CIMZIA(聚乙二醇结合赛妥珠单抗，certolizumab pegol)冻干粉或为皮下使用溶液-临床治疗银屑病关节炎
一般描述
CIMZIA(聚乙二醇结合赛妥珠单抗[certolizumab pegol])是一种TNF阻断剂。CIMZIA是一种有对人类肿瘤坏死因子α(TNFα)特异性的重组，人源化抗体Fab'片段，结合至一个约40kDa聚乙二醇(PEG2MAL40K)。Fab'片段是在大肠杆菌中制造和随后纯化和结合至PEG2MAL40K，生成聚乙二醇结合赛妥珠单抗。Fab'片段由214氨基酸轻链和229氨基酸重链组成。聚乙二醇结合赛妥珠单抗的分子量约91千道尔顿。
作用机制
聚乙二醇结合赛妥珠单抗结合至人类TNFα有一个KD为90pM. TNFα是一个关键促炎性细胞因子在炎性过程中起中心作用。聚乙二醇结合赛妥珠单抗选择性地中和TNFα(IC90为4 ng/mL 在体外L929鼠类纤维母细胞瘤细胞毒性试验对人类TNFα的抑制作用)但不中和淋巴毒素α TNFβ)。聚乙二醇结合赛妥珠单抗与啮齿类和兔TNF交叉反应差，因此体内用动物模型评价疗效其中人类TNFα是生理学上活性分子。
聚乙二醇结合赛妥珠单抗被显示以依赖剂量方式中和膜结合和可溶性人类TNFα。在人类单核细胞中单核细胞与聚乙二醇结合赛妥珠单抗培育导致依赖剂量的LPS-诱导TNFα和IL-1β生成的抑制作用。
聚乙二醇结合赛妥珠单抗不含可结晶的(Fc)区片段，在完整抗体中正常存在，和因此在体外不固定补体或引起抗体依赖细胞介导的细胞毒性。在体外不诱导人类外周学衍生单核细胞或淋巴细胞凋亡，聚乙二醇结合赛妥珠单抗也不诱导中性粒细胞脱颗粒[degranulation]。进行一项在体外体内(ex vivo)组织反应性研究评价聚乙二醇结合赛妥珠单抗与正常人类组织冰冻切片的潜在交叉反应性。聚乙二醇结合赛妥珠单抗显示与被设计的人类正常组织标准名单无反应性。
适应证和用途
CIMZIA是一种肿瘤坏死因子(TNF)阻断剂适用为：
（1）在克罗恩病对常规治疗反应不佳的有中度至严重活动性疾病成年患者中减轻体征和症状和维持临床反应。
（2）治疗有中度至严重活动性类风湿样关节炎成年。
（3）治疗有活动性银屑病关节炎成年患者。
剂量和给药方法
CIMZIA是通过皮下注射给药。CIMZIA的初始剂量是400mg(给予两次皮下注射200mg)。
克罗恩病
（1）初始400 mg和在第2和4周时。如发生反应，接着每4周400mg。
类风湿样关节炎
（2）初始400 mg和在2和4周时，接着每隔周200mg；为维持给药可考虑每4周400mg。
银屑病关节炎
（3）初始400mg和在第2和4周时，接着每隔周200mg；为维持给药可考虑每4周400mg。
剂型和规格
（1）为重建200mg冻干粉，在单次使用玻璃小瓶内，与1mL无菌注射用水，USP。
（2）200mg/mL溶液在一个单次使用预装注射器内。
禁忌证
无。
警告和注意事项
（1）严重感染 –活动性感染期间不要开始CIMZIA。如发生一种感染，小心监视，和如感染变成严重停止CIMZIA。
（2）侵袭性真菌感染– 对用CIMZIA发生全身性疾病患者，对对至真菌是地方病的地区居住和旅游患者考虑经验性抗真菌治疗。
（3）接受TNF阻断剂患者中曾观察到淋巴瘤和其他恶性病病例。
（4）可能发生心衰，恶化或新发作。
（5）可能发生过敏性反应或严重的过敏反应
（6）乙型肝炎病毒再激活 – 开始CIMZIA前测试HBV感染。治疗期间和几个月后监视HBV携带者。如发生再激活，停止CIMZIA和开始抗-病毒治疗。
（7）可能发生脱髓鞘疾病，加重或新发作。
（8）血细胞减少，全血细胞减少 – 劝告患者如发生症状立即求医，和考虑停止CIMZIA。
（9）狼疮样综合征–如发生症状停止CIMZIA。
不良反应
最常见不良反应(发生率≥7%和较高于安慰剂)：上呼吸道感染，皮疹，和泌尿道感染。
药物相互作用
（1）与生物制品DMARDs使用 –严重感染的风险增加。
（2）活疫苗 – 不要与CIMZIA给予。
（3）实验室测试 – 可能干扰aPTT测试。

【产地国家：德  国】
【原产地英文商品名】CIMZIA STARTER KIT 200MG/ML/SYRINGE  2SYRINGE/KIT
【原产地英文药品名】CERTOLIZUMAB PEGOL
【中文参考商品译名】
·CIMZIA 200毫克/毫升/填充注射器 2注射器/套 
【中文参考药品译名】赛妥珠单抗
【生产中/英文厂家译名】脐血公司/UCB公司
Cimzia 200 mg solution for injection
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 the full list of excipients, see section 6.1.
3. Pharmaceutical form
Solution for injection (injection).
Clear to opalescent, colourless to yellow solution. The pH of the solution is approximately 4.7.
4. Clinical particulars
4.1 Therapeutic indications
Rheumatoid arthritis
Cimzia, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe, active rheumatoid arthritis (RA) in adult patients when the response to disease-modifying antirheumatic drugs (DMARDs) including 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.
Axial spondyloarthritis
Cimzia is indicated for the treatment of adult patients with severe active axial spondyloarthritis, comprising:
Ankylosing spondylitis (AS)
Adults with severe active ankylosing spondylitis who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs).
Axial spondyloarthritis without radiographic evidence of AS
Adults with severe active axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated C-reactive protein (CRP) and /or magnetic resonance imaging (MRI), who have had an inadequate response to, or are intolerant to NSAIDs.
Psoriatic arthritis
Cimzia, in combination with MTX, is indicated for the treatment of active psoriatic arthritis in adults when the response to previous DMARD therapy has been inadequate.
Cimzia can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
For details on therapeutic effects, see section 5.1.
4.2 Posology and method of administration
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which Cimzia is indicated. Patients should be given the special alert card.
Posology
Loading dose
The recommended starting dose of Cimzia for adult patients is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. For rheumatoid arthritis and psoriatic arthritis, MTX should be continued during treatment with Cimzia where appropriate.
Maintenance dose
Rheumatoid arthritis
After the starting dose, the recommended maintenance dose of Cimzia for adult patients with rheumatoid arthritis is 200 mg every 2 weeks. Once clinical response is confirmed, an alternative maintenance dosing of 400 mg every 4 weeks can be considered. MTX should be continued during treatment with Cimzia where appropriate.
Axial spondyloarthritis
After the starting dose, the recommended maintenance dose of Cimzia for adult patients with axial spondyloarthritis is 200 mg every 2 weeks or 400 mg every 4 weeks.
Psoriatic arthritis
After the starting dose, the recommended maintenance dose of Cimzia for adult patients with psoriatic arthritis is 200 mg every 2 weeks. Once clinical response is confirmed, an alternative maintenance dosing of 400 mg every 4 weeks can be considered. MTX should be continued during treatment with Cimzia where appropriate.
For the above indications, available data suggest that clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment.
Missed dose
Patients who miss a dose should be advised to inject the next dose of Cimzia as soon as they remember and then continue injecting subsequent doses as originally instructed.
Special populations
Paediatric population (< 18 years old)
The safety and efficacy of Cimzia in children and adolescents below age 18 years have not yet been established. No data are available.
Elderly patients (≥ 65 years old)
No dose adjustment is required. Population pharmacokinetic analyses showed no effect of age (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 using the pre-filled syringe if their physician determines that it is appropriate and with medical follow-up as necessary. The pre-filled syringe with needle guard should only be used by healthcare professionals.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active tuberculosis or other severe infections such as sepsis or opportunistic infections (see section 4.4).
Moderate to severe heart failure (NYHA classes III/IV) (see section 4.4).
4.4 Special warnings and precautions for use
 Infections
Patients must be monitored closely for signs and symptoms of infections including tuberculosis before, during and after treatment with Cimzia. Because the elimination of certolizumab pegol may take up to 5 months, monitoring should be continued throughout this period (see section 4.3).
Treatment with Cimzia must not be initiated in patients with a clinically important active infection, including chronic or localised infections, until the infection is controlled (see section 4.3).
Patients who develop a new infection while undergoing treatment with Cimzia should be monitored closely. Administration of Cimzia should be discontinued if a patient develops a new serious infection until the infection is controlled. Physicians should exercise caution when considering the use of Cimzia in patients with a history of recurring or opportunistic infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications.
Patients with rheumatoid arthritis may not manifest typical symptoms of infection, including fever, due to their disease and concomitant medicinal products. Therefore, early detection of any infection, particularly atypical clinical presentations of a serious infection, is critical to minimise delays in diagnosis and initiation of treatment.
Serious infections, including sepsis and tuberculosis (including miliary, disseminated and extrapulmonary disease), and opportunistic infections (e.g. histoplasmosis, nocardia, candidiasis) have been reported in patients receiving Cimzia. Some of these events have been fatal.
Tuberculosis
Before initiation of therapy with Cimzia, all patients must be evaluated for both active or inactive (latent) tuberculosis infection. This evaluation should include a detailed medical history for patients with a personal history of tuberculosis, with possible previous exposure to others with active tuberculosis, and with previous and/or current use of immunosuppressive therapy. Appropriate screening tests, e.g. tuberculin skin test and chest X-ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient's alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.
If active tuberculosis is diagnosed prior to or during treatment, Cimzia therapy must not be initiated and must be discontinued (see section 4.3).
If inactive ('latent') tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. In all situations described below, the benefit/risk balance of Cimzia therapy should be very carefully considered.
If latent tuberculosis is diagnosed, appropriate anti-tuberculosis therapy must be started before initiating treatment with Cimzia and in accordance with local recommendations.
Use of anti-tuberculosis therapy should also be considered before the initiation of Cimzia in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and in patients who have significant risk factors for tuberculosis despite a negative test for latent tuberculosis. Biological tests for tuberculosis screening should be considered before starting Cimzia treatment if there is any potential latent tuberculosis infection, regardless of BCG vaccination.
Patients should be instructed to seek medical advice if signs/symptoms (e.g. persistent cough, wasting/weight loss, low grade fever, listlessness) suggestive of a tuberculosis infection occur during or after therapy with Cimzia.
Hepatitis B virus (HBV) reactivation
Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including certolizumab pegol, who are chronic carriers of this virus (i.e., surface antigen positive). Some cases have had a fatal outcome.
Patients should be tested for HBV infection before initiating treatment with Cimzia. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Carriers of HBV who require treatment with Cimzia should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, Cimzia should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
Malignancies and lymphoproliferative disorders
The potential role of TNF-antagonist therapy in the development of malignancies is not known. Caution should be exercised when considering TNF-antagonist therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy.
With the current knowledge, a possible risk for the development of lymphomas, leukaemia or other malignancies in patients treated with a TNF-antagonist cannot be excluded.
In clinical trials with Cimzia and other TNF-antagonists, more cases of lymphoma and other malignancies have been reported among patients receiving TNF-antagonists than in control patients receiving placebo (see section 4.8). In the post marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation.
No trials have been conducted that include patients with a history of malignancy, or that continue treatment in patients who develop malignancy, while receiving Cimzia.
Skin cancers
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-antagonists including certolizumab pegol (see section 4.8). Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.
Paediatric malignancy
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age) in the post marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.
Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), have been reported in patients treated with TNF-antagonists. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. The majority of reported TNF-antagonist cases occurred in adolescent and young adult males with Crohn's disease or ulcerative colitis. Almost all of these patients had received treatment with the immunosuppressants azathioprine and/or 6-mercaptopurine concomitantly with a TNF-antagonist at or prior to diagnosis. A risk for development of hepatosplenic T-cell lymphoma in patients treated with Cimzia cannot be excluded.
Chronic obstructive pulmonary disease (COPD)
In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking.
Congestive heart failure
Cimzia is contraindicated in moderate or severe heart failure (see section 4.3). In a clinical trial with another TNF-antagonist, worsening congestive heart failure and increased mortality due to congestive heart failure have been observed. Cases of congestive heart failure have also been reported in rheumatoid arthritis patients receiving Cimzia. Cimzia should be used with caution in patients with mild heart failure (NYHA class I/II). Treatment with Cimzia must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.
Haematological reactions
Reports of pancytopaenia, including aplastic anaemia, have been rare with TNF-antagonists. Adverse reactions of the haematologic system, including medically significant cytopaenia (e.g. leukopaenia, pancytopaenia, thrombocytopaenia) have been reported with Cimzia (see section 4.8). All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on Cimzia. Discontinuation of Cimzia therapy should be considered in patients with confirmed significant haematological abnormalities.
Neurological events
Use of TNF-antagonists has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of TNF-antagonist treatment should be carefully considered before initiation of Cimzia therapy. Rare cases of neurological disorders, including seizure disorder, neuritis and peripheral neuropathy, have been reported in patients treated with Cimzia.
Hypersensitivity
Severe hypersensitivity reactions have been reported rarely following Cimzia administration. Some of these reactions occurred after the first administration of Cimzia. If severe reactions occur, administration of Cimzia should be discontinued immediately and appropriate therapy instituted.
There are limited data on the use of Cimzia in patients who have experienced a severe hypersensitivity reaction towards another TNF-antagonist; in these patients caution is needed.
Immunosuppression
Since tumour necrosis factor (TNF) mediates inflammation and modulates cellular immune responses, the possibility exists for TNF-antagonists, including Cimzia, to cause immunosupression, affecting host defences against infections and malignancies.
Autoimmunity
Treatment with Cimzia may result in the formation of antinuclear antibodies (ANA) and, uncommonly, in the development of a lupus-like syndrome (see section 4.8). The impact of long-term treatment with Cimzia on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Cimzia, treatment must be discontinued. Cimzia has not been studied specifically in a lupus population (see section 4.8).
Vaccinations
Patients treated with Cimzia may receive vaccinations, except for live vaccines. No data are available on the response to live vaccinations or the secondary transmission of infection by live vaccines in patients receiving Cimzia. Live vaccines should not be administered concurrently with Cimzia.
In a placebo-controlled clinical trial in patients with rheumatoid arthritis, similar antibody response between Cimzia and placebo treatment were observed when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with Cimzia. Patients receiving Cimzia and concomitant methotrexate had a lower humoral response compared with patients receiving Cimzia alone. The clinical significance of this is unknown.
Concomitant use with other biologics
Severe infections and neutropaenia were reported in clinical trials with concurrent use of anakinra (an interleukin-1 antagonist) or abatacept (a CD28 modulator) and another TNF-antagonist, etanercept, with no added benefit compared to TNF-antagonist therapy alone. Because of the nature of the adverse events seen with the combination of another TNF-antagonist with either abatacept or anakinra therapy, similar toxicities may also result from the combination of anakinra or abatacept and other TNF-antagonists. Therefore the use of certolizumab pegol in combination with anakinra or abatacept is not recommended (see section 4.5).
Surgery
There is limited safety experience with surgical procedures in patients treated with Cimzia. The 14-day half-life of certolizumab pegol should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Cimzia should be closely monitored for infections, and appropriate actions should be taken.
Activated partial thromboplastin time (aPTT) assay
Interference with certain coagulation assays has been detected in patients treated with Cimzia. Cimzia may cause erroneously elevated aPTT assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilised silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. There is no evidence that Cimzia therapy has an effect on coagulation in vivo. After patients receive Cimzia, careful attention should be given to interpretation of abnormal coagulation results. Interference with thrombin time (TT) and prothrombin time (PT) assays have not been observed.
Elderly patients
In the clinical trials, there was an apparently higher incidence of infections among subjects ≥ 65 years of age, compared to younger subjects, although experience is limited. Caution should be exercised when treating the elderly patients, and particular attention paid with respect to occurrence of infections.
4.5 Interaction with other medicinal products and other forms of interaction
 Concomitant treatment with methotrexate, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics showed no effect on the pharmacokinetics of certolizumab pegol based on a population pharmacokinetics analysis.
The combination of certolizumab pegol and anakinra or abatacept is not recommended (see section 4.4).
Co-administration of Cimzia with methotrexate had no significant effect on the pharmacokinetics of methotrexate. In study-to-study comparison, the pharmacokinetics of certolizumab pegol appeared similar to those observed previously in healthy subjects.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should use adequate contraception to prevent pregnancy and continue its use for at least 5 months after the last Cimzia administration.
Pregnancy
There are no adequate data from the use of Cimzia in pregnant women.
Animal studies using a rodent anti-rat TNFα did not reveal evidence of impaired fertility or harm to the foetus. However, these are insufficient with respect to human reproductive toxicity (see section 5.3). Due to its inhibition of TNFα, Cimzia administered during pregnancy could affect normal immune response in the newborn. Therefore, Cimzia is not recommended during pregnancy.
Non-clinical studies suggest low or negligible level of placental transfer of a homologue Fab-fragment of certolizumab pegol (no Fc region) (see section 5.3). Limited clinical data show low levels of certolizumab pegol in plasma of an infant born by a treated woman. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to certolizumab pegol in utero is not recommended for a minimum of 5 months following the mother's last Cimzia administration during pregnancy (see section 4.4).
Breastfeeding
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 breastfeeding child cannot be excluded. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with Cimzia should be made taking into account the benefit of breastfeeding to the child and the benefit of Cimzia therapy to the woman.
Fertility
Effects on sperm motility measures and a trend of reduced sperm count in male rodents have been observed with no apparent effect on fertility (see section 5.3).
In a clinical trial to assess the effect of certolizumab pegol on semen quality parameters, 20 healthy male subjects were randomized to receive a single subcutaneous dose of 400 mg of certolizumab pegol or placebo. During the 14-week follow-up, no treatment effects of certolizumab pegol were seen on semen quality parameters compared to placebo.
4.7 Effects on ability to drive and use machines
Cimzia may have a minor influence on the ability to drive and use machines. Dizziness (including vertigo, vision disorder and fatigue) may occur following administration of Cimzia (see section 4.8).
4.8 Undesirable effects
 Summary of the safety profile
Rheumatoid arthritis
Cimzia was studied in 4,049 patients with rheumatoid arthritis in controlled and open label trials for up to 92 months. The data in Table 1 are based primarily on the placebo controlled Studies involving 2,965 patients receiving Cimzia and 1,137 patients receiving placebo during the controlled period.
In the placebo-controlled studies, patients receiving Cimzia had an approximately 4 times greater duration of exposure compared with the placebo group. This difference in exposure is primarily due to patients on placebo being more likely to withdraw early. In addition, Studies RA-I and RA-II had a mandatory withdrawal for non-responders at Week 16, the majority of whom were on placebo.
The proportion of patients who discontinued treatment due to adverse events during the controlled trials was 4.4% for patients treated with Cimzia and 2.7% for patients treated with placebo.
The most common adverse reactions belonged to the system organ classes Infections and infestations, reported in 14.4% of patients on Cimzia and 8.0% of patients on placebo, General disorders and administration site conditions, reported in 8.8% of patients on Cimzia and 7.4% of patients on placebo, and Skin and subcutaneous tissue disorders, reported in 7.0% of patients on Cimzia and 2.4% of patients on placebo.
Axial spondyloarthritis
Cimzia was studied in 325 patients with active axial spondyloarthritis in a placebo-controlled clinical trial (AS001) for up to 30 months. The safety profile for axial spondyloarthritis patients treated with Cimzia was consistent with the safety profile in rheumatoid arthritis and previous experience with Cimzia.
Psoriatic arthritis
Cimzia was studied in 409 patients with psoriatic arthritis in a placebo-controlled clinical trial (PsA001) for up to 30 months. The safety profile for psoriatic arthritis patients treated with Cimzia was consistent with the safety profile in rheumatoid arthritis and previous experience with Cimzia.
Tabulated list of adverse reactions
Adverse reactions reported in rheumatoid arthritis clinical trials and postmarketing cases at least possibly related to Cimzia are listed in Table 1 below, according to frequency and system organ class. Frequency categories are defined as follows: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1000 to < 1/100); Rare (≥ 1/10,000 to < 1/1000); Very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1 Adverse reactions in clinical trials and postmarketing

System Organ Class	Frequency	Adverse reactions
Infections and infestations	Common	bacterial infections (including abscess), viral infections (including herpes, papillomavirus, influenza)
	Uncommon	sepsis (including multi-organ failure, septic shock), tuberculosis, fungal infections (includes opportunistic)
Neoplasms benign, malignant and unspecified (including cysts and polyps)	Uncommon	blood and lymphatic system malignancies (including lymphoma and leukaemia), solid organ tumours, non-melanoma skin cancers, pre-cancerous lesions (including oral leukoplakia, melanocytic nevus), benign tumours and cysts (including skin papilloma)
	Rare	gastrointestinal tumours, melanoma
	Not known	Merkel cell carcinoma*
Blood and the lymphatic system disorders	Common	eosinophilic disorders, leukopaenia (including neutropaenia, lymphopaenia)
	Uncommon	anaemia, lymphadenopathy, thrombocytopaenia, thrombocytosis
	Rare	pancytopaenia, splenomegaly, erythrocytosis, white blood cell morphology abnormal
Immune system disorders	Uncommon	vasculitides, lupus erythematosus, drug hypersensitivity (including anaphylactic shock), allergic disorders, auto-antibody positive
	Rare	angioneurotic oedema, sarcoidosis, serum sickness, panniculitis (including erythema nodosum)
Endocrine disorders	Rare	thyroid disorders
Metabolism and nutrition disorders	Uncommon	electrolyte imbalance, dyslipidaemia, appetite disorders, weight change
	Rare	haemosiderosis
Psychiatric disorders	Uncommon	anxiety and mood disorders (including associated symptoms)
	Rare	suicide attempt, delirium, mental impairment
Nervous system disorders	Common	headaches (including migraine), sensory abnormalities
	Uncommon	peripheral neuropathies, dizziness, tremor
	Rare	seizure, cranial nerve inflammation, impaired coordination or balance
	Not known	multiple sclerosis*, Guillain-Barré syndrome*
Eye disorders	Uncommon	visual disorder (including decreased vision), eye and eyelid inflammation, lacrimation disorder
Ear and labyrinth disorders	Uncommon	tinnitus, vertigo
Cardiac disorders	Uncommon	cardiomyopathies (including heart failure), ischaemic coronary artery disorders , arrhythmias (including atrial fibrillation), palpitations
	Rare	pericarditis, atrioventricular block
Vascular disorders	Common	hypertension
	Uncommon	haemorrhage or bleeding (any site), hypercoagulation (including thrombophlebitis, pulmonary embolism), syncope, oedema (including peripheral, facial), ecchymoses (including haematoma, petechiae)
	Rare	cerebrovascular accident, arteriosclerosis, Raynaud's phenomenon, livedo reticularis, telangiectasia
Respiratory, thoracic and mediastinal disorders	Uncommon	asthma and related symptoms, pleural effusion and symptoms, respiratory tract congestion and inflammation, cough
	Rare	interstitial lung disease, pneumonitis
Gastrointestinal disorders	Common	nausea
	Uncommon	ascites, gastrointestinal ulceration and perforation, gastrointestinal tract inflammation (any site), stomatitis, dyspepsia, abdominal distension, oropharyngeal dryness
	Rare	odynophagia, hypermotility
Hepatobiliary disorders	Common	hepatitis (including hepatic enzyme increased)
	Uncommon	hepatopathy (including cirrhosis), cholestasis, blood bilirubin increased
	Rare	cholelithiasis
Skin and subcutaneous tissue disorders	Common	rash
	Uncommon	alopecia, new onset or worsening of psoriasis (including palmoplantar pustular psoriasis) and related conditions, dermatitis and eczema, sweat gland disorder, skin ulcer, photosensitivity, acne, skin discolouration, dry skin, nail and nail bed disorders
	Rare	skin exfoliation and desquamation, bullous conditions, hair texture disorder
Musculoskeletal, connective tissue and bone disorders	Uncommon	muscle disorders, blood creatine phosphokinase increased
Renal and urinary disorders	Uncommon	renal impairment, blood in urine, bladder and urethral symptoms
	Rare	nephropathy (including nephritis)
Reproductive system and breast disorders	Uncommon	menstrual cycle and uterine bleeding disorders (including amenorrhea), breast disorders
	Rare	sexual dysfunction
General disorders and administration site conditions	Common	pyrexia, pain (any site), asthaenia, pruritus (any site), injection site reactions
	Uncommon	chills, influenza-like illness, altered temperature perception, night sweats, flushing
	Rare	fistula (any site)
Investigations	Uncommon	blood alkaline phosphatase increased, coagulation time prolonged
	Rare	blood uric acid increased
Injury, poisoning and procedural complications	Uncommon	skin injuries, impaired healing

*These events have been related to the class ofCimzia TNF-antagonists, but incidence with certolizumab pegol is not known.
The additional following adverse reactions have been observed uncommonly with Cimzia in other indications: gastrointestinal stenosis and obstructions, general physical health deterioration, abortion spontaneous and azoospermia.
Description of selected adverse reactions
Infections
The incidence rate of new cases of infections in placebo-controlled clinical trials in rheumatoid arthritis was 1.03 per patient-year for all Cimzia-treated patients and 0.92 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, urinary tract infections, and lower respiratory tract infections and herpes viral infections (see sections 4.3 and 4.4).
In the placebo-controlled clinical trials, there were more new cases of serious infection in the Cimzia treatment groups (0.07 per patient-year; all doses), compared with placebo (0.02 per patient-year). The most frequent serious infections included pneumonia, tuberculosis infections. Serious infections also included invasive opportunistic infections (e.g. pneumocystosis, fungal oesophagitis, nocardiosis and herpes zoster disseminated). There is no evidence of an increased risk of infections with continued exposure over time (see section 4.4).
Malignancies and lymphoproliferative disorders
Excluding non-melanoma of the skin, 121 malignancies including 5 cases of lymphoma were observed in the Cimzia RA clinical trials in which a total of 4,049 patients were treated, representing 9,277 patient-years. Cases of lymphoma occurred at an incidence rate of 0.05 per 100 patient-years and melanoma at an incidence rate of 0.08 per 100 patient-years with Cimzia in rheumatoid arthritis clinical trials (see section 4.4). One case of lymphoma was also observed in the Phase III psoriatic arthritis clinical trial.
Autoimmunity
In the pivotal studies, for subjects who were ANA negative at baseline, 16.7% of those treated with Cimzia developed positive ANA titers, compared with 12.0% of subjects in the placebo group. For subjects who were anti-dsDNA antibody negative at baseline, 2.2% of those treated with Cimzia developed positive anti-dsDNA antibody titers, compared with 1.0% of subjects in the placebo group. In both placebo-controlled and open-label follow-up clinical trials for rheumatoid arthritis, cases of lupus-like syndrome were reported uncommonly. There have been rare reports of other immune-mediated conditions; the causal relationship to Cimzia is not known. The impact of long-term treatment with Cimzia on the development of autoimmune diseases is unknown.
Injection site reactions
In the placebo-controlled rheumatoid arthritis clinical trials, 5.8% of patients treated with Cimzia developed injection site reactions such as erythema, itching, haematoma, pain, swelling or bruising, compared to 4.8% of patients receiving placebo. Injection site pain was observed in 1.5% of patients treated with Cimzia with no cases leading to withdrawal.
Creatine phosphokinase elevations
The frequency of creatine phosphokinase (CPK) elevations was generally higher in patients with axSpA as compared to the RA population. The frequency was increased both in patients treated with placebo (2.8% vs 0.4% in axSpA and RA populations, respectively) as well as in patients treated with Cimzia (4.7% vs 0.8% in axSpA and RA populations, respectively). The CPK elevations in the axSpA study were mostly mild to moderate, transient in nature and of unknown clinical significance with no cases leading to withdrawal.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
UK
The Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
Pharmacovigilance Section
Irish Medicines Board
Kevin O'Malley House
Earlsfort Centre
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
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: immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors, ATC code: L04AB05
Mechanism of action
Cimzia has a high affinity for human TNFα and binds with a dissociation constant (KD) of 90 pM. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Cimzia selectively neutralises TNFα (IC90 of 4 ng/ml for inhibition of human TNFα in the in vitro L929 murine fibrosarcoma cytotoxicity assay) but does not neutralise lymphotoxin α (TNFβ).
Cimzia was shown to neutralise membrane associated and soluble human TNFα in a dose-dependent manner. Incubation of monocytes with Cimzia resulted in a dose-dependent inhibition of lipopolysaccharide (LPS)-induced TNFα and IL1β production in human monocytes.
Cimzia does not contain a fragment crystallisable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, or neutrophil degranulation.
Clinical efficacy
Rheumatoid arthriti
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 ACR 20 response rate at this timepoint was 91%.The reduction (RA-I) from Baseline in DAS28 (ESR) also was significantly greater (p<0.001) at Week 52 (RA-I) and Week 24 (RA-II) compared to placebo and maintained through 2 years in the open-label extension trial to RA-I.
Table 3 ACR response in clinical trials RA-I and RA-II

Study RA-I Methotrexate combination (24 and 52 weeks)		Study RA-II Methotrexate combination (24 weeks)
Response	Placebo + MTX N=199	Cimzia 200 mg + MTX every 2 weeks N=393	Placebo + MTX N=127	Cimzia 200 mg + MTX every 2 weeks N=246
ACR 20
Week 24	14%	59%**	9%	57%**
Week 52	13%	53%**	N/A	N/A
ACR 50
Week 24	8%	37%**	3%	33%**
Week 52	8%	38%**	N/A	N/A
ACR 70
Week 24	3%	21%**	1%	16%*
Week 52	4%	21%**	N/A	N/A
Major Clinical Responsea.	1%	13%**

Cimzia vs. placebo: *p≤0.01, ** p<0.001
a. Major clinical response is defined as achieving ACR 70 response at every assessment over a continuous 6-month period
Wald p-values are quoted for the comparison of treatments using logistic regression with factors for treatment and region.
Percentage response based upon number of subjects contributing data (n) to that endpoint and time point which may differ from N
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

Placebo + MTX N=199 Mean (SD)	Cimzia 200 mg + MTX N=393 Mean (SD)	Cimzia 200 mg + MTX – Placebo + MTX Mean Difference
mTSS
Week 52	2.8 (7.8)	0.4 (5.7)	-2.4
Erosion Score
Week 52	1.5 (4.3)	0.1 (2.5)	-1.4
JSN Score
Week 52	1.4 (5.0)	0.4 (4.2)	-1.0

p-values were < 0.001 for both mTSS and erosion score and ≤ 0.01 for JSN score. An ANCOVA was fitted to the ranked change from baseline for each measure with region and treatment as factors and rank baseline as a covariate.
Of the 783 patients initially randomised to active treatment in RA-I, 508 completed 52 weeks of placebo-controlled treatment and entered the open-label extension study. Sustained inhibition of progression of structural damage was demonstrated in a subset of 449 of these patients who completed at least 2 years of treatment with Cimzia (RA-I and open-label extension study) and had evaluable data at the 2-year timepoint.
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.
DoseFlex clinical trial
The efficacy and safety of 2 dose regimens (200 mg every 2 weeks and 400 mg every 4 weeks) of Cimzia versus placebo were assessed in an 18-week, open-label, run-in, and 16-week randomised, double-blind, placebo-controlled clinical trial in adult patients with active rheumatoid arthritis diagnosed according to the ACR criteria who had inadequate response to MTX.
Patients received loading doses of Cimzia 400 mg at weeks 0, 2, and 4 followed by Cimzia 200 mg every 2 weeks during the initial open label period. Responders (achieved ACR 20) at week 16 were randomised at week 18 to Cimzia 200 mg every 2 weeks, Cimzia 400 mg every 4 weeks, or placebo in combination with MTX for an additional 16 weeks (total trial length: 34 weeks). These 3 groups were well balanced with regards to clinical response following the active run-in period (ACR 20: 83-84% at week 18).
The primary endpoint of the study was the ACR 20 responder rate at week 34. The results at week 34 are shown in Table 5. Both Cimzia regimens showed sustained clinical response and were statistically significant compared to placebo at week 34. The ACR 20 endpoint was achieved for both Cimzia 200 mg every 2 weeks and 400 mg every 4 weeks.
Table 5 ACR response in DoseFlex clinical trial at week 34

Treatment regimen week 0 to 16	Cimzia 400 mg + MTX at week 0, 2 and 4, followed by Cimzia 200 mg + MTX every 2 weeks
Randomised, double-blind treatment regimen week 18 to 34	Placebo + MTX   N=69	Cimzia 200 mg + MTX every 2 weeks N=70	Cimzia 400 mg + MTX every 4 weeks N=69
ACR 20 p-value*	45% N/A	67% 0.009	65% 0.017
ACR 50 p-value*	30% N/A	50% 0.020	52% 0.010
ACR 70 p-value*	16% N/A	30% 0.052	38% 0.005

N/A: Not Applicable
*Wald p-values for Cimzia 200 mg vs. placebo and Cimzia 400 mg vs. placebo comparisons are estimated from a logistic regression model with factors for treatment.
Axial spondyloarthritis
The efficacy and safety of Cimzia were assessed in one multicenter, randomized, double-blind, placebo-controlled trial (AS001) in 325 patients ≥18 years of age with adult-onset active axial spondyloarthritis for at least 3 months as defined by the Assessment of Spondyloarthritis International Society (ASAS) Classification Criteria for axial spondyloarthritis. The axial spondyloarthritis overall population included subpopulations with and without (non-radiographic axial spondyloarthritis [nr-axSpA]) radiographic evidence for ankylosing spondylitis (AS). Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4, spinal pain ≥ 4 on a 0 to 10 Numerical Rating Scale (NRS) and increased CRP or current evidence of sacroiliitis on Magnetic Resonance Imaging (MRI).Patients must have been intolerant to or had an inadequate response to at least one NSAID. Overall, 16% of patients had prior TNF-antagonist exposure. Patients were treated with a loading dose of Cimzia 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either 200 mg of Cimzia every 2 weeks or 400 mg of Cimzia every 4 weeks or placebo. 87.7% of patients received concomitant NSAIDs.The primary efficacy endpoint was the ASAS20 response rate at Week 12.
Key efficacy outcomes
In AS001 clinical trial, at Week 12 ASAS20 responses were achieved by 58% of patients receiving Cimzia 200 mg every 2 weeks and 64% of patients receiving Cimzia 400 mg every 4 weeks as compared to 38% of patients receiving placebo (p<0.01). In the overall population, the percentage of ASAS20 responders was clinically relevant and significantly higher for the Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 4 weeks treatment groups compared to placebo group at every visit from Week 1 through Week 24 (p≤0.001 at each visit). At Weeks 12 and 24, the percentage of subjects with an ASAS40 response was greater in the Cimzia-treated groups compared to placebo.
Similar results were achieved in both the ankylosing spondylitis and non-radiographic axial spondyloarthritis subpopulations. In women, ASAS20 responses were not statistically significantly different from placebo until after the Week 12 time point.
Improvements in ASAS5/6, Partial Remission and BASDAI-50 were statistically signficant at Week 12 and Week 24 and were sustained up to Week 48 in the overall popualtion as well as in the subpopulations. Key efficacy outcomes from the AS001 clinical trial are shown in Table -6.
Table 6 Key efficacy outcomes in AS001 clinical trial (percent of patients)

Parameters	Ankylosing spondylitis		Non-radiographic axial spondyloarthritits		Axial spondyloarthritis Overall Population
	Placebo N=57	Cimzia all dosing regimens(a) N=121	Placebo N=50	Cimzia all dosing regimens(a) N=97	Placebo N=107	Cimzia all dosing regimens(a) N=218
ASAS20(b,c) Week 12 Week 24	37% 33%	60%* 69%**	40% 24%	61%* 68%**	38% 29%	61%** 68%**
ASAS40(c,d) Week 12 Week 24	19% 16%	45%** 53%**	16% 14%	47%** 51%**	18% 15%	46%** 52%**
ASAS 5/6(c,d) Week 12 Week 24	9% 5%	42%** 40%**	8% 4%	44%** 45%**	8% 5%	43%** 42%**
Partial remission(c,d) Week 12 Week 24	2% 7%	20%** 28%**	6% 10%	29%** 33%**	4% 9%	24%** 30%**
BASDAI 50(c,d) Week 12 Week 24	11% 16%	41%** 49%**	16% 20%	49%** 57%**	13% 18%	45%** 52%**

(a) Cimzia all dosing regimen = data from Cimzia 200 mg administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 plus Cimzia 400 mg administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
(b) Results are from the randomized set
(c) Wald p-values are quoted for the comparison of treatments using logistic regression with factors for treatment and region.
(d) Full Analysis Set
NA = not available
*p≤0.05, Cimzia vs placebo
**p<0.001, Cimzia vs placebo
Spinal mobility
Spinal mobility was assessed by BASMI at Baseline, Week 12 and Week 24. Clinically meaningful and statistically significant differences in Cimzia-treated patients compared with placebo-treated patients were demonstrated at each post-baseline visit. The difference from placebo tended to be greater in nr-axSpA than in the AS subpopulation which may be due to less chronic structural damage in nr-axSpA patients.
Physical function response and health-related outcomes
In the AS001 clinical trial, Cimzia-treated patients reported significant improvements in physical function as assessed by the BASFI and in pain as assessed by the Total and Nocturnal Back Pain NRS scales as compared to placebo. Cimzia-treated patients reported significant improvements in tiredness (fatigue) as reported by the BASDAI-fatigue item and in health-related quality of life as measured by the ankylosing spondylitis QOL (ASQoL) and the SF-36 Physical and Mental Component Summaries and all domain scores as compared to placebo. Cimzia-treated patients reported significant improvements in axial spondyloarthritis-related productivity at work and within household, as reported by the Work Productivity Survey as compared to placebo. These improvements were sustained up to Week 48.
Inhibition of inflammation in Magnetic Resonance Imaging (MRI)
In an imaging sub-study including 153 patients, signs of inflammation were assessed by MRI at week 12 and expressed as change from baseline in SPARCC (Spondyloarthritis Research Consortium of Canada) score for sacroiliac joints and ASspiMRI-a score in the Berlin modifications for the spine. Significant inhibition of inflammatory signs in both sacroiliac joints and the spine was observed in the Cimzia-treated patients (all dose group), in the overall axial spondyloarthritis population as well as in the sub-populations of ankylosing spondylitis and non-radiographic axial spondyloarthritis.
Psoriatic arthritis
The efficacy and safety of Cimzia were assessed in a multicentre, randomised, double-blind, placebo controlled clinical trial (PsA001) in 409 patients ≥ 18 years of age with adult-onset active psoriatic arthritis for at least 6 months as defined by the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria. Patients had ≥ 3 swollen and tender joints and increased acute phase reactants. Patients also had active psoriatic skin lesions or a documented history of psoriasis and had failed 1 or more DMARDs. Previous treatment with one TNF-antagonist was allowed and 20% of patients had prior TNF-antagonist exposure. Patients received a loading dose of Cimzia 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either Cimzia 200 mg every 2 weeks or 400 mg every 4 weeks or placebo every 2 weeks. Patients receiving concomitant NSAIDs and conventional DMARDs were 72.6% and 70.2% respectively. The two primary endpoints were the percentage of patients achieving ACR 20 response at Week 12 and change from baseline in modified Total Sharp Score (mTSS) at Week 24. Efficacy and safety of Cimzia in patients with PsA whose predominant symptoms were sacroiliitis or axial spondyloarthritis have not been separately analysed.
ACR response
Cimzia-treated patients had a statistically significant higher ACR 20 response rate at Week 12 and Week 24 compared with placebo-treated patients (p<0.001). The percentage of ACR 20 responders was clinically relevant for the Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 4 weeks treatment groups compared to placebo group at every visit after baseline through Week 24 (nominal p≤0.001 at each visit). At week 12 and 24 improvements in parameters of peripheral activity characteristic of psoriatic arthritis (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) were seen in the Cimzia-treated patients (nominal p-value p<0.01). Among 273 patients initially randomised to Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 4 weeks, 237 (86.8%) were still on this treatment at Week 48. Of the 138 patients randomised to Cimzia 200 mg every 2 weeks, 92, 68 and 48 had an ACR 20/50/70 response, respectively. Of the 135 patients randomised to Cimzia 400 mg every 4 weeks, 89, 62 and 41 patients had an ACR 20/50/70 response, respectively. Cimzia treated patients also had significant improvements in ACR 50 and 70 response rates. Key efficacy outcomes from the PsA001 clinical trial are shown in Table 7.
Table 7 Key efficacy outcomes in PsA001 clinical trial (percent of patients)

Response	Placebo N=136	Cimzia(a)200 mg Q2W N=138	Cimzia(b) 400 mg Q4W N=135
ACR20 Week 12 Week 24	24% 24%	58%** 64%**	52%** 56%**
ACR50 Week 12 Week 24	11% 13%	36%** 44%**	33%** 40%**
ACR70 Week 12 Week 24	3% 4%	25%** 28%**	13%* 24%**
Response	Placebo N=86	Cimzia(a)200 mg Q2W N=90	Cimzia(b) 400 mg Q4W N=76
PASI 75 (c) Week 12 Week 24 Week 48	14% 15% N/A	47%*** 62%*** 67%	47%*** 61%*** 62%

(a) Cimzia administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
(b) Cimzia administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
(c) In subjects with at least 3% psoriasis BSA at Baseline
*p<0.01, Cimzia vs placebo
**p<0.001, Cimzia vs placebo
***p<0.001(nominal), Cimzia vs placebo
Results are from the randomized set.Treatment Difference: Cimzia 200 mg-placebo, Cimzia 400 mg-placebo (and corresponding 95% CI and p-value) are estimated using a standard two-sided Wald asymptotic standard errors test. Non-responder Imputation (NRI) is used for patients who escaped therapy or had missing data.
Radiographic response
In PsA001 clinical trial, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified total Sharp score (mTSS) and its components, the Erosion Score (ES) and Joint Space Narrowing score (JSN) at Week 24, compared to baseline. The mTSS Score was modified for psoriatic arthritis by addition of hand distal interphalangeal joints. Cimzia treatment inhibited the radiographic progression compared with placebo treatment at Week 24 as measured by change from baseline in total mTSS Score (LS mean [±SE] score was 0.28 [±0.07] in the placebo group compared with 0.06 [±0.06] in the Cimzia all doses group; p=0.007). Inhibition of radiographic progression was maintained with Cimzia treatment up to Week 48 in the subset of patients at higher risk of radiographic progression (patients with a Baseline mTSS score of > 6).
Physical function response and health-related outcomes
In PsA001 clinical trial, Cimzia-treated patients reported significant improvements in physical function as assessed by the Health Assessment Questionnaire – Disability Index (HAQ-DI), in pain as assessed by the Patient Assessment of Arthritis Pain (PAAP) and in tiredness (fatigue) as reported by the Fatigue Assessment Scale (FAS) as compared to placebo. Cimzia-treated patients reported significant improvements in health-related quality of life as measured by the psoriatic arthritis QoL (PsAQoL) and the SF-36 Physical and Mental Components and in psoriatic arthritis-related productivity at work and within household, as reported by the Work Productivity Survey compared to placebo. These improvements were sustained up to Week 48.
Immunogenicity
Rheumatoid arthritis
The overall percentage of patients with antibodies to Cimzia detectable on at least 1 occasion was 9.6% in RA placebo-controlled trials. Approximately one-third of antibody-positive patients 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.
The data reflect the percentage of patients whose test results were considered positive for antibodies to Cimzia in an ELISA, and are highly dependent 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.
Axial spondyloarthritis
The overall percentage of patients with antibodies to Cimzia detectable on at least one occasion up to Week 24 was 4.4% in the phase III placebo controlled trial in patients with axial spondyloarthritis. Antibody formation was associated with lowered drug plasma concentration.
Psoriatic arthritis
The overall percentage of patients with antibodies to Cimzia detectable on at least one occasion up to Week 24 was 11.7% in the Phase III placebo-controlled trial in patients with psoriatic arthritis. Antibody formation was associated with lowered drug plasma concentration.
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 (t1/2) was approximately 14 days for all doses tested.
Clearance following subcutaneous dosing was estimated to be 21.0 ml/h in a rheumatoid arthritis population pharmacokinetic analysis, with an inter-subject variability of 30.8% (CV) and an inter-occasion variability of 22.0%. The presence of antibodies to certolizumab pegol resulted in an approximately three-fold increase in clearance. Compared with a 70 kg person, clearance is 29% lower and 38% higher, respectively, in individual RA patients weighing 40 kg and 120 kg.
The Fab' fragment comprises protein compounds and is expected to be degraded to peptides and amino acids by proteolysis. The de-conjugated PEG component is rapidly eliminated from plasma and is to an unknown extent excreted renally.
Special populations
Renal impairment
Specific clinical trials have not been performed to assess the effect of renal impairment on the pharmacokinetics of certolizumab pegol or its PEG fraction. However, population pharmacokinetic analysis based on subjects with mild renal impairment showed no effect of creatinine clearance. There are insufficient data to provide a dosing recommendation in moderate and severe renal impairment. The pharmacokinetics of the PEG fraction of certolizumab pegol are expected to be dependent on renal function but have not been assessed in patients with renal impairment.
Hepatic impairment
Specific clinical trials have not been performed to assess the effect of hepatic impairment on the pharmacokinetics of certolizumab pegol.
Elderly patients (≥ 65 years old)
Specific clinical trials have not been performed in elderly patients subjects. However, no effect of age was observed in a population pharmacokinetic analysis in patients with rheumatoid arthritis in which 78 subjects (13.2% of the population) were aged 65 or greater and the oldest subject was aged 83 years.
Gender
There was no effect of gender on the pharmacokinetics of certolizumab pegol. As clearance decreases with decreasing body weight, females may generally obtain somewhat higher systemic exposure of certolizumab pegol.
Pharmacokinetic/pharmacodynamic relationship
On the basis of Phase II and Phase III clinical trial data, a population exposure-response relationship was established between average plasma concentration of certolizumab pegol during a dosing interval (Cavg) and efficacy (ACR 20 responder definition). The typical Cavg that produces half the maximum probability of ACR 20 response (EC50) was 17 µg/ml (95% CI: 10-23 µg/ml).
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. Data from a human closed-circuit placental transfer model in vitro suggest low or negligible transfer to the foetal compartment (see section 4.6).
No mutagenic or clastogenic effects were demonstrated in preclinical studies. Carcinogenicity studies have not been performed with certolizumab pegol.
6. Pharmaceutical particulars
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
 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.
Pack size of 2 syringes and 2 alcohol wipes.
Multipack containing 6 (3 packs of 2) pre-filled syringes and 6 (3 packs of 2) alcohol wipes.
Pack size of 2 pre-filled syringes with needle guard and 2 alcohol wipes (for use by healthcare professionals only).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
 Comprehensive instructions for the preparation and administration of Cimzia in a pre-filled syringe are given in the package leaflet.
This medicinal product is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
UCB Pharma S.A.
Allée de la Recherche 60
B-1070 Bruxelles
Belgium
8. Marketing authorisation number(s)
EU/1/09/544/001
EU/1/09/544/002
EU/1/09/544/003
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 01 October 2009
Date of latest renewal: 16 May 2014
10. Date of revision of the text
May 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

优时比旗下赛妥珠单抗获FDA批准用于成人银屑病性关节炎
优时比制药旗下赛妥珠单抗（Cimzia）获美国食品药品管理局（FDA）批准用于治疗成人患者银屑病关节炎。这次赛妥珠单抗的获批是基于一项409名患者参与的III期临床试验，该试验显示每个剂量组14周与24周ACR20（即病症20%的改善）、50和70的缓解率相较安慰剂组要高。治疗也可使银屑病关节炎患者皮肤的临床症状得到改善，尽管优时比强调赛妥珠单抗治疗斑块状银屑病的安全性和有效性还未得到确认。
然而，该生物药物已可以在欧美用于治疗类风湿关节炎和克罗恩氏病。FDA也正在对赛妥珠单抗治疗中轴型脊柱炎的适应症进行审评，包括强直性脊柱炎。欧洲的药品监管机构目前正在对这款药物用于银屑病关节炎进行审评，并且这个月初欧洲药品管理局（EMA）人用医药产品委员会对这款药物用于中轴型脊柱炎给出了积极的推荐意见。
优时比公司首席医疗官IrisLoew-Friedrich指出，这次批准是赛妥珠单抗在美国获批的第三个适应症，“并再次肯定了我们致力于开发治疗严重、慢性病症药物的价值”。据估计，美国750万银屑病患者中有多达30%的患者将会发展成银屑病关节炎。
优时比与Vectura公司开展炎症性药物合作
同时，优时比已经与英国的Vectura集团在严重炎症性呼吸道疾病领域合作开发“创新型生物免疫调节产品”。
两家合作伙伴表示，这次合作将使Vectura在吸入治疗领域的专长与优时比的生物及免疫学资产有机结合起来。它将专注于对来自布鲁塞尔集团总部试验室的一种生物疗法进行概念性验证，该疗法以免疫系统的一个关键分子为靶点。