
renal function but have not been assessed in patients with renal impairment.
Hepatic impairment
Specific clinical trials have not been performed to assess the effect of hepatic impairment on the
pharmacokinetics of certolizumab pegol.
Elderly (≥65 years old)
Specific clinical trials have not been performed in elderly subjects. However, no effect of age was
observed in a population pharmacokinetic analysis in patients with rheumatoid arthritis in which 78
subjects (13.2% of the population) were aged 65 or greater and the oldest subject was aged 83 years.
13
Gender
There was no effect of gender on the pharmacokinetics of certolizumab pegol. As clearance decreases
with decreasing body weight, females may generally obtain somewhat higher systemic exposure of
certolizumab pegol.
Pharmacokinetic/pharmacodynamic relationship
On the basis of Phase II and Phase III clinical trial data, a population exposure-response relationship
was established between average plasma concentration of certolizumab pegol during a dosing interval
(C
avg
) and efficacy (ACR 20 responder definition). The typical C
avg
that produces half the maximum
probability of ACR 20 response (EC50) was 17 µg/ml (95% CI: 10-23 µg/ml).
5.3 Preclinical safety data
The pivotal non-clinical safety studies were conducted in the cynomolgus monkey. In rats and
monkeys, at doses higher than those given to humans, histopathology revealed cellular vacuolation,
present mainly in macrophages, in a number of organs (lymph nodes, injection sites, spleen, adrenal,
uterine, cervix, choroid plexus of the brain, and in the epithelial cells of the choroid plexus). It is likely
that this finding was caused by cellular uptake of the PEG moiety.
In vitro
functional studies of human
vacuolated macrophages indicated all functions tested were retained. Studies in rats indicated that
>90% of the administered PEG was eliminated in 3 months following a single dose, with the urine
being the main route of excretion.
Certolizumab pegol does not cross-react with rodent TNF. Therefore, reproductive toxicology studies
have been performed with a homologous reagent recognising rat TNF. The value of these data to the
evaluation of human risk may be limited. No adverse effects were seen on maternal well-being or
female fertility, embryo-foetal and peri- and post-natal reproductive indices in rats using a rodent anti-
rat TNFα PEGylated Fab' (cTN3 PF) following sustained TNFα suppression. In male rats, reduced
sperm motility and a trend of reduced sperm count were observed.
Distribution studies have demonstrated that placental and milk transfer of cTN3 PF to the foetal and
neonatal circulation is negligible. It is presently unknown whether the same is true for Cimzia in
humans.
No mutagenic or clastogenic effects were demonstrated in preclinical studies. Carcinogenicity studies
have not been performed with Cimzia.
6.
6.1 List of excipients
Sodium acetate
Sodium chloride
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
14
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
6.5
Nature and contents of container
One ml pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber), containing
200 mg of certolizumab pegol.
None of the components of the syringe contain latex.
Pack size of 2 syringes and 2 alcohol wipes, and multipack containing 6 (3 packs of 2) pre-filled
syringes and 6 (3 packs of 2) alcohol wipes.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
This medicinal product is for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
Comprehensive instructions for the preparation and administration of Cimzia in a pre-filled syringe are
given in the package leaflet.
7.
UCB Pharma SA
Allée de la Recherche 60
B-1070 Bruxelles
Belgium
8.
EU/1/09/544/001-002
9.
Date of first authorisation: 01 October 2009
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
15
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
16
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Sandoz GmbH
Biochemiestraße 10
A-6250 Kundl
Austria
Name and address of the manufacturer responsible for batch release
UCB Pharma S.A.
Chemin du Foriest
B-1420 Braine l'Alleud
Belgium
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder (MAH) shall ensure that, prior to launch, all physicians
who are expected to prescribe/use Cimzia are provided with a physician information pack
containing the following:
•
The Summary of Product Characteristics
•
Physician information
•
Patient Alert Card
The physician information should contain the following key messages:
•
The risk of serious infections, including opportunistic bacterial, viral and fungal
infections in patients treated with Cimzia,
•
The need to evaluate patients for both active and inactive tuberculosis prior to starting
the treatment, including use of appropriate screening tests,
•
The contraindication of Cimzia in patients with history of moderate to severe heart
failure (NYHA III/IV), and potential risk of congestive heart failure being worsened
by Cimzia,
•
The risk of acute injection-related reactions and delayed serious systemic
hypersensitivity reactions, the need for instructing patients on techniques for
administration, and guidance for Health Care Professionals on how to report
administration errors,
•
The role and use of patient alert card.
•
OTHER CONDITIONS
Pharmacovigilance system
17
The MAH must ensure that the system of pharmacovigilance, as described in version 1.0 (28 February
2010) presented in Module 1.8.1. of the Marketing Authorisation, is in place and functioning before
and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 3.0 (dated 15 May 2009) of the Risk Management
Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any
subsequent updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
18
ANNEX III
LABELLING AND PACKAGE LEAFLET
19
A. LABELLING
20
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton (for packs of 2 pre-filled syringes and 2 alcohol wipes)
1.
Cimzia 200 mg solution for injection
certolizumab pegol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One pre-filled syringe contains 200 mg certolizumab pegol in one ml.
3.
LIST OF EXCIPIENTS
Excipients: Sodium acetate, sodium chloride and water for injections.
See the package leaflet for further information.
4.
•
2 single-use pre-filled syringes containing 1 ml solution for injection.
•
2 alcohol wipes
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
21
•
Solution for injection
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
UCB Pharma SA
Allée de la Recherche 60
1070 Brussels
Belgium
EU/1/09/544/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Cimzia 200 mg
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Multipack of 6 (3 packs of 2 pre-filled syringes and 2 alcohol wipes) – with blue box
1.
Cimzia 200 mg solution for injection
certolizumab pegol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One pre-filled syringe contains 200 mg certolizumab pegol in one ml.
3.
LIST OF EXCIPIENTS
Excipients: Sodium acetate, sodium chloride and water for injections.
See the package leaflet for further information.
4.
•
Solution for injection
•
Multipack containing 6 (3 packs of 2) pre-filled syringes and 6 (3 packs of 2) alcohol wipes.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
23
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
UCB Pharma SA
Allée de la Recherche 60
1070 Brussels
Belgium
EU/1/09/544/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Cimzia 200 mg
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Multipack of 6 (3 packs of 2 pre-filled syringes and 2 alcohol wipes) – without blue box
1.
Cimzia 200 mg solution for injection
certolizumab pegol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One pre-filled syringe contains 200 mg certolizumab pegol in one ml.
3.
LIST OF EXCIPIENTS
Excipients: Sodium acetate, sodium chloride and water for injections.
See the package leaflet for further information.
4.
•
Solution for injection
•
Multipack containing 6 (3 packs of 2) pre-filled syringes and 6 (3 packs of 2) alcohol wipes.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
25
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
UCB Pharma SA
Allée de la Recherche 60
1070 Brussels
Belgium
EU/1/09/544/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Cimzia 200 mg
26
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SYRINGE LABEL
1.
Cimzia 200 mg solution for injection
certolizumab pegol
Subcutaneous use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 ml
6.
OTHER
27
B. PACKAGE LEAFLET
28
PACKAGE LEAFLET: INFORMATION FOR THE USER
Cimzia 200 mg solution for injection
certolizumab pegol
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, please ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects becomes serious, or if you notice any side effects not listed in this
leaflet, please tell your doctor or pharmacist.
In this leaflet
:
1. What Cimzia is and for what it is used
2. Before you use Cimzia
3. How to use Cimzia
4. Possible side effects
5.
How to store Cimzia
6.
Further information
Your physician will also give you a Patient Alert Card, which contains important safety information of
which you need to be aware before you are given Cimzia and during treatment with Cimzia. Keep this
Patient Alert Card with you.
1.
WHAT CIMZIA IS AND WHAT IT IS USED FOR
Cimzia contains the active substance certolizumab pegol, a human antibody fragment. Antibodies are
proteins that specifically recognise and bind to other proteins. Cimzia binds to a specific protein called
tumour necrosis factor α (TNFα). Thereby this TNFα is blocked by Cimzia and this decreases
inflammation in rheumatoid arthritis. Medicines that bind to TNFα are also called TNF blockers.
Cimzia is used for the treatment of moderate to severe rheumatoid arthritis in adult patients, when
other medicines fail to control your symptoms. Cimzia is usually used together with another medicine
called methotrexate. If your doctor determines that methotrexate is inappropriate, Cimzia can be given
alone.
2.
BEFORE YOU USE Cimzia
Do NOT use Cimzia
-
If you are
ALLERGIC
(hypersensitive) to certolizumab pegol or any of the other ingredients of
Cimzia
-
If you have a severe infection, including active
TUBERCULOSIS
(TB).
-
If you have moderate to severe
HEART FAILURE
. Tell your doctor if you have had or have a
serious heart condition.
Take special care with Cimzia
Tell your doctor before treatment with Cimzia if any of the following applies to you:
Allergic reactions
-
If you experience
ALLERGIC REACTIONS
such as chest tightness, wheezing, dizziness,
swelling or rash, stop using Cimzia and contact your doctor
IMMEDIATELY
.
Infections
29
-
Keep this leaflet. You may need to read it again.
-
If you have had
RECURRENT INFECTIONS
or other conditions that increase the risk of
infections (such as treatment with immunosuppressants, which are medicines that could reduce
your ability to fight infections).
-
If you have an infection or if you develop symptoms such as fever, wounds, tiredness or dental
problems. You might get an infection more easily while you are being treated with Cimzia,
including serious, or in rare cases, life-threatening infections.
-
TUBERCULOSIS (TB)
cases have been reported in patients treated with Cimzia, your doctor
will check you for signs and symptoms of tuberculosis before starting Cimzia. This will include
a thorough medical history, a chest X-ray and a tuberculin test. The conduct of these tests
should be recorded on your Patient Alert Card. If latent (inactive) tuberculosis is diagnosed, you
might be required to receive appropriate anti-tuberculosis medicines before starting Cimzia. It is
very important that you tell your doctor if you have ever had tuberculosis, or if you have been in
close contact with someone who has had tuberculosis. If symptoms of tuberculosis (persistent
cough, weight loss, listlessness, mild fever), or any other infection appear during or after
therapy with Cimzia tell your doctor immediately.
-
If you are at risk of or are a carrier of or have active
HEPATITIS B VIRUS
(HBV) infection,
Cimzia may increase the risk of reactivation in people who carry this virus. If this occurs, you
should stop using Cimzia.
Heart failure
-
If you have mild
HEART FAILURE
and you are being treated with Cimzia, your heart failure
status must be closely monitored by your doctor. It is important to tell your doctor if you have
had or have a serious heart condition. If you develop new or worsening symptoms of heart
failure (e.g. shortness of breath or swelling of your feet), you must contact your doctor
immediately. Your doctor may decide to stop treatment with Cimzia.
Cancer
-
It is uncommon, but cases of certain types of
CANCER
have been reported in patients treated
with Cimzia or other TNF blockers. People with more severe rheumatoid arthritis that have had
the disease for a long time may have a higher than average risk of getting a kind of cancer that
affects the lymph system, called lymphoma. If you take Cimzia, your risk of getting lymphoma or
other cancers may increase. In addition, uncommon cases of non-melanoma skin cancer have been
observed in patients taking Cimzia. If new skin lesions appear during or after therapy with Cimzia
or existing skin lesions change appearance, tell your doctor. Patients with chronic obstructive
pulmonary disease (COPD), or who are heavy smokers, may be at increased risk for cancer with
Cimzia treatment. If you have COPD or are a heavy smoker, you should discuss with your doctor
whether treatment with a TNF blocker is appropriate for you.
-
There have been cases of cancers, including unusual types, in children and teenage patients taking
TNF-blocking agents, which sometimes resulted in death (see further down “Children”).
Other disorders
-
If you have a nervous system disorder, such as multiple sclerosis, your doctor will decide
whether you should use Cimzia.
-
In some patients the body may fail to produce enough of the blood cells that help your body
fight infections or help you to stop bleeding. If you develop a fever that does not go away,
bruise or bleed very easily or look very pale, call your doctor immediately. Your doctor may
decide to stop treatment with Cimzia.
-
It is uncommon, but symptoms of a disease called lupus (for example persistent rash, fever, joint
pain and tiredness) may occur. If you experience these symptoms, contact your doctor. Your
doctor may decide to stop treatment with Cimzia.
Vaccinations
-
Talk to your doctor if you have had, or are due to have a vaccine. You should not receive
certain (live) vaccines while using Cimzia.
Operations or dental procedures
30
-
Talk to your doctor if you are going to have any operations or dental procedures. Tell your
surgeon or dentist performing the procedure that you are having treatment with Cimzia by
showing them your Patient Alert Card.
Children
Cimzia is not recommended for use in children and adolescents under the age of 18 years.
Taking other medicines
You should
NOT
take Cimzia if you are using the following medicines used to treat rheumatoid
arthritis:
-
anakinra
-
abatacept
If you have questions, please ask your doctor.
Cimzia can be taken together with:
-
methotrexate,
-
corticosteroids, or
-
pain medicines including nonsteroidal anti-inflammatory medicines (also called NSAIDs).
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
There is a lack of experience with Cimzia in pregnant women. Therefore, Cimzia should
NOT
be used
in pregnant women. Women of childbearing potential must use adequate contraception while using
Cimzia and for at least 5 months after the last Cimzia treatment.
It is not known whether Cimzia passes into breast milk. You should talk to your doctor before breast-
feeding during Cimzia treatment.
Driving and using machines
Cimzia may have a minor influence on your ability to drive and use machines. Dizziness (including
room spinning sensation, blurred vision and tiredness) may occur after you take Cimzia.
Important information about some of the ingredients of Cimzia
This medicinal product contains less than 1 mmol sodium (23 mg) per 400 mg, i.e. essentially
‘sodium-free’.
3.
HOW TO USE Cimzia
Always use Cimzia exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure of how to use Cimzia.
The
starting dose
for adults with rheumatoid arthritis is 400 mg given at
weeks 0, 2 and 4
. This is
followed by a
maintenance dose
of 200 mg every other week
starting at week 6
. Methotrexate is
continued while using Cimzia. If your doctor determines that methotrexate is inappropriate, Cimzia
can be given alone.
Cimzia will usually be given to you by a specialist doctor or healthcare professional. You will be
given Cimzia as either one (200 mg dose) or two injections (400 mg dose) under the skin
(subcutaneous use). It is usually injected into the thigh or tummy.
Instructions for preparing and giving an injection of Cimzia
31
After suitable training, your doctor may also allow you to inject Cimzia yourself. Please read the
instructions at the end of this leaflet on how to inject Cimzia.
If your doctor has allowed you to self-inject, you should follow up with your doctor before the 7
th
dose
to have the doctor determine if Cimzia is working for you or if another treatment needs to be
considered.
If you use more Cimzia than you should
If your doctor has allowed you to self-inject and you accidentally inject Cimzia more frequently than
prescribed, you should tell your doctor. Always take the Patient Alert Card and the outer carton from
the Cimzia package with you, even if it is empty.
If you forget to use Cimzia
If your doctor has allowed you to self-inject and you forget to give yourself an injection, you should
inject the next dose of Cimzia as soon as you remember. Then inject the following doses every 2
weeks as originally instructed.
If you stop using Cimzia
Do not stop using Cimzia without talking to your doctor first.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Cimzia can cause side effects, although not everybody gets them.
Tell your doctor
IMMEDIATELY
if you notice any of the following side effects:
•
severe rash, hives or other signs of allergic reaction (urticaria)
•
swollen face, hands, feet (angioedema)
•
trouble breathing, swallowing (multiple causes for these symptoms)
•
shortness of breath with exertion or upon lying down or swelling of the feet (heart failure)
•
symptoms of blood disorders such as persistent fever, bruising, bleeding, paleness (pancytopaenia,
anaemia, low platelet count, low white blood cell count)
Tell your doctor
AS SOON AS POSSIBLE
if you notice any of the following side effects:
•
signs of infection such as fever, malaise, wounds, dental problems, burning on urination feeling
weak or tired
•
coughing.
•
tingling
•
numbness
•
double vision
•
arm or leg weakness
•
bump or open sore that doesn't heal
The symptoms described above can be due to some of the side effects listed below, which have been
observed with Cimzia:
Side effects may occur with certain frequencies, which are defined as follows:
•
Very common: affects at least 1 user in 10.
•
Common: affects at least 1 user in 100 but less than 10 users in 100.
•
Uncommon: affects at least 1 user in 1,000 but less than 10 users in 1,000.
•
Rare: affects at least 1 user in 10,000 but less than 10 users in 10,000.
•
Very rare: affects less than 1 user in 10,000.
•
not known: frequency cannot be estimated from the available data.
32
Common side effects:
•
bacterial infections in any site (a collection of pus)
•
viral infections (including cold sores, shingles, and influenza)
•
fever
•
high blood pressure
•
rash or itching
•
headaches (including migraines)
•
sensory abnormalities such as numbness, tingling, burning sensation
•
feeling weak and generally unwell
•
pain
•
blood disorders
•
liver problems
•
injection site reactions
Uncommon side effects:
•
allergic conditions including allergic rhinitis and allergic reactions to the drug (including
anaphylactic shock)
•
blood and lymphatic system cancers like lymphoma and leukaemia
•
solid organ cancers
•
skin cancers, pre-cancers
•
benign (non-cancerous) tumours and cysts (including those of the skin)
•
heart problems including weakened heart muscle, heart failure, heart attack, chest discomfort or
chest pressure, abnormal heart rhythm including irregular heart beats
•
oedema (swelling in the face or legs)
•
lupus (immune/connective tissue disease) symptoms (joint pain, skin rashes, photosensitivity and
fever)
•
inflammation of the blood vessels
•
sepsis (serious infection which can result in organ failure, shock or death)
•
tuberculosis infection
•
fungal infections (occur when the ability to fight off infection is lessened)
•
respiratory disorders and inflammation (including asthma, shortness of breath, cough, blocked
sinuses, pleurisy, or difficulty breathing)
•
stomach problems including abdominal fluid collection, ulcers (including oral ulcers), perforation,
distension, inflammation heartburn, upset, dry mouth
•
bile problems
•
muscle problems including increased muscle enzymes
•
changes in blood levels of different salts
•
changes in cholesterol and fat levels in the blood
•
blood clots in the veins or lungs
•
bleeding or bruising
•
changed numbers of blood cells, including low red cell count (anaemia), low platelet counts,
increased platelet counts
•
swollen lymph nodes
•
flu-like symptoms, chills, altered temperature perception, night sweats, flushing
•
anxiety and mood disorders such as depression, appetite disorders, weight change
•
vertigo (dizziness)
•
feeling faint, including loss of consciousness
•
nerve disorders in the extremities including symptoms of numbness, tingling, burning sensation,
dizziness, tremor
•
skin disorders such as new onset or worsening of psoriasis, sweat gland disorders, ulcers,
photosensitivity, acne, hair loss, discoloration, nail separation, dry skin and injuries
•
impaired healing
•
kidney and urinary problems including impairment of kidney function, blood in the urine and
urinary disturbances
33
•
menstrual cycle (monthly period) disorders including lack of bleeding, or heavy or irregular
bleeding
•
breast disorders
•
eye and eyelid inflammation, vision disturbances, problems with tears
•
itching
•
prolonged coagulation (clotting) test times
Rare side effects:
•
gastrointestinal cancer, melanoma
•
lung inflammation
•
stroke, blockage in blood vessels
•
enlarged spleen
•
Formation of stones in the gall bladder
•
immune disorders such as sarcoidosis (rash, joint pain, fever), serum sickness, inflammation of the
fat tissue, angioneurotic oedema (swelling of the lips, face, throat)
•
thyroid disorders (goitre, tiredness, weight loss)
•
changes in blood levels of uric acid (increased)
•
suicide attempt, mental impairment, delirium
•
inflammation of the nerves for hearing, seeing, or of the face, impaired coordination or balance
•
ringing in the ears
•
increased gastrointestinal motility
•
fistula (tract from one organ to another) (any site)
•
oral disorders including pain on swallowing
•
skin sloughing, blistering, hair texture disorder
•
sexual dysfunction
•
seizure
Other side effects
When Cimzia has been used to treat other diseases the following uncommon side effects have
occurred:
•
Gastrointestinal stenosis (narrowing of part of the digestive system).
•
Gastrointestinal obstructions (blockages of the digestive system).
•
General physical health deterioration.
•
Spontaneous abortion.
•
Azoospermia (lack of sperm production).
When other TNF blockers have been used to treat rheumatoid arthritis, multiple sclerosis or
Guillain-Barré syndrome have occurred. The risk of multiple sclerosis or Guillain-Barré syndrome
with Cimzia is not known.
If any of the side effects becomes serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
5.
HOW TO STORE Cimzia
Keep out of the reach and sight of children.
Do not use Cimzia after the expiry date which is stated on the pack and syringe after EXP. The expiry
date refers to the last day of the month.
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
34
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer need. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Cimzia contains
−
The active substance is certolizumab pegol. Each pre-filled syringe contains 200 mg of
certolizumab pegol in one ml.
−
The other ingredients are: sodium acetate, sodium chloride and water for injections.
What Cimzia looks like and contents of the pack
One Cimzia pack contains:
•
two pre-filled syringes of solution, and
•
two alcohol wipes (for cleansing the areas chosen for injection).
None of the components of the syringe contain latex.
Packs of 2 syringes and 2 alcohol wipes, and a multipack containing 6 (3 packs of 2) syringes and 6 (3
packs of 2) alcohol wipes are available.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
UCB Pharma SA
Allée de la Recherche 60
B-1070 Bruxelles
Belgium
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
UCB Pharma SA/NV
Tel/Tél: + 32 / (0)2 559 92 00
Luxembourg/Luxemburg
UCB Pharma SA/NV
Tél/Tel: + 32 / (0)2 559 92 00
България
Ю СИ БИ България ЕООД
Teл.: + 359 (0) 2 962 30 49
Magyarország
UCB Magyarország Kft.
Tel.: + 36-(1) 391 0060
Česká republika
UCB s.r.o.
Tel: + 420 221 773 411
Malta
Pharmasud Ltd.
Tel: + 356 / 21 37 64 36
Danmark
UCB Nordic A/S
Tlf: + 45 / 32 46 24 00
Nederland
UCB Pharma B.V.
Tel.: + 31 / (0)76-573 11 40
Deutschland
UCB Pharma GmbH
Tel: + 49 /(0) 2173 48 4848
Norge
UCB Nordic A/S
Tlf: + 45 / 32 46 24 00
Eesti
UCB Pharma Oy Finland
Tel: + 358 10 234 6800
Österreich
UCB Pharma GmbH
Tel: + 43 (1) 291 80 00
35
Ελλάδα
UCB Α.Ε.
Τηλ: + 30 / 2109974000
Polska
UCB Pharma Sp. z o.o.
Tel.: + 48 22 696 99 20
España
UCB Pharma, S.A.
Tel: + 34 / 91 570 34 44
Portugal
UCB Pharma (Produtos Farmacêuticos), Lda
Tel: + 351 / 21 302 5300
France
UCB Pharma S.A.
Tél: + 33 / (0)1 47 29 44 35
România
UCB Pharma Romania S.R.L.
Tel: + 40 21 300 29 04
Ireland
UCB (Pharma) Ireland Ltd.
Tel: + 353 / (0)1-46 37 395
Slovenija
Medis, d.o.o.
Tel: + 386 1 589 69 00
Ísland
Vistor hf.
Tel: + 354 535 7000
Slovenská republika
UCB s.r.o., organizačná zložka
Tel: + 421 (0) 2 5920 2020
Italia
UCB Pharma S.p.A.
Tel: + 39 / 02 300 791
Suomi/Finland
UCB Pharma Oy Finland
Puh/Tel: + 358 10 234 6800
Κύπρος
Lifepharma (Z.A.M.) Ltd
Τηλ: + 357 22 34 74 40
Sverige
UCB Nordic A/S
Tel: + 46 / (0) 40 29 49 00
Latvija
UCB Pharma Oy Finland
Tel: + 358 10 234 6800
United Kingdom
UCB Pharma Ltd.
Tel : + 44 / (0)1753 534 655
Lietuva
UCB Pharma Oy Finland
Tel: + 358 10 234 6800
This leaflet was last approved in
{MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency web site:
INSTRUCTIONS FOR PREPARING AND GIVING AN INJECTION OF CIMZIA
After proper training, the injection can be self-administered or given by another person, for example a
family member or friend. The following instructions explain how to inject Cimzia. Please read the
instructions carefully and follow them step by step. You will be instructed by your doctor or
healthcare giver on the technique of self-injection. Do not attempt to self-inject until you are sure that
you understand how to prepare and give the injection.
This injection should not be mixed in the same syringe with any other medicine.
1. Setting up
•
Wash your hands thoroughly.
•
Remove the following items from the Cimzia carton and set them up on a clean surface:
36
◦
One pre-filled syringe
◦
One alcohol wipe
•
Look at the expiry date on the syringe and pack. Do not use Cimzia after the expiry date which is
stated on the pack and syringe after EXP. The expiry date refers to the last day of the month
shown.
•
Allow the pre-filled syringe to reach room temperature. This will take up to 30 minutes. Do not try
to warm up the syringe.
2. Choosing and preparing an injection site
•
Choose a site on your thigh or tummy.
•
Each new injection should be given on a separate site from the last injection site.
◦
Do not inject in an area where the skin is reddened, bruised, or hard.
◦
Wipe the injection site with the enclosed alcohol wipe, using a circular motion moving
from the inside out.
◦
Do not touch the area again before injecting.
3. Injection
•
Do NOT shake the syringe.
•
Remove the cap from the needle, being careful not to touch the needle or let the needle touch any
surface.
•
Hold the syringe with needle facing up.
•
Tap the syringe to push any air bubbles to the top.
37
•
Press the plunger slowly until you expel any air. Stop when a small drop appears at the tip of the
needle.
•
Gently grasp the cleaned area of skin with one hand and hold firmly.
•
With the other hand, hold syringe at a 45-degree angle to skin.
•
With one quick, short motion, push the needle all the way into the skin.
•
Push plunger to inject solution. It can take up to 10 seconds to empty the syringe.
•
When the syringe is empty, carefully remove the needle from the skin at the same angle at which it
was inserted.
•
Release the skin with the first hand.
•
Use a piece of gauze, apply pressure over the injection site for a few seconds. Do not rub the
injection site. You may cover the injection site with a small adhesive bandage, if necessary.
4. Throwing away supplies
•
You must NOT re-use the syringe or re-cap the needle.
•
After injection, immediately throw away the used syringe in a special container as instructed by
your doctor, nurse or pharmacist.
•
Keep the container out of the reach and sight of children.
38
Source: European Medicines Agency
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