1. NAME OF THE MEDICINAL PRODUCT

LIFMIOR 25 mg powder and solvent for solution for injection.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 25 mg of etanercept.

Etanercept is a human tumour necrosis factor receptor p75 Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression system. Etanercept is a dimer of a chimeric protein genetically engineered by fusing the extracellular ligand binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75) to the Fc domain of human IgG1. This Fc component contains the hinge, CH2 and CH3 regions, but not the CH1 region of IgG1. Etanercept contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. The specific activity of etanercept is 1.7 × 106 units/mg.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection (powder for injection).

The powder is white. The solvent is a clear, colourless liquid.

• 4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Rheumatoid arthritis

LIFMIOR in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate.

LIFMIOR an be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

LIFMIOR is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

LIFMIOR, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.

Juvenile idiopathic arthritis

Treatment of polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis in children and adolescents from the age of 2 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.

Treatment of psoriatic arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.

Treatment of enthesitis-related arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, conventional therapy.

LIFMIOR has not been studied in children aged less than 2 years.

Psoriatic arthritis

Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate. LIFMIOR has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression o peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical su the disease.

Axial spondyloarthritis

Ankylosing spondylitis (AS)

Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Non-radiographic axial spondyloarthritis

Treatment of adults with severe non-radiographic axial spondyloarthritis w bjective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence, who have had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).

Plaque psoriasis

Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy, including ciclosporin, methotrexate or psoralen and ultraviolet-A light (PUVA) (see section 5.1).

Paediatric plaque psoriasis

Treatment of chronic severe plaque psoria hildren and adolescents from the age of 6 years who

are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

e initiated and supervised by specialist physicians experienced in the eumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, -radiographic axial spondyloarthritis, plaque psoriasis or paediatric plaque with LIFMIOR should be given the Patient Alert Card.

atoid arthritis

LIFMIOR administered twice weekly is the recommended dose. Alternatively, 50 mg istered once weekly has been shown to be safe and effective (see section 5.1).

Psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis

The recommended dose is 25 mg LIFMIOR administered twice weekly, or 50 mg administered once

For all of the above indications, available data suggest that a clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

Plaque psoriasis

The recommended dose of LIFMIOR is 25 mg administered twice weekly or 50 mg administered once weekly. Alternatively, 50 mg given twice weekly may be used for up to 12 weeks followed, if necessary, by a dose of 25 mg twice weekly or 50 mg once weekly. Treatment with LIFMIOR should continue until remission is achieved, for up to 24 weeks. Continuous therapy beyond 24 weeks may be appropriate for some adult patients (see section 5.1). Treatment should be discontinued in patients who show no response after 12 weeks. If re-treatment with LIFMIOR is indicated, the same guidance on treatment duration should be followed. The dose should be 25 mg twice weekly or 50 mg once weekly.

Special populations

Renal and hepatic impairment No dose adjustment is required.

Elderly

No dose adjustment is required. Posology and administration are the same as for ad age.

Paediatric population

Juvenile idiopathic arthritis

The recommended dose is 0.4 mg/kg (up to a maximum of 25 mg p subcutaneous injection with an interval of 3–4 days between doses o

50 mg per dose) given once weekly. Discontinuation of trea who show no response after 4 months.

The 10 mg vial strength may be more appropriate f weight of 25 kg.

No formal clinical trials have been conducted in children aged 2 to 3 years. However, limited safety data from a patient registry suggest that the safety profile in children from 2 to 3 years of age is similar to that seen in adults and children aged 4 years and older, when dosed every week with 0.8 mg/kg subcutaneously (see section 5.1).

f LIFMIOR in children aged below 2 years in the indication

Paediatric plaque psoriasis (age 6 years and above)

The recommen e is 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly for up to

24 weeks. Trea hould be discontinued in patients who show no response after 12 weeks.

ith LIFMIOR is indicated, the above guidance on treatment duration should be dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.

generally no applicable use of LIFMIOR in children aged below 6 years in the indication e psoriasis.

ethod of administration

LIFMIOR is administered by subcutaneous injection. LIFMIOR powder for solution must be reconstituted in 1 ml of solvent before use (see section 6.6).

Comprehensive instructions for the preparation and administration of the reconstituted LIFMIOR vial are given in the package leaflet, section 7, „Instructions for preparation and giving an injection of LIFMIOR.“

4.3 Contraindications

4.4 Special warnings and precautions for use

receiving TNF-antagonist therapy. In the postmarketing setting, cases of leukaemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.

Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded. 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 a 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), including LIFMIOR, in the postmarketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies typically associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.

Skin cancers

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with

TNF-antagonists, including LIFMIOR. Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with LIFMIOR. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Combining the results of controlled clinical trials, more cases of NMSC were observed in patients receiving LIFMIOR compared with control patients, particularly in patients with psoriasis.

Vaccinations

Live vaccines should not be given concurrently wit secondary transmission of infection by live vaccines in patients receiving LIFMIOR. In a double-blind, placebo-controlled, randomised clinical study in adult patients with psoriatic arthritis, 184 patients also received a multivalent pneumococcal polysaccharide vaccine at week 4. In this study, most psoriatic arthritis patients receiving LIFMIOR were able to mount effective B-cell immune response to pneumococcal polysaccharide vaccine, but titres in aggregate were moderately lower, and few patients had two-fold rises in titres compared to patients not receiving LIFMIOR. The clinical significance of this is unknown.

Autoantibody formation ikJ..... .. .. ........

Treatment with LIFMIOR may result in the formation of autoimmune antibodies (see section 4.8).

Haematologic rcOction^ ^

Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome, have been reported in patients treated with LIFMIOR. Caution should be exercised in patients being treated with LIFMIOR who have a previous history of blood dyscrasias. All patients and parents/caregivers should be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias or infections (e.g., persistent fever, sore throat, bruising, bleeding, paleness) whilst on LIFMIOR, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, LIFMIOR should be discontinued.

Neurological disorders

There have been rare reports of CNS demyelinating disorders in patients treated with LIFMIOR (see section 4.8). Additionally, there have been rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have been performed evaluating LIFMIOR therapy in patients with multiple sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have shown increases in disease activity. A careful risk/benefit evaluation, including a neurologic assessment, is recommended when prescribing

LIFMIOR to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.

Combination therapy

In a controlled clinical trial of two years duration in rheumatoid arthritis patients, the combination of LIFMIOR and methotrexate did not result in unexpected safety findings, and the safety profile of

LIFMIOR when given in combination with methotrexate was similar to the profiles reported in studies of LIFMIOR and methotrexate alone. Long-term studies to assess the safety of the combination are ongoing. The long-term safety of LIFMIOR in combination with other disease-modifying antirheumatic drugs (DMARD) has not been established.

The use of LIFMIOR in combination with other systemic therapies or phototherapy for the trea of psoriasis has not been studied.

Renal and hepatic impairment

Based on pharmacokinetic data (see section 5.2), no dose adjustment is needed in pati or hepatic impairment; clinical experience in such patients is limited.

Congestive heart failure (Cardiac failure congestive)

Physicians should use caution when using LIFMIOR in patients who have congestive heart failure (CHF). There have been postmarketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking LIFMIOR. There have also been rare (< 0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Two large clinical trials evaluating the use of

LIFMIOR in the treatment of CHF were terminated early d conclusive, data from one of these trials suggest a possi patients assigned to LIFMIOR treatment.

Alcoholic hepatitis

In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with LIFMIOR or placebo for moderate to severe alcoholic hepatitis, LIFMIOR was not efficacious, and the mortality rate in patients treated with LIFMIOR was significantly higher after 6 months. Consequently, LIFMIOR should not be used in patients for the treatment of alcoholic hepatitis. Physicians should use

nts who also have moderate to severe alcoholic hepatitis.

Wegener's gra­nulomatosis

A placebo-controlled trial, in which 89 adult patients were treated with LIFMIOR in addition to standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median duration of 25 months, has not shown LIFMIOR to be an effective treatment for Wegener’s gra­nulomatosis. The incidence of non-cutaneous malignancies of various types was significantly higher in patients treated with LIFMIOR than in the control group. LIFMIOR is not recommended for the treatment of Wegener’s gra­nulomatosis.

emia in patients treated for diabetes

been reports of hypoglycaemia following initiation of LIFMIOR in patients receiving for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Elderly

In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no overall differences in adverse events, serious adverse events, and serious infections in patients age 65 or older who received LIFMIOR were observed compared with younger patients. However, caution should be exercised when treating the elderly and particular attention paid with respect to occurrence of infections.

Paediatric population

Vaccinations

It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating LIFMIOR therapy (see Vaccinations, above).

Inflammatory bowel disease (IBD) and uveitis in patients with juvenile idiopathic arthritis (JIA) There have been reports of IBD and uveitis in JIA patients being treated with LIFMIOR (see section 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent treatment with anakinra

Adult patients treated with LIFMIOR and anakinra were observed to have a higher rat infection when compared with patients treated with either LIFMIOR or anakinra alon data).

In addition, in a double-blind, placebo-controlled trial in adult patients receivin methotrexate, patients treated with LIFMIOR and anakinra were observed ve a higher rate of

serious infections (7%) and neutropenia than patients treated with LIFMIO e sections 4.4 and 4.8). The combination LIFMIOR and anakinra has not demonstrated increased clinical benefit, and is therefore not recommended.

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatace incidences of serious adverse events. This combination benefit; such use is not recommended (see section 4.4).

Concurrent treatment with sulfasalazine

In a clinical study of adult patients who were receiving established doses of sulfasalazine, to which LIFMIOR was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with LIFMIOR or sulfasalazine alone. The clinical significance of this interaction is unknown. Physicians should use caution when considering combination therapy with sulfasalazine.

ons have been observed when LIFMIOR was administered with (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), See section 4.4 for vaccination advice.

cant pharmacokinetic drug-drug interactions were observed in studies with in or warfarin.

en of childbearing potential

en of childbearing potential should consider the use of appropriate contraception to avoid ecoming pregnant during LIFMIOR therapy and for three weeks after discontinuation of therapy.

Pregnancy

Developmental toxicity studies performed in rats and rabbits have revealed no evidence of harm to the foetus or neonatal rat due to etanercept. The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. A higher rate of major birth defects was observed in one observational study comparing pregnancies exposed to etanercept (n=370) during the first trimester with pregnancies not exposed to etanercept or other TNF-antagonists (n=164) (adjusted odds ratio 2.4, 95% CI: 1.0–5.5). The types of major birth defects were consistent with those most

commonly reported in the general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. In another observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept during the first 90 days of pregnancy (n=425) to those exposed to non-biologic drugs (n=3497), there was no observed increased risk of major birth defects (crude odds ratio [OR]= 1.22, 95% CI: 0.79–1.90; adjusted OR = 0.96, 95% CI: 0.58–1.60 after adjusting for country, maternal disease, parity, maternal age and smoking in early pregnancy). This study also showed no increased risks of minor birth defects, preterm birth, stillbirth, or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. LIFMIOR should only be used during pregnancy if clearly needed.

Etanercept crosses the placenta and has been detected in the serum of infants born to female patie treated with LIFMIOR during pregnancy. The clinical impact of this is unknown, however, infant may be at increased risk of infection. Administration of live vaccines to infants for 16 weeks after mother’s last dose of LIFMIOR is generally not recommended.

Breast-feeding

Etanercept has been reported to be excreted in human milk following subcutaneous administration. In lactating rats following subcutaneous administration, etanercept was excreted in the milk and detected in the serum of pups. Because immunoglobulins, in common with many m nal products, can be

excreted in human milk, a decision must be made whether to discontinue b -feeding or to discontinue LIFMIOR therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Preclinical data about peri- and postnatal toxicity of eta and general reproductive performance are not available.

4.7 Effects on ability to drive and use machi

No studies on the effects on the ability to drive and use machines have been performed.

reactions are injection site reactions (such as pain, swelling, the puncture site), infections (such as upper respiratory infections, s and skin infections), allergic reactions, development of autoantibodies,

ave also been reported for LIFMIOR. TNF-antagonists, such as LIFMIOR, stem and their use may affect the body’s defenses against infection and cancer. s affect fewer than 1 in 100 patients treated with LIFMIOR. Reports have included threatening infections and sepsis. Various malignancies have also been reported with use , including cancers of the breast, lung, skin and lymph glands (lymphoma).

Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia and very rare reports of aplastic anaemia. Central and peripheral demyelinating events have been seen rarely and very rarely, respectively, with LIFMIOR use. There have been rare reports of lupus, lupus-related conditions, and vasculitis.

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical trials in adults and on postmarketing experience.

Within the organ system classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (>1/10);

Description of selected adverse reactions

Malignancies and lymphoproliferative disorders

One hundred and twenty-nine (129) new malignancies of various types were observed in

4,114 rheumatoid arthritis patients treated in clinical trials with LIFMIOR for up to approximately 6 years, including 231 patients treated with LIFMIOR in combination with methotrexate in the 2-year active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. A total of 2 malignancies were reported in clinical studies of approximately 2 years duration involving 240 LIFMIOR-treated psoriatic arthritis patients. In clinical studies conducted for m an 2 years with 351 ankylosing spondylitis patients, 6 malignancies were

reported in LIFMIOR-tr patients. In a group of 2,711 plaque psoriasis patients treated with

LIFMIOR in double-blind and open-label studies of up to 2.5 years, 30 malignancies and 43 nonmelanoma skin cancers were reported.

16 patients treated with LIFMIOR in rheumatoid arthritis, psoriatic arthritis, dylitis and psoriasis clinical trials, 18 lymphomas were reported.

f various malignancies (including breast and lung carcinoma and lymphoma) have also been n the postmarketing period (see section 4.4).

Injection site reactions

Compared to placebo, patients with rheumatic diseases treated with LIFMIOR had a significantly higher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the first month. Mean duration was approximately 3 to 5 days. No treatment was given for the majority of injection site reactions in the LIFMIOR treatment groups, and the majority of patients who were given treatment received topical preparations, such as corticosteroids, or oral antihistamines. Additionally, some patients developed recall injection site reactions characterised by a skin reaction at the most recent site of injection, along with the simultaneous appearance of injection site reactions at previous injection sites. These reactions were generally transient and did not recur with treatment.

There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a lupus-like syndrome or rashes that are compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.

Undesirable effects in paediatric patients with juvenile idiopathic arthritis

In general, th se events in paediatric patients with juvenile idiopathic arthritis were similar in frequency to those seen in adult patients. Differences from adults and other special consider re discussed in the following paragraphs.

pes of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years enerally mild to moderate and consistent with those commonly seen in outpatient paediatric populations. Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae (see also section 4.4), appendicitis, gastroenteritis, depression/per­sonality disorder, cutaneous ulcer, oesophagitis/gas­tritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection.

In one study in children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 (62%) children experienced an infection while receiving LIFMIOR during 3 months of the study (part 1, open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of openlabel extension therapy. The types and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of LIFMIOR in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile

4.9 Overdose

Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate in Patients with RA of <3 Years Duration

0.8

Clinical Efficacy Results at 12 Months: Comparison of LIFMIOR vs. Methotrexate vs.

LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration

• b: Values for Disease Activity Score (DAS) are means.

• c: Remission is defined as DAS <1.6.

Pairwise comparison p-values: f = p < 0.05 for comparisons of LFMIOR^ methotrexate vs. methotrexate and 0 = p < 0.05 for comparisons of LIFM thotrexate vs. LIFMIOR.

Radiographic progression at 12 months was significantl in the LIFMIOR group than in the methotrexate group, while the combination was significantly better than either monotherapy at slowing radiographic progression (see figure below).

Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate vs. LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration

Month Results)

Methotrexate

LIFMIOR

LI FMI OR + Methotrexate

Pairwise comparison p-values: * = p < 0.05 for comparisons of LIFMIOR vs.

methotrexate, f = p < 0.05 for comparisons of LIFMIOR + methotrexate vs.

methotrexate and 0 = p < 0.05 for comparisons of LIFMIOR + methotrexate vs. LIFMIOR.

Significant advantages for LIFMIOR in combination with methotrexate compared with LIFMIOR monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for LIFMIOR monotherapy compared with methotrexate monotherapy were also observed after 24 months.

In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, the percentage of patients without progression (TSS change < 0.5) at 24 months was higher in the LIFMIOR in combination with methotrexate group compared with the LIFMIOR alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p<0.05). The difference between LIFMIOR alone and methotrexate alone was also significant (p<0.05). Among patients who completed a full 24 months of therapy in the study, the non-progression rates were 78%, 70%, and 61%, respectively.

The safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly were evaluated in a double-blind, placebo-controlled study of 420 patients with active RA. In this study, 53 patients received placebo, 214 patients received 50 mg LIFMIOR once weekly and 153 patients received 25 mg LIFMIOR twice weekly. The safety and efficacy profiles of the two LIFMIOR treatment regimens were comparable at week 8 in their effect on signs and symptoms of RA; data at week 16 did not show comparability (non-inferiority) between the two regimens.

Adult patients with psoriatic arthritis

The efficacy of LIFMIOR was assessed in a randomised, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (> 3 swollen joints and > 3 tender joints) in atJeOstWe^lf the following forms: (1) distal interphalangeal (DIP) involvement; (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or

(5) spondylitis-like ankylosis. Patients also had plaque psoriasis with a qualifying target lesion > 2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on methotrexate therapy (stable for > 2 months) could continue at a stable dose of < 25 mg/week methotrcXate. Doses of 25 mg of LIFMIOR (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months. At the end of the double-blind study, patients could enter a long-term open-label extension study for a total duration of up to 2 years.

Clinical responses were expressed as percentages of patients achieving the ACR 20, 50, and 70 response and percentages w are summarised in the table

Mean (SE) Annualized Change from Baseline in Total Sharp Score

No study has been performed in patients with psoriatic arthritis using the 50 mg once-weekly dosing regimen. Evidence of efficacy for the once-weekly dosing regimen in this patient population has been based on data from the study in patients with ankylosing spondylitis.

Adult patients with ankylosing spondylitis

The efficacy of LIFMIOR in ankylosing spondylitis was assessed in 3 randomised, double-blind studies comparing twice-weekly administration of 25 mg LIFMIOR with placebo. A total of 401 patients were enrolled, from which 203 were treated with LIFMIOR. The largest of these trials (n= 277) enrolled patients who were between 18 and 70 years of age and had active ankylosing spondylitis defined as visual analog scale (VAS) scores of > 30 for average of duration and intensity of morning stiffness plus VAS scores of > 30 for at least 2 of the following 3 parameters: patient ♦ global assessment; average of VAS values for nocturnal back pain and total back pain; average o 10 questions on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients receivin DMARDs, NSAIDS, or corticosteroids could continue them on stable doses. Patients wi ankylosis of the spine were not included in the study. Doses of 25 mg of LIFMIOR (b dose-finding studies in patients with rheumatoid arthritis) or placebo were administere subcutaneously twice a week for 6 months in 138 patients.

The primary measure of efficacy (ASAS 20) was a >20% improvement in at lea

4 Assessment in Ankylosing Spondylitis (ASAS) domains (patient global assessments, back pain, BASFI, and inflammation) and absence of deterioration in the remaining domain. ASAS 50 and 70 responses used the same criteria with a 50% improvement or a 7 rovement, respectively.

Compared to placebo, treatment with LIFMIOR resulted in signific rovements in the ASAS 20,

ASAS 50 and ASAS 70 as early as 2 weeks after the initiation of therapy.

Responses of Patients with Ankylosing Spondylitis in a

P \^^Percent of Patients

Similar results were obtained in the 2 smaller ankylosing spondylitis trials.

In a fourth study, the safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly vs. 25 mg LIFMIOR administered twice weekly were evaluated in a double-blind, placebo-controlled study of 356 patients with active ankylosing spondylitis. The safety and efficacy profiles of the 50 mg once-weekly and 25 mg twice-weekly regimens were similar.

Adult patients with non-radiographic axial spondyloarthritis

The efficacy of LIFMIOR in patients with non-radiographic axial spondyloarthritis (nr-AxSpa) was assessed in a randomised, 12-week double-blind, placebo-controlled study. The study evaluated 215 adult patients (modified intent-to-treat population) with active nr-AxSpa (18 to 49 years of age), defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meet the modified New York criteria for AS. Patients were also required to have an inadequate response or intolerance to two or more NSAIDs. In the double-blind period, patients received LIFMIOR 50 mg weekly or placebo for 12 weeks. The primary measure of efficacy (ASAS 40) w 40% improvement in at least three of the four ASAS domains and absence of deterioration in the remaining domain. The double-blind period was followed by an open-label period during which

patients receive LIFMIOR 50 mg weekly for up to an additional 92 weeks. MRIs of the sacroiliac joint and spine were obtained to assess inflammation at baseline and at weeks 12 and 104.

Compared to placebo, treatment with LIFMIOR resulted in statistically significant i ASAS 40, ASAS 20 and ASAS 5/6. Significant improvement was also observe remission and BASDAI 50. Week 12 results are shown in the table below.

gnificant improvement in the SPARCC (Spondyloarthritis

Research Consortium of Canada) score for the sacroiliac joint (SIJ) as measured by MRI for patients receiving LIFMIOR. Adjusted mean change from baseline was 3.8 for LIFMIOR treated (n=95) versus 0.8 for placebo treated (n=105) patients (p<0.001). At week 104, the mean change from baseline in the CC score measured on MRI for all LIFMIOR-treated subjects was 4.64 for the SIJ (n=153) an the spine (n=154).

LIFMIO statistically significantly greater improvement from baseline to week 12 compared

to placeb most health-related quality of life and physical function assessments, including BASFI (Bath Ankylosing Spondylitis Functional Index), EuroQol 5D Overall Health State Score and SF-36 Physical Component Score.

linical responses among nr-AxSpa patients who received LIFMIOR were apparent at the time of the irst visit (2 weeks) and were maintained through 2 years of therapy. Improvements in health-related quality of life and physical function were also maintained through 2 years of therapy. The 2 year data did not reveal any new safety findings. At week 104, 8 subjects had progressed to a score of bilateral Grade 2 on spinal X-ray according to the modified New York Radiological Grade, indicative of axial spondyloarthro­pathy.

Adult patients with plaque psoriasis

LIFMIOR is recommended for use in patients as defined in section 4.1. Patients who “failed to respond to” in the target population is defined by insufficient response (PASI<50 or PGA less than good), or worsening of the disease while on treatment, and who were adequately dosed for a sufficiently long duration to assess response with at least each of the three major systemic therapies as available.

The efficacy of LIFMIOR versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing LIFMIOR with other systemic therapies. Instead, the safety and efficacy of LIFMIOR were assesse in four randomised, double-blind, placebo-controlled studies. The primary efficacy endpoint in a studies was the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at a 75% improvement in the Psoriasis Area and Severity Index score from baseline) at 12 weeks.

Study 1 was a Phase 2 study in patients with active, but clinically stable, plaque psoriasi 10% of the body surface area who were > 18 years old. One hundred and twelve (112)^ randomised to receive a dose of 25 mg of LIFMIOR (n=57) or placebo (n=55) twice a w 24 weeks.

Study 3 evaluated 583 patients and had the same inclusion criteria as study 2. Patients in this study received a dose of 25 mg or 50 mg LIFMIOR, or placebo twice a week for 12 weeks and then all patients received open-label 25 mg LIFMIOR twice weekly for an additional 24 weeks.

ilar inclusion criteria to studies 2 and 3. Patients in this or placebo once weekly for 12 weeks and then all patients ce weekly for an additional 12 weeks.

In study 1, the LIFMIOR-treated group had a significantly higher proportion of patients with a PASI ) compared to the placebo-treated group (2%) (p<0.0001). At 24 weeks,

OR-treated group had achieved the PASI 75 compared to 5% of ey results of studies 2, 3 and 4 are shown below.

reated group had a higher proportion of patients with PASI 75 at week 12 cebo-treated group (2%) (p<0.0001). For patients who received 50 mg once dy, the efficacy responses continued to improve with 71% achieving PASI

In long-term (up to 34 months) open-label studies where LIFMIOR was given without interruption, nical responses were sustained and safety was comparable to shorter-term studies.

analysis of clinical trial data did not reveal any baseline disease characteristics that would assist linicians in selecting the most appropriate dosing option (intermittent or continuous). Consequently, the choice of intermittent or continuous therapy should be based upon physician judgment and individual patient needs.

Antibodies to LIFMIOR

Antibodies to etanercept have been detected in the sera of some subjects treated with etanercept. These antibodies have all been non-neutralising and are generally transient. There appears to be no correlation between antibody development and clinical response or adverse events.

In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of anti-etanercept antibodies were approximately 6% of subjects with rheumatoid arthritis, 7.5% of subjects with psoriatic arthritis, 2% of subjects with ankylosing spondylitis, 7% of subjects with psoriasis, 9.7% of subjects with paediatric psoriasis, and 4.8% of subjects with juvenile idiopathic arthritis.

safety of LIFMIOR monotherapy (n=103), LIFMIOR plus methotrexate (n=294), or ate monotherapy (n=197) were assessed for up to 3 years in a registry of 594 children aged 2 s with juvenile idiopathic arthritis, 39 of whom were 2 to 3 years of age. Overall, infections were more commonly reported in patients treated with etanercept compared to methotrexate alone (3.8 versus 2%), and the infections associated with etanercept use were of a more severe nature.

In another open-label single-arm study, 60 patients with extended oligoarthritis (15 patients aged 2 to 4, 23 patients aged 5 to 11 and 22 patients aged 12 to 17 years old), 38 patients with enthesitis-related arthritis (12 to 17 years old), and 29 patients with psoriatic arthritis (12 to 17 years old) were treated with LIFMIOR at a dose of 0.8 mg/kg (up to a maximum of 50 mg per dose) administered weekly for 12 weeks. In each of the JIA subtypes, the majority of patients met ACR Pedi 30 criteria and demonstrated clinical improvement in secondary endpoints such as number of tender joints and physician global assessment. The safety profile was consistent with that observed in other JIA studies.

Studies have not been done in patients with juvenile idiopathic arthritis to assess the effects of continued LIFMIOR therapy in patients who do not respond within 3 months of initiating LIFMIOR therapy. Additionally, studies have not been conducted to assess the effects of discontinuing or reducing the recommended dose of LIFMIOR following its long-term use in patients with JIA.

Paediatric patients with plaque psoriasis

The efficacy of LIFMIOR was assessed in a randomised, double-blind, placebo-controlled study in 211 paediatric patients aged 4 to 17 years with moderate to severe plaque psoriasis (as defined by an sPGA score > 3, involving > 10% of the BSA, and PASI > 12). Eligible patients had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy.

Patients received LIFMIOR 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. A week 12, more patients randomised to LIFMIOR had positive efficacy responses (e.g., P those randomised to placebo.

Paediatric Plaque Psoriasis Outcomes at 12 Weeks

LIFMIOR 0.8 mg/kg Once Weekly (N = 106) 60 (57 79 (75

sPGA “clear” or “minimal”, n (%) ________________15

Abbreviation: sPGA-static Physician Global Assessm a. p < 0.0001 compared with placebo

After the 12-week double-blind treatment period, all patients received LIFMIOR 0.8 mg/kg (up to 50 mg) once weekly for additional 24 weeks. Responses observed during the open-label period were similar to those observed in the double-blind period.

significantly more patients re-randomised to placebo

I 75 response) compared with patients re-randomised to esponses were maintained up to 48 weeks.

ectiveness of LIFMIOR 0.8 mg/kg (up to 50 mg) once weekly was tension study of 181 paediatric subjects with plaque psoriasis for up to week study discussed above. Long-term experience with LIFMIOR was to the original 48-week study and did not reveal any new safety findings.

5.2 Pharmacokinetic properties

sorption

tanercept is slowly absorbed from the site of subcutaneous injection, reaching maximum concentration approximately 48 hours after a single dose. The absolute bioavailability is 76%. With twice-weekly doses, it is anticipated that steady-state concentrations are approximately twice as high as those observed after single doses. After a single subcutaneous dose of 25 mg LIFMIOR, the average maximum serum concentration observed in healthy volunteers was 1.65 ± 0.66 ^g/ml. and the area under the curve was 235 ± 96.6 p.g^hr/ml.

Mean serum concentration profiles at steady state in treated RA patients were Cmax of 2.4 mg/l vs.

2.6 mg/l, Cmin of 1.2 mg/l vs. 1.4 mg/l, and partial AUC of 297 mgh/l vs. 316 mgh/l for 50 mg

LIFMIOR once weekly (n=21) vs. 25 mg LIFMIOR twice weekly (n=16), respectively. In an open-label, single-dose, two-treatment, crossover study in healthy volunteers, etanercept administered as a single 50 mg/ml injection was found to be bioequivalent to two simultaneous injections of 25 mg/ml.

In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady

state AUCs were 466 |Jg^hr/ml and 474 ^g^hr/ml for 50 mg LIFMIOR once weekly (N= 154) and 25 mg twice weekly (N = 148), respectively.

Distribution

A biexponential curve is required to describe the concentration time curve of etanercept. The cent volume of distribution of etanercept is 7.6 l, while the volume of distribution at steady-state is 10.

Elimination

Etanercept is cleared slowly from the body. The half-life is long, approximately 70 ho approximately 0.066 l/hr in patients with rheumatoid arthritis, somewhat lower than th 0.11 l/hr observed in healthy volunteers. Additionally, the pharmacokinetics of LIFMI rheumatoid arthritis patients, ankylosing spondylitis and plaque psoriasis patients are similar.

There is no apparent pharmacokinetic difference between males and femal

Linearity

Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.

Special populations

Renal impairment

Although there is elimination of radioactivity in uri to patients and volunteers, increased etanercept acute renal failure. The presence of renal i

ot observed in patients with acute hepatic failure. The require a change in dosage.

Elderly

The impact of advanced age was studied in the population pharmacokinetic analysis of etanercept serum concentrations. Clearance and volume estimates in patients aged 65 to 87 years were similar to estimates in patients less than 65 years of age.

tients with juvenile idiopathic arthritis

lyarticular-course juvenile idiopathic arthritis trial with LIFMIOR, 69 patients (aged 4 to rs) were administered 0.4 mg LIFMIOR/kg twice weekly for three months. Serum concentration es were similar to those seen in adult rheumatoid arthritis patients. The youngest children years of age) had reduced clearance (increased clearance when normalised by weight) compared with older children (12 years of age) and adults. Simulation of dosing suggests that while older children (10–17 years of age) will have serum levels close to those seen in adults, younger children will have appreciably lower levels.

Paediatric patients with plaque psoriasis

Patients with paediatric plaque psoriasis (aged 4 to 17 years) were administered 0.8 mg/kg (up to a maximum dose of 50 mg per week) of etanercept once weekly for up to 48 weeks. The mean serum steady-state trough concentrations ranged from 1.6 to 2.1 mcg/ml at weeks 12, 24, and 48. These mean concentrations in patients with paediatric plaque psoriasis were similar to the concentrations observed in patients with juvenile idiopathic arthritis (treated with 0.4 mg/kg etanercept twice weekly, up to maximum dose of 50 mg per week). These mean concentrations were similar to those seen in adult patients with plaque psoriasis treated with 25 mg etanercept twice-weekly.

5.3 Preclinical safety data

In the toxicological studies with LIFMIOR, no dose-limiting or target organ toxicity was evident. LIFMIOR was considered to be non-genotoxic from a battery of in vitro and in vivo studies. Carcinogenicity studies, and standard assessments of fertility and postnatal toxicity, were not performed with LIFMIOR due to the development of neutralising antibodies in rodents.

LIFMIOR did not induce lethality or notable signs of toxicity in mice or rats following a single subcutaneous dose of 2000 mg/kg or a single intravenous dose of 1000 mg/kg. LIFMIOR did not dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneo administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AU drug concentrations that were over 27-fold higher than that obtained in humans at the dose of 25 mg.

• 6. PHARMACEUTICAL PARTICULARS

  6.1 List of excipients

  
  

Powder

Mannitol (E421)

Sucrose

Trometamol

Solvent

Water for injections

In the absence of compatibility products.

Chemical and p l in-use stability has been demonstrated for 6 hours at temperatures of up to 25°C after reconstitution. From a microbiological point of view, the reconstituted medicinal product should be used immediately. If not used immediately, storage times and conditions prior to use are the e user and would normally not be longer than 6 hours at temperatures of up to stitution has taken place in controlled and validated aseptic conditions.

Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

LIFMIOR may be stored at temperatures up to a maximum of 25°C for a single period of up to four weeks; after which, it should not be refrigerated again. LIFMIOR should be discarded if not used within four weeks of removal from refrigeration.

For storage conditions of the reconstituted medicinal product, see section 6.3.

• 6.5 Nature and contents of container

Clear glass vial (4 ml, type I glass) with rubber stoppers, aluminium seals, and flip-off plastic caps. LIFMIOR is supplied with pre-filled syringes containing water for injection. The syringes are type I glass. Cartons contain 4, 8 or 24 vials of LIFMIOR with 4, 8 or 24 pre-filled solvent syringes, 4, 8 or 24 needles, 4, 8 or 24 vial adaptors and 8, 16 or 48 alcohol swabs. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Instructions for use and handling

LIFMIOR is reconstituted with 1 ml water for injections before use, and administered by subcutaneo injection. LIFMIOR contains no antibacterial preservative, and therefore solutions prepared with wat for injections should be administered as soon as possible and within 6 hours following reconstitution The solution should be clear and colourless to pale yellow or pale brown, with no lumps, flakes or particles. Some white foam may remain in the vial – this is normal. LIFMIOR should notbeusedTf all the powder in the vial is not dissolved within 10 minutes. If this is the case, start again with another vial.

Comprehensive instructions for the preparation and administration of the reconstituted LIFMIOR vial are given in the package leaflet, section 7, “INSTRUCTIONS FOR PREP TION AND GIVING AN INJECTION OF LIFMIOR”.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

EU/1/16/1165/002

EU/1/16/1165/003

EU/1/16/1165/004

ST AUTHORISATION/RENEWAL OF THE AUTHORISATION

ATE OF REVISION OF THE TEXT

1. NAME OF THE MEDICINAL PRODUCT

LIFMIOR 25 mg solution for injection in pre-filled syringe. LIFMIOR 50 mg solution for injection in pre-filled syringe.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

• 25 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 25 mg of etanercept.

50 mg solution for injection in pre-filled syringe Each pre-filled syringe contains 50 mg of etanercept.

Etanercept is a human tumour necrosis factor receptor p75 Fc fusion DNA technology in a Chinese hamster ovary (CHO) mammalian exp dimer of a chimeric protein genetically engineered by fusing the extracellular ligand binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75) to the Fc domain of human IgG1. This Fc component contains the hinge, CH2 and CH3 regions, but not the CH1 region of IgG1. Etanercept contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. The specific activity of etanercept is 1.7 × 106 units/mg.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

The solution is clear, and colourless to pale yellow or pale brown.

XT

• 4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Rheumato idarthritis

LIFMIOR in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate.

LIFMIOR can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

LIFMIOR is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

LIFMIOR, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.

Psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis

The recommended dose is 25 mg LIFMIOR administered twice weekly, or 50 mg administered once weekly.

For all of the above indications, available data suggest that a clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

Plaque psoriasis

The recommended dose of LIFMIOR is 25 mg administered twice weekly or 50 mg administered onc weekly. Alternatively, 50 mg given twice weekly may be used for up to 12 weeks followed, if necessary, by a dose of 25 mg twice weekly or 50 mg once weekly. Treatment with LIFMIOR sh continue until remission is achieved, for up to 24 weeks. Continuous therapy beyond 24 week appropriate for some adult patients (see section 5.1). Treatment should be discontinued i show no response after 12 weeks. If re-treatment with LIFMIOR is indicated, the sam treatment duration should be followed. The dose should be 25 mg twice weekly or 50 weekly.

Renal and hepatic impairment No dose adjustment is required.

Elderly

No dose adjustment is required. Posology and administratio age.

Paediatric plaque psoriasis (age 6 years and above)

The recommended dose is 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks.

If re-treatment with LIFMIOR is indicated, the above guidance on treatment duration should be followed. The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.

There is generally no applicable use of LIFMIOR in children aged below 6 years in the indication plaque psoriasis.

Method of administration

LIFMIOR is administered by subcutaneous injection (see section 6.6).

Comprehensive instructions for administration are given in the package leaflet, section 7, "Instructions for preparation and giving an injection of LIFMIOR”.

4.3 Contraindications

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

Sepsis or risk of sepsis.

Treatment with LIFMIOR should not be initiated in patients with active infections, including chronic or localised infections.

4.4 Special warnings and precautions for use

In order to improve the traceability of biological medicinal products, the trademark and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

Infections

Patients should be evaluated for infections before, during, and after treatment with LIFMIOR, taking into consideration that the mean elimination half-life of etanercept is approximately 70 hours (range 7 to 300 hours).

Serious infections, sepsis, tuberculosis, and opportunistic infections, including invasive fungal infections, listeriosis and legionellosis, have been reported with the use of LIFMIOR (see section 4.8). These infections were due to bacteria, mycobacteria, fungi, viruses and parasites (including protozoa). In some cases, particular fungal and other opportunistic infections have not been recognised, resulting

sometimes death. In evaluating patients for infections, the patient’s risk for relevant opportunistic infections (e.g., exposure to endemic mycoses) should be considered.

Patients who develop a new infection while undergoing treatment with LIFMIOR should be monitored closely. Administration of LIFMIOR should be discontinued if a patient develops a serious infection. The safety and efficacy of LIFMIOR in patients with chronic infections have not been evaluated. Physicians should exercise caution when considering the use of LIFMIOR in patients with a history of recurring or chronic infections or with underlying conditions that may predispose patients to infections, such as advanced or poorly controlled diabetes.

Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with extra-pulmonary location, have been reported in patients treated with LIFMIOR.

Before starting treatment with LIFMIOR, all patients must be evaluated for both active and inactive (‘latent’) tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e., 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.

Concurrent treatment with anakinra

Concurrent administration of LIFMIOR and anakinra has been associated with an increased risk of serious infections and neutropenia compared to LIFMIOR alone. This combination has not demonstrated increased clinical benefit. Thus, the combined use of LIFMIOR and anakinra is not recommended (see sections 4.5 inistration of abatacept and LIFMIOR resulted in increased e events. This combination has not demonstrated increased clinical mmended (see section 4.5).

r of the pre-filled syringe contains latex (dry natural rubber) that may cause reactions when handled by, or when LIFMIOR is administered to, persons with eactions associated with LIFMIOR administration have been reported commonly. Allergic have included angioedema and urticaria; serious reactions have occurred. If any serious c or anaphylactic reaction occurs, LIFMIOR therapy should be discontinued immediately and appropriate therapy initiated.

Immunosuppression

The possibility exists for TNF-antagonists, including LIFMIOR, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 adult patients with rheumatoid arthritis treated with LIFMIOR, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations.

Two juvenile idiopathic arthritis patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. Patients with a significant exposure to varicella virus should temporarily discontinue LIFMIOR therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin.

The safety and efficacy of LIFMIOR in patients with immunosuppression have not been evaluated.

Malignancies and lymphoproliferative disorders

Solid and haematopoietic malignancies (excluding skin cancers)

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the postmarketing period (see section 4.8).

In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. In the postmarketing setting, cases of leukaemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.

Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded. 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 a malignancy.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiatiOnof therapy < 18 years of age), including LIFMIOR, in the postmarketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies typically associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.

cancer (NMSC) have been reported in patients treated with

TNF-antagonists, including LIFMIOR. Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with LIFMIOR. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Combining the results of controlled clinical trials, more cases of NMSC were observed in patients

ompared with control patients, particularly in patients with psoriasis.

Vaccinations^.

Live vaccines should not be given concurrently with LIFMIOR. No data are available on the secondary transmission of infection by live vaccines in patients receiving LIFMIOR. In a double-blind, placebo-controlled, randomised clinical study in adult patients with psoriatic arthritis, 184 patients also received a multivalent pneumococcal polysaccharide vaccine at week 4. In this study, most psoriatic arthritis patients receiving LIFMIOR were able to mount effective B-cell immune response to pneumococcal polysaccharide vaccine, but titres in aggregate were moderately lower, and few patients had two-fold rises in titres compared to patients not receiving LIFMIOR. The clinical significance of this is unknown.

Autoantibody formation

Treatment with LIFMIOR may result in the formation of autoimmune antibodies (see section 4.8).

Haematologic reactions

Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome, have been reported in patients treated with LIFMIOR. Caution should be exercised in patients being treated with LIFMIOR who have a previous history of blood dyscrasias. All patients and parents/caregivers should be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias or infections (e.g., persistent fever, sore throat, bruising, bleeding, paleness) whilst on LIFMIOR, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, LIFMIOR should be discontinued.

Neurological disorders

There have been rare reports of CNS demyelinating disorders in patients treated with LIFMIOR (see section 4.8). Additionally, there have been rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have been performed evaluating LIFMIOR therapy in patients with multiple sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have shown increases in disease activity. A careful risk/benefit evaluation, including a neurologic assessment, is recommended when prescribing LIFMIOR to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.

Combination therapy

In a controlled clinical trial of two years duration in rheumatoid arthritis patients, the combination of LIFMIOR and methotrexate did not result in unexpected safety findings, and the safety profile of LIFMIOR when given in combination with methotrexate was similar to the profiles reported in studies of LIFMIOR and methotrexate alone. Long-term studies to assess the safety of the combination are ongoing. The long-term safety of LIFMIOR in combination with other disease-modifying antirheumatic drugs (DMARD) has not been established.

The use of LIFMIOR in combination with other systemic therapies or phototherapy for the treatment of psoriasis has not been studied.

Renal and hepatic impairment

Based on pharmacokinetic data (see section 5.2), no dose adjustment is needed in patients with renal or hepatic impairment; clinical experience in such patients is limited.

Congestive heart failure (Cardiacfailure congestive)

Physicians should use caution when using LIFMIOR in patients who have congestive heart failure (CHF). There have been postmarketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking LIFMIOR. There have also been rare (< 0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Two large clinical trials evaluating the use of LIFMIOR in the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to LIFMIOR treatment.

In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with LIFMIOR or placebo for moderate to severe alcoholic hepatitis, LIFMIOR was not efficacious, and the mortality rate in patients treated with LIFMIOR was significantly higher after 6 months. Consequently, LIFMIOR should not be used in patients for the treatment of alcoholic hepatitis. Physicians should use caution when using LIFMIOR in patients who also have moderate to severe alcoholic hepatitis.

Wegener's gra­nulomatosis

A placebo-controlled trial, in which 89 adult patients were treated with LIFMIOR in addition to standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median duration of 25 months, has not shown LIFMIOR to be an effective treatment for Wegener’s gra­nulomatosis. The incidence of non-cutaneous malignancies of various types was significantly higher in patients treated with LIFMIOR than in the control group. LIFMIOR is not recommended for the treatment of Wegener’s gra­nulomatosis.

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of LIFMIOR in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Special populations

Elderly

In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no overall differences in adverse events, serious adverse events, and serious infections in patients age 65 or older who received LIFMIOR were observed compared with younger patients. However, caution should be exercised when treating the elderly and particular attention paid with respect to occurrence of infections.

Paediatric population

Vaccinations

It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating LIFMIOR therapy (see

Vaccinations, above).

Inflammatory bowel disease (IBD) and uveitis in patients with j There have been reports of IBD and uveitis in JIA patients bein 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent treatment with anakinra

Adult patients treated with LIFMIOR and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either LIFMIOR or anakinra alone (historical data).

In addition, in a double-blind, placebo-controlled trial in adult patients receiving background methotrexate, patients treated with LIFMIOR and anakinra were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with LIFMIOR (see sections 4.4 and 4.8). The combination LIFMIOR and anakinra has not demonstrated increased clinical benefit, and is therefore not recommended.

Concurrent treatment, with abatacept

In clinical studies, concurrent administration of abatacept and LIFMIOR resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see section 4.4).

rnt treatment with sulfasalazine

In a clinical study of adult patients who were receiving established doses of sulfasalazine, to which LIFMIOR was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with LIFMIOR or sulfasalazine alone. The clinical significance of this interaction is unknown. Physicians should use caution when considering combination therapy with sulfasalazine.

Non-interactions

In clinical trials, no interactions have been observed when LIFMIOR was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or methotrexate. See section 4.4 for vaccination advice.

4.6 Fertility, pregnancy and lactation

Serious adverse reactions have also been reported for LIFMIOR. TNF-antagonists, such as LIFMIOR, affect the immune system and their use may affect the body’s defenses against infection and cancer. Serious infections affect fewer than 1 in 100 patients treated with LIFMIOR. Reports have included fatal and life-threatening infections and sepsis. Various malignancies have also been reported with use of LIFMIOR, including cancers of the breast, lung, skin and lymph glands (lymphoma).

Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia and very rare reports of aplastic anaemia. Central and peripheral demyelinating events have been seen rarely and very rarely, respectively, with LIFMIOR use. There have been rare reports of lupus, lupus-related conditions, and vasculitis.

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical trials in adults and postmarketing experience.

Within the organ system classes, adverse reactions are listed under headings of freque patients expected to experience the reaction), using the following categories: very com common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to (<1/10,000); not known (cannot be estimated from the available data).

including 231 patients treated with LIFMIOR in combination with methotrexate in the 2-year active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. A total of 2 malignancies were reported in clinical studies of approximately 2 years duration involving 240 LIFMIOR-treated psoriatic arthritis patients. In clinical studies conducted for more than 2 years with 351 ankylosing spondylitis patients, 6 malignancies were reported in LIFMIOR-treated patients. In a group of 2,711 plaque psoriasis patients treated with LIFMIOR in double-blind and open-label studies of up to 2.5 years, 30 malignancies and 43 nonmelanoma skin cancers were reported.

In a group of 7,416 patients treated with LIFMIOR in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis clinical trials, 18 lymphomas were reported.

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have al received in the postmarketing period (see section 4.4).

Injection site reactions

Compared to placebo, patients with rheumatic diseases treated with LIFMIOR had higher incidence of injection site reactions (36% vs. 9%). Injection site reactions u the first month. Mean duration was approximately 3 to 5 days. No treatment was g

majority of injection site reactions in the LIFMIOR treatment groups, and the majority of patients who were given treatment received topical preparations, such as corticosteroids, or oral antihistamines.

Additionally, some patients developed recall injection site reactions terised by a skin reaction at

the most recent site of injection, along with the simultaneous appearanc f injection site reactions at

previous injection sites. These reactions were generally transie ot recur with treatment.

In controlled trials in patients with plaque psoriasis, ap LIFMIOR developed injection site reactions compared the first 12 weeks of treatment.

the incidence of serious infections (fatal, life-threatening, or tibiotics) was observed. Serious infections occurred in 6.3% h LIFMIOR for up to 48 months. These included abscess (at sitis, cellulitis, cholecystitis, diarrhoea, diverticulitis, tis, hepatitis B, herpes zoster, leg ulcer, mouth infection, onia, pyelonephritis, sepsis, septic arthritis, sinusitis, skin infection, vasculitis, and wound infection. In the 2-year e patients were treated with either LIFMIOR alone, methotrexate alone or th methotrexate, the rates of serious infections were similar among the

ever, it cannot be excluded that the combination of LIFMIOR with associated with an increase in the rate of infections.

ifferences in rates of infection among patients treated with LIFMIOR and those lacebo for plaque psoriasis in placebo-controlled trials of up to 24 weeks duration. ctions experienced by LIFMIOR-treated patients included cellulitis, gastroenteritis, cholecystitis, osteomyelitis, gastritis, appendicitis, Streptococcal fasciitis, myositis, septic

hock, diverticulitis and abscess. In the double-blind and open-label psoriatic arthritis trials, 1 patient eported a serious infection (pneumonia).

Serious and fatal infections have been reported during use of LIFMIOR; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks after initiating treatment with LIFMIOR in patients who have underlying conditions (e.g., diabetes, congestive heart failure, history of active or chronic infections) in addition to their rheumatoid arthritis (see section 4.4). LIFMIOR treatment may increase mortality in patients with established sepsis.

Opportunistic infections have been reported in association with LIFMIOR, including invasive fungal, parasitic (including protozoal), viral (including herpes zoster), bacterial (including Listeria and Legionella ), and atypical mycobacterial infections. In a pooled data set of clinical trials, the overall incidence of opportunistic infections was 0.09% for the 15,402 subjects who received LIFMIOR. The exposure-adjusted rate was 0.06 events per 100 patient-years. In postmarketing experience, approximately half of all of the case reports of opportunistic infections worldwide were invasive fungal infections. The most commonly reported invasive fungal infections included Candida, Pneumocystis, Aspergillus, and Histoplasma. Invasive fungal infections accounted for more than half of the fatalities amongst patients who developed opportunistic infections. The majority of the reports with a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, and aspergillosis (see section 4.4).

Autoantibodies

Adult patients had serum samples tested for autoantibodies at multiple timepoints. Of t arthritis patients evaluated for antinuclear antibodies (ANA), the percentage of patient new positive ANA (>1:40) was higher in patients treated with LIFMIOR (11%) than i

treated patients (5%). The percentage of patients who developed new

DNA antibodies was also higher by radioimmunoassay (15% of patients treated with LIFMIOR compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with LIFMIOR compared to none of placebo-treated patients). The proportion of patients treated with LIFMIOR who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with LIFMIOR on the development of autoimmune diseases is unknown.

In studies when adult patients received concurrent treatment with LIFMIOR plus anakinra, a higher rate of serious infections compared to LIFMIOR alone was observed and 2% of patients (3/139) eutropenia (absolute neutrophil count < 1000/mm3). While neutropenic, one patient ellulitis that resolved after hospitalisation (see sections 4.4 and 4.5).

Elevated liver enzymes

In the double-blind periods of controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of adverse events of elevated liver enzymes in patients receiving etanercept without concomitant methotrexate was 0.54% (frequency uncommon). In the double-blind periods of controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of adverse events of elevated liver enzymes was 4.18% (frequency common).

Autoimmune hepatitis

In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of autoimmune hepatitis in patients receiving etanercept without concomitant methotrexate was 0.02%

(frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0.24% (frequency uncommon).

Paediatric population

Undesirable effects in paediatric patients with juvenile idiopathic arthritis

In general, the adverse events in paediatric patients with juvenile idiopathic arthritis were similar in frequency and type to those seen in adult patients. Differences from adults and other special considerations are discussed in the following paragraphs.

♦

The types of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years were generally mild to moderate and consistent with those commonly seen in outpatient paediatric populations. Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae (see also section 4.4), appendicitis, gastroenteritis, depression/per­sonality disorder, cutaneous ulcer, oesophagitis/gas­tritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection.

In one study in children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 (62%) children experienced an infection while receiving LIFMIOR during 3 months of the study (part 1, open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of LIFMIOR in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile idiopathic arthritis patients receiving 3 months of LIFMIOR compared to the 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 event per patient year), abdominal pain (19%, 0.74 events per patient year), and vomiting (13%, 0.74 events per patient year).

There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.

There have been reports of inflammatory bowel disease and uveitis in JIA patients being treated with LIFMIOR from post-marketing sources, including a very small number of cases indicating a positive rechallenge (see section 4.4).

Undesirable effects in paediatric patients with plaque psoriasis

In a 48-week study in 211 children aged 4 to 17 years with paediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.

Reporting of suspectedadVerse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continuedmOmtormg of the benefit/risk balance of the medicinal product. Healthcare professionBlsare asked to report any suspected adverse reactions via the national reporting system listed^nAppendix V.

4.9 Overdose

No dose-limiting toxicities were observed during clinical trials of rheumatoid arthritis patients. The highest dose level evaluated has been an intravenous loading dose of 32 mg/m2 followed by subcutaneous doses of 16 mg/m2 administered twice weekly. One rheumatoid arthritis patient mistakenly self-administered 62 mg LIFMIOR subcutaneously twice weekly for 3 weeks without experiencing undesirable effects. There is no known antidote to LIFMIOR.

• 5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

*p < 0.05

2.2

Patients in the LIFMIOR in combination with methotrexate therapy group had significantly higher ACR 20, ACR 50, ACR 70 responses and improvement for DAS and HAQ scores at both 24 and 52 weeks than patients in either of the single therapy groups (results shown in table below).

Significant advantages for LIFMIOR in combination with methotrexate compared with LIFMIOR monotherapy and methotrexate monotherapy were also observed after 24 months.

Clinical Efficacy Results at 12 Months: Comparison of LIFMIOR vs. Methotrexate vs.

Endpoint

ACR Responses

ACR 20

ACR 50

ACR 70

DAS

Baseline scoreb

Week 52 scoreb Remissionc

HAQ

Baseline

Week 52

Radiographic progression at 12 months was significantly less in the LIFMIOR group than in the methotrexate group, while the combination was significantly better than either monotherapy at slowing radiographic progression (see figure below).

Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate vs. LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration (12 Month Results)

Pairwise comparison p-values: * = p < 0.05 for com methotrexate, f = p < 0.05 for comparisons of L methotrexate and 0 = p < 0.05 for comparisoi LIFMIOR.

Significant advantages for LIFMIOR in combination with methotrexate compared with LIFMIOR monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for LIFMIOR monotherapy compared with methotrexate monotherapy were also observed after 24 months.

ed out of the study for any reason were considered to iWout progression (TSS change < 0.5) at 24 months was methotrexate group compared with the LIFMIOR alone

, and 36%, respectively; p<0.05). The difference between

e was also significant (p<0.05). Among patients who completed dy, the non-progression rates were 78%, 70%, and 61%,

The safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly were evaluated in a double-blind, placebo-controlled study of 420 patients with active RA. In this study, 53 patients received placebo, 214 patients received 50 mg LIFMIOR once weekly and 153 patients received 25 mg LIFMIOR twice weekly. The safety and efficacy profiles of the two LIFM ent regimens were comparable at week 8 in their effect on signs and symptoms of

RA; eek 16 did not show comparability (non-inferiority) between the two regimens. A single injection of LIFMIOR was found to be bioequivalent to two simultaneous injections of ml.

Adult patients with psoriatic arthritis

The efficacy of LIFMIOR was assessed in a randomised, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (> 3 swollen joints and > 3 tender joints) in at least one of the following forms:

(1) distal interphalangeal (DIP) involvement; (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or

(5) spondylitis-like ankylosis. Patients also had plaque psoriasis with a qualifying target lesion > 2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on methotrexate therapy (stable for > 2 months) could continue at a stable dose of < 25 mg/week methotrexate. Doses of 25 mg of LIFMIOR (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months. At the end of the double-blind study, patients could enter a long-term open-label extension study for a total duration of up to 2 years.

Clinical responses were expressed as percentages of patients achieving the ACR 20, 50, and 70 response and percentages with improvement in Psoriatic Arthritis Response Criteria (PsARC). Results are summarised in the table below.

Responses of Patients with Psoriatic Arthritis in a Placebo-Controlled Trial

Psoriatic Arthritis Response

ACR 20

Month 3

Month 6

ACR 50

Month 3

Month 6

ACR 70

Month 3

Month 6

PsARC

Month 3

Month 6 _________

a: 25 mg LIFMIOR S b: p < 0.001, LIFMI c: p < 0.01, LIFMIO

hanges were assessed in the psoriatic arthritis study. Radiographs of hands and wrists t baseline and months 6, 12, and 24. The modified TSS at 12 months is presented in

e below. In an analysis in which all patients who dropped out of the study for any reason were red to have progressed, the percentage of patients without progression (TSS change < 0.5) at ths was higher in the LIFMIOR group compared with the placebo group (73% vs. 47%, respectively, p < 0.001). The effect of LIFMIOR on radiographic progression was maintained in patients who continued on treatment during the second year. The slowing of peripheral joint damage was observed in patients with polyarticular symmetrical joint involvement.

Mean (SE) Annualized

from Baseline in Total

Score

SE = standard error. a. p = 0.0001.

LIFMIOR treatment resulted in improvement in physical function during the double-blind period, an this benefit was maintained during the longer-term exposure of up to 2 years.

There is insufficient evidence of the efficacy of LIFMIOR in patients with ankylosing spondyliti and arthritis mutilans psoriatic arthropathies due to the small number of patients studied.

0) was a >20% improvement in at least 3 of the 4

Assessment in Ankylosing Spondylitis (ASAS) domains (patient global assessments, back pain,

ce of deterioration in the remaining domain. ASAS 50 and 70 ith a 50% improvement or a 70% improvement, respectively.

Compared to placebo, treatment with LIFMIOR resulted in significant improvements in the ASAS 20, ASAS 50 and ASAS 70 as early as 2 weeks after the initiation of therapy.

Adult patients with plaque psoriasis

LIFMIOR is recommended for use in patients as defined in section 4.1. Patients who “failed to respond to” in the target population is defined by insufficient response (PASI<50 or PGA less than good), or worsening of t ease while on treatment, and who were adequately dosed for a

sufficiently long duratio ssess response with at least each of the three major systemic therapies as

available.

The efficacy of LIFMIOR versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing LIFMith other systemic therapies. Instead, the safety and efficacy of LIFMIOR were assessed in fou omised, double-blind, placebo-controlled studies. The primary efficacy endpoint in all four studies was the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at least a 75% improvement in the Psoriasis Area and Severity Index score from baseline) at 12 weeks.

Study 1 was a Phase 2 study in patients with active, but clinically stable, plaque psoriasis involving ^*^> 10% of the body surface area who were > 18 years old. One hundred and twelve (112) patients were randomised to receive a dose of 25 mg of LIFMIOR (n=57) or placebo (n=55) twice a week for 24 weeks.

Study 2 evaluated 652 patients with chronic plaque psoriasis using the same inclusion criteria as study 1 with the addition of a minimum psoriasis area and severity index (PASI) of 10 at screening.

LIFMIOR was administered at doses of 25 mg once a week, 25 mg twice a week or 50 mg twice a week for 6 consecutive months. During the first 12 weeks of the double-blind treatment period, patients received placebo or one of the above three LIFMIOR doses. After 12 weeks of treatment,

patients in the placebo group began treatment with blinded LIFMIOR (25 mg twice a week); patients in the active treatment groups continued to week 24 on the dose to which they were originally randomised.

Among patients with plaque psoriasis who received LIFMIOR, significant responses relative to placebo were a t at the time of the first visit (2 weeks) and were maintained through 24 weeks of therapy.

rug withdrawal period during which patients who achieved a PASI improvement % at week 24 had treatment stopped. Patients were observed off treatment for the f rebound (PASI >150% of baseline) and for the time to relapse (defined as a loss of at of the improvement achieved between baseline and week 24). During the withdrawal period,

s of psoriasis gradually returned, with a median time to disease relapse of 3 months. No ound flare of disease and no psoriasis-related serious adverse events were observed. There was ome evidence to support a benefit of re-treatment with LIFMIOR in patients initially responding to treatment.

In study 3, the majority of patients (77%) who were initially randomised to 50 mg twice weekly and had their LIFMIOR dose decreased at week 12 to 25 mg twice weekly maintained their PASI 75 response through week 36. For patients who received 25 mg twice weekly throughout the study, the PASI 75 response continued to improve between weeks 12 and 36.

In study 4, the LIFMIOR-treated group had a higher proportion of patients with PASI 75 at week 12 (38%) compared to the placebo-treated group (2%) (p<0.0001). For patients who received 50 mg once weekly throughout the study, the efficacy responses continued to improve with 71% achieving PASI 75 at week 24.

In long-term (up to 34 months) open-label studies where LIFMIOR was given without interruption, clinical responses were sustained and safety was comparable to shorter-term studies.

An analysis of clinical trial data did not reveal any baseline disease characteristics that would assist clinicians in selecting the most appropriate dosing option (intermittent or continuous). Consequently, the choice of intermittent or continuous therapy should be based upon physician judgment and individual patient needs.

Antibodies to LIFMIOR

Antibodies to etanercept have been detected in the sera of some subjects treated with e These antibodies have all been non-neutralising and are generally transient. There appe correlation between antibody development and clinical response or adverse events.

In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of anti-etanercept antibodies were approximately 6% of subjects with rheumatoid arthritis, 7.5% of subjects with psoriatic arthritis, 2% of subjects with ankylosing spondylitis, 7% of subjects with psoriasis, 9.7% of subjects with paediatric psoriasis, and 4.8% of subjects with juvenile idiopathic arthritis.

The proportion of subjects who developed antibodies to etanercept in longer-term trials (of up to 3.5 years) increases over time, as expected. However, due to their transient nature, the incidence of antibodies detected at each assessment point was typically less than 7% in rheumatoid arthritis subjects and psoriasis subjects.

In a long-term psoriasis study in which patients received 50 mg twice weekly for 96 weeks, the incidence of antibodies observed at each assessment point was up to approximately 9%.

Paediatric patients with juvenil athic arthritis

The safety and efficacy of L were assessed in a two-part study in 69 children with polyarticular-course juvenil diopathic arthritis who had a variety of juvenile idiopathic arthritis onset types (polyarthritis, pauciarthritis, systemic onset). Patients aged 4 to 17 years with moderately to severely active polyarticular-course juvenile idiopathic arthritis refractory to, or intolerant of,

enrolled; patients remained on a stable dose of a single nonsteroidal

g and/or prednisone (< 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients (maximum 25 mg per dose) LIFMIOR subcutaneously twice weekly. In part 2, inical response at day 90 were randomised to remain on LIFMIOR or receive placebo hs and assessed for disease flare. Responses were measured using the ACR Pedi 30, 30% improvement in at least three of six and > 30% worsening in no more than one of six

JRA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and erythrocyte sedimentation rate (ESR). Disease flare was defined as a > 30% worsening in three of six JRA core set criteria and > 30% improvement in not more than one of the six JRA core set criteria and a minimum of two active joints.

In part 1 of the study, 51 of 69 (74%) patients demonstrated a clinical response and entered part 2. In part 2, 6 of 25 (24%) patients remaining on LIFMIOR experienced a disease flare compared to 20 of 26 (77%) patients receiving placebo (p=0.007). From the start of part 2, the median time to flare was > 116 days for patients who received LIFMIOR and 28 days for patients who received placebo. Of patients who demonstrated a clinical response at 90 days and entered part 2 of the study, some of the patients remaining on LIFMIOR continued to improve from month 3 through month 7, while those who received placebo did not improve.

In an open-label, safety extension study, 58 paediatric patients from the above study (from the age of 4 years at time of enrolment) continued to receive LIFMIOR for up to 10 years. Rates of serious adverse events and serious infections did not increase with long-term exposure.

Long-term safety of LIFMIOR monotherapy (n=103), LIFMIOR plus methotrexate (n=294), or methotrexate monotherapy (n=197) were assessed for up to 3 years in a registry of 594 children aged 2 to 18 years with juvenile idiopathic arthritis, 39 of whom were 2 to 3 years of age. Overall, infections were more commonly reported in patients treated with etanercept compared to methotrexate alone (3.8 versus 2%), and the infections associated with etanercept use were of a more severe nature.

In another open-label single-arm study, 60 patients with extended oligoarthritis (15 patients aged 4, 23 patients aged 5 to 11 and 22 patients aged 12 to 17 years old), 38 patients with enthesitis-re arthritis (12 to 17 years old), and 29 patients with psoriatic arthritis (12 to 17 years old) were trea with LIFMIOR at a dose of 0.8 mg/kg (up to a maximum of 50 mg per dose) administered weekl 12 weeks. In each of the JIA subtypes, the majority of patients met ACR Pedi 30 criteria and demonstrated clinical improvement in secondary endpoints such as number of tender joints and physician global assessment. The safety profile was consistent with that observed in other JIA studies.

Studies have not been done in patients with juvenile idiopathic arthritis to continued LIFMIOR therapy in patients who do not respond within 3 m therapy. Additionally, studies have not been conducted to assess the reducing the recommended dose of LIFMIOR following its long-te

Paediatric patients with plaque psoriasis

The efficacy of LIFMIOR was assessed in a randomised, double-blind, placebo-controlled study in 211 paediatric patients aged 4 to 17 years with moderate to severe plaque psoriasis (as defined by an sPGA score > 3, involving > 10% of the BSA, and > 12). Eligible patients had a history of receiving phototherapy or systemic therapy, or wer equately controlled on topical therapy.

Patients received LIFMIOR 0.8 mg/kg ( 12, more patients randomised to LIFMIO randomised to placebo.

LIFMIOR 0.8 mg/kg Once Weekly (N = 106) 60 (57%)a 79 (75%)a

viation: sPGA-static Physician Global Assessment < 0.0001 compared with placebo er the 12-week double-blind treatment period, all patients received LIFMIOR 0.8 mg/kg (up to 50 mg) once weekly for additional 24 weeks. Responses observed during the open-label period were similar to those observed in the double-blind period.

During a randomised withdrawal period, significantly more patients re-randomised to placebo experienced disease relapse (loss of PASI 75 response) compared with patients re-randomised to LIFMIOR. With continued therapy, responses were maintained up to 48 weeks.

The long-term safety and effectiveness of LIFMIOR 0.8 mg/kg (up to 50 mg) once weekly was assessed in an open-label extension study of 181 paediatric subjects with plaque psoriasis for up to 2 years beyond the 48 week study discussed above. Long-term experience with LIFMIOR was generally comparable to the original 48-week study and did not reveal any new safety findings.

5.2 Pharmacokinetic properties

he half-life is long, approximately 70 hours. Clearance is ith rheumatoid arthritis, somewhat lower than the value of rs. Additionally, the pharmacokinetics of LIFMIOR in ing spondylitis and plaque psoriasis patients are similar.

cokinetic difference between males and females.

as not been formally evaluated, but there is no apparent saturation of clearance

Renal impairment

Although there is elimination of radioactivity in urine after administration of radiolabelled etanercept to patients and volunteers, increased etanercept concentrations were not observed in patients with acute renal failure. The presence of renal impairment should not require a change in dosage.

Hepatic impairment

Increased etanercept concentrations were not observed in patients with acute hepatic failure. The presence of hepatic impairment should not require a change in dosage.

5.3 Preclinical safety data

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

LIFMIOR may be stored at temperatures up to a maximum of 25°C for a single period of up to four weeks; after which, it should not be refrigerated again. LIFMIOR should be discarded if not use within four weeks of removal from refrigeration.

Keep the pre-filled syringes in the outer carton in order to protect from light.

6.5 Nature and contents of container

Clear glass syringe (type I glass) with stainless steel needle, rubber needle cove

Cartons contain 4, 8 or 24 pre-filled syringes of LIFMIOR and 4, 8 or 24 alcohol swabs. The needle cover contains dry natural rubber (latex) (see section 4.4). Not all pack ay be marketed.

• 50 mg solution for injection in pre-filled syringe

Clear glass syringe (type I glass) with stainless steel needle, rubber cover and plastic plunger. Cartons contain 2, 4 or 12 pre-filled syringes of LIFMIOR with 2, 4 or 12 alcohol swabs. The needle cover contains dry natural rubber (latex) (see section 4. t all pack sizes may be marketed.

6.6 Special precautions for disposal and other

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1165/005

EU/1/16/1165/006

EU/1/16/1165/007

50 mg solution for injection in pre-filled syringe

EU/1/16/1165/008

EU/1/16/1165/009

EU/1/16/1165/010

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 February 2017

Date of last renewal: {DD month YYYY}

10. DATE OF REVISION OF THE TEXT

1. NAME OF THE MEDICINAL PRODUCT

LIFMIOR 50 mg solution for injection in pre-filled pen.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled pen contains 50 mg of etanercept.

Etanercept is a human tumour necrosis factor receptor p75 Fc fusion protein produced by recombinant

DNA technology in a Chinese hamster ovary (CHO) mammalian expression system dimer of a chimeric protein genetically engineered by fusing the extracellular ligand binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75) to the Fc domain of h component contains the hinge, CH2 and CH3 regions, but not the CH1 region of IgG1. Etanercept contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. The specific activity of etanercept is 1.7 × 106 units/mg.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

The solution is clear, and colourless to

• 4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Rheumatoid arthritis

LIFMIOR in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate.

LIFMIOR an be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

LIFMIOR is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

LIFMIOR, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.

Juvenile idiopathic arthritis

Treatment of polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis in children and adolescents from the age of 2 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.

Treatment of psoriatic arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.

Treatment of enthesitis-related arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, conventional therapy.

LIFMIOR has not been studied in children aged less than 2 years.

Psoriatic arthritis

Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate. LIFMIOR has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression o peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical su the disease.

Axial spondyloarthritis

Ankylosing spondylitis (AS)

Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Non-radiographic axial spondyloarthritis

Treatment of adults with severe non-radiographic axial spondyloarthritis w bjective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence, who have had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).

Plaque psoriasis

Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporin, methotrexate or psoralen and ultraviolet-A light (PUVA) (see section 5.1).

Paediatric plaque psoriasis

Treatment of chronic severe plaque psoria hildren and adolescents from the age of 6 years who

are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

e initiated and supervised by specialist physicians experienced in the eumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, -radiographic axial spondyloarthritis, plaque psoriasis or paediatric plaque with LIFMIOR should be given the Patient Alert Card.

illed pen is available in a 50 mg strength. Other presentations of LIFMIOR are gths of 10 mg, 25 mg and 50 mg.

heumatoid arthritis

mg LIFMIOR administered twice weekly is the recommended dose. Alternatively, 50 mg administered once weekly has been shown to be safe and effective (see section 5.1).

Psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis

The recommended dose is 25 mg LIFMIOR administered twice weekly, or 50 mg administered once weekly.

For all of the above indications, available data suggest that a clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

Plaque psoriasis

The recommended dose of LIFMIOR is 25 mg administered twice weekly or 50 mg administered once weekly. Alternatively, 50 mg given twice weekly may be used for up to 12 weeks followed, if necessary, by a dose of 25 mg twice weekly or 50 mg once weekly. Treatment with LIFMIOR should continue until remission is achieved, for up to 24 weeks. Continuous therapy beyond 24 weeks may be appropriate for some adult patients (see section 5.1). Treatment should be discontinued in patients who show no response after 12 weeks. If re-treatment with LIFMIOR is indicated, the same guidance on treatment duration should be followed. The dose should be 25 mg twice weekly or 50 mg once weekly.

Special populations

Renal and hepatic impairment No dose adjustment is required.

Elderly

No dose adjustment is required. Posology and administration are the same as fo age.

aediatric plaque psoriasis (age 6 years and above)

he recommended dose is 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly for up to 24 eeks. Treatment should be discontinued in patients who show no response after 12 weeks.

f re-treatment with LIFMIOR is indicated, the above guidance on treatment duration should be followed. The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.

There is generally no applicable use of LIFMIOR in children aged below 6 years in the indication plaque psoriasis.

Method of administration

LIFMIOR is administered by subcutaneous injection (see section 6.6).

Comprehensive instructions for administration are given in the package leaflet, section 7, “Using the MYCLIC pre-filled pen to inject LIFMIOR.”

4.3 Contraindications

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

Sepsis or risk of sepsis.

Treatment with LIFMIOR should not be initiated in patients with active infections including chronic or localised infections.

4.4 Special warnings and precautions for use

In order to improve the traceability of biological medicinal products, the trademark an number of the administered product should be clearly recorded (or stated) in the patien

Patients who develop a new infection while undergoing treatment with LIFMIOR should be monitored closely. Administration of LIFMIOR sh e discontinued if a patient develops a serious infection.

ients with chronic infections have not been evaluated.

onsidering the use of LIFMIOR in patients with a history of derlying conditions that may predispose patients to infections diabetes.

Tuberculosis

Cases of active tuberculosis including miliary tuberculosis and tuberculosis with extra-pulmonary location have been reported in patients treated with LIFMIOR.

Before starting treatment with LIFMIOR, all patients must be evaluated for both active and inactive (‘latent’ erculosis. This evaluation should include a detailed medical history with personal history of tu sis or possible previous contact with tuberculosis and previous and/or current im pressive therapy. Appropriate screening tests, i.e., tuberculin skin test and chest X-ray, e 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, LIFMIOR therapy must not be initiated. If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before the initiation of LIFMIOR, and in accordance with local recommendations. In this situation, the benefit/risk balance of LIFMIOR therapy should be very carefully considered.

All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g., persistent cough, wasting/weight loss, low-grade fever) appear during or after LIFMIOR treatment.

Hepatitis B reactivation

Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant TNF-antagonists, including LIFMIOR, has been reported. This includes reports of reactivation of hepatitis B in patients who were anti-HBc positive but HBsAg negative. Patients should be tested for HBV infection before initiating treatment with LIFMIOR. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment o hepatitis B is recommended. Caution should be exercised when administering LIFMIOR in patients previously infected with HBV. These patients should be monitored for signs and symptoms of activ HBV infection throughout therapy and for several weeks following termination of therapy. Adequat

data from treating patients infected with HBV with anti-viral therapy in conjunction wit TNF-antagonist therapy are not available. In patients who develop HBV infection, LIFM be stopped and effective anti-viral therapy with appropriate supportive treatment should

Worsening of hepatitis C

There have been reports of worsening of hepatitis C in patients receiving LIFM be used with caution in patients with a history of hepatitis C.

Concurrent treatment with anakinra

Concurrent administration of LIFMIOR and anakinra has been associated with an increased risk of serious infections and neutropenia compared to LIFMIOR alone. This combination has not demonstrated increased clinical benefit. Thus the combined f LIFMIOR and anakinra is not recommended (see sections 4.5 and 4.8).

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and LIFMIOR resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see section 4.5).

R administration have been reported commonly. Allergic rticaria; serious reactions have occurred. If any serious IFMIOR therapy should be discontinued immediately and

The needle cap of the pre-filled pen contains latex (dry natural rubber) that may cause hypersensitivity reactions when ed by or when LIFMIOR is administered to persons with known or possible latex

sensitivity.

uppression

bjllty'exists for TNF-antagonists, including LIFMIOR, to affect host defences against and malignancies since TNF mediates inflammation and modulates cellular immune. In a study of 49 adult patients with rheumatoid arthritis treated with LIFMIOR, there was ce of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or enumeration of effector cell populations.

wo juvenile idiopathic arthritis patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. Patients with a significant exposure to varicella virus should temporarily discontinue LIFMIOR therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin.

The safety and efficacy of LIFMIOR in patients with immunosuppression have not been evaluated.

Malignancies and lymphoproliferative disorders

Solid and haematopoietic malignancies (excluding skin cancers)

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the postmarketing period (see section 4.8).

In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. In the postmarketing setting, cases of leukaemia have been reporte in patients treated with TNF-antagonists. There is an increased background risk for lymphoma an leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory diseas which complicates risk estimation.

Based on current knowledge, a possible risk for the development of lymphomas, leu haematopoietic or solid malignancies in patients treated with a TNF-antagonist cann Caution should be exercised when considering TNF-antagonist therapy for patients malignancy or when considering continuing treatment in patients who develop a ma

Tibody formation

ent with LIFMIOR may result in the formation of autoimmune antibodies (see section 4.8).

aematologic reactions

Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome, have been reported in patients treated with LIFMIOR. Caution should be exercised in patients being treated with LIFMIOR who have a previous history of blood dyscrasias. All patients and parents/caregivers should be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias or infections (e.g., persistent fever, sore throat, bruising, bleeding, paleness) whilst on LIFMIOR, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, LIFMIOR should be discontinued.

Neurological disorders

There have been rare reports of CNS demyelinating disorders in patients treated with LIFMIOR (see section 4.8). Additionally, there have been rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have been performed evaluating LIFMIOR therapy in patients with multiple sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have shown increases in disease activity. A careful risk/benefit evaluation, including a neurologic assessment, is recommended when prescribing LIFMIOR to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.

Combination therapy

In a controlled clinical trial of two years duration in rheumatoid arthritis patients, the combinati LIFMIOR and methotrexate did not result in unexpected safety findings, and the safety p LIFMIOR when given in combination with methotrexate was similar to the profiles repo of LIFMIOR and methotrexate alone. Long-term studies to assess the safety of the combi ongoing. The long-term safety of LIFMIOR in combination with other disease-modifying antirheumatic drugs (DMARD) has not been established.

-controlled study of 48 hospitalised patients treated with LIFMIOR or ere alcoholic hepatitis, LIFMIOR was not efficacious, and the mortality LIFMIOR was significantly higher after 6 months. Consequently, be used in patients for the treatment of alcoholic hepatitis. Physicians should use IFMIOR in patients who also have moderate to severe alcoholic hepatitis.

-controlled trial, in which 89 adult patients were treated with LIFMIOR in addition to herapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median of 25 months, has not shown LIFMIOR to be an effective treatment for Wegener’s ranu­lomatosis. The incidence of non-cutaneous malignancies of various types was significantly igher in patients treated with LIFMIOR than in the control group. LIFMIOR is not recommended for

the treatment of Wegener’s gra­nulomatosis.

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of LIFMIOR in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Special populations

Elderly

In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no overall differences in adverse events, serious adverse events, and serious infections in patients age 65 or older who received LIFMIOR were observed compared with younger patients. However, caution should be

exercised when treating the elderly and particular attention paid with respect to occurrence of infections.

Paediatric population

Vaccinations

It is recommended that paediatric patients, if possible, be brought up to date with all immunisa agreement with current immunisation guidelines prior to initiating LIFMIOR therapy (see Vaccinations, above).

Inflammatory bowel disease (IBD) and uveitis in patients with juvenile idiopathic arth IA) There have been reports of IBD and uveitis in JIA patients being treated with LIFMIOR (see section 4.8).

4.5 Interaction with other medicinal products and other forms of i

Concurrent treatmentwithsul­fasalazine

adult patients who were receiving established doses of sulfasalazine, to which , patients in the combination group experienced a statistically significant te blood cell counts in comparison to groups treated with LIFMIOR or

e alone. The clinical significance of this interaction is unknown. Physicians should use n considering combination therapy with sulfasalazine.

Non-interactions

In clinical trials, no interactions have been observed when LIFMIOR was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or methotrexate. See section 4.4 for vaccination advice.

No clinically significant pharmacokinetic drug-drug interactions were observed in studies with methotrexate, digoxin or warfarin.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should consider the use of appropriate contraception to avoid becoming pregnant during LIFMIOR therapy and for three weeks after discontinuation of therapy.

4.7 E

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have also been received in the postmarketing period (see section 4.4).

Injection site reactions

Compared to placebo, patients with rheumatic diseases treated with LIFMIOR had a significantly higher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the first month. Mean duration was approximately 3 to 5 days. No treatment was given for the majority of injection site reactions in the LIFMIOR treatment groups, and the majority of patients who were given treatment received topical preparations such as corticosteroids, or oral antihistamines. Additionally, some patients developed recall injection site reactions characterised by a skin reaction a the most recent site of injection along with the simultaneous appearance of injection site reaction previous injection sites. These reactions were generally transient and did not recur with treatmen

In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients tre LIFMIOR developed injection site reactions compared with 3.4% of placebo-treated pati the first 12 weeks of treatment.

ections have been reported during use of LIFMIOR; reported pathogens include ia (including tuberculosis), viruses and fungi. Some have occurred within a few treatment with LIFMIOR in patients who have underlying conditions (e.g., heart failure, history of active or chronic infections) in addition to their

itis (see section 4.4). LIFMIOR treatment may increase mortality in patients with psis.

istic infections have been reported in association with LIFMIOR, including invasive fungal, itic (including protozoal), viral (including herpes zoster), bacterial (including Listeria and gionella ), and atypical mycobacterial infections. In a pooled data set of clinical trials, the overall incidence of opportunistic infections was 0.09% for the 15,402 subjects who received LIFMIOR. The exposure-adjusted rate was 0.06 events per 100 patient-years. In postmarketing experience, approximately half of all of the case reports of opportunistic infections worldwide were invasive fungal infections. The most commonly reported invasive fungal infections included Candida, Pneumocystis, Aspergillus, and Histoplasma. Invasive fungal infections accounted for more than half of the fatalities amongst patients who developed opportunistic infections. The majority of the reports with a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, and aspergillosis (see section 4.4).

Autoantibodies

Adult patients had serum samples tested for autoantibodies at multiple timepoints. Of the rheumatoid arthritis patients evaluated for antinuclear antibodies (ANA), the percentage of patients who developed new positive ANA (>1:40) was higher in patients treated with LIFMIOR (11%) than in placebo-treated patients (5%). The percentage of patients who developed new positive anti-double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with LIFMIOR compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with LIFMIOR compared to none of placebo-treated patients). The proportion of patients treated with LIFMIOR who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with LIFMIOR on the development of autoimmune diseases is unknown.

There have been rare reports of patients, including rheumatoid factor positive patients, who ha developed other autoantibodies in conjunction with a lupus-like syndrome or rashes that are compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.

Undesirable effects in paediatric patients with juvenile idiopathic arthritis

In general, the adverse events in paediatric patients with juvenile idiopathic arthritis were similar in frequency and type to those seen in adult patients. Differences from adults and other special considerations are discussed in the following paragraphs.

The types of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years were generally mild to moderate and consistent with those commonly seen in outpatient paediatric populations. Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae (see also section 4.4), appendicitis, gastroenteritis, depression/per­sonality disorder, cutaneous ulcer, oesophagitis/gas­tritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection.

In one study in children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 (62%) children experienced an infection while receiving LIFMIOR during 3 months of the study (part 1, open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of LIFMIOR in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile idiopathic arthritis patients receiving 3 months of LIFMIOR compared to the 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 event per patient year), abdominal pain (19%, 0.74 events per patient year), and vomiting (13%, 0.74 events per patient year).

There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.

There have been reports of inflammatory bowel disease and uveitis in JIA patients being treated with LIFMIOR from post-marketing sources, including a very small number of cases indicating a positive rechallenge (see section 4.4).

Undesirable effects in paediatric patients with plaque psoriasis

In a 48-week study in 211 children aged 4 to 17 years with paediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.

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 sus^ectcd^dverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

No dose-limiting toxicities were observed during clinical trials of rheumatoid arthritis patients. The highest dose level evaluated has been an intravenous loading dose of 32 mg/m2 followed by subcutaneous doses of 16 mg/m2 administered twice weekly. One rheumatoid arthritis patient mistakenly self-administered 62 mg LIFMIOR subcutaneously twice weekly for 3 weeks without experiencing undesirable effects. There is no known antidote to LIFMIOR.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Jharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-a) inhibitors, ATC code: L04AB01

Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of rheumatoid arthritis. Elevated levels of TNF are also found in the synovium and psoriatic plaques of patients with psoriatic arthritis and in serum and synovial tissue of patients with ankylosing spondylitis. In plaque psoriasis, infiltration by inflammatory cells including T-cells leads to increased TNF levels in psoriatic lesions compared with levels in uninvolved skin. Etanercept is a competitive inhibitor of TNF-binding to its cell surface receptors and thereby inhibits the biological activity of TNF. TNF and lymphotoxin are pro-inflammatory cytokines that bind to two distinct cell surface receptors: the 55-kilodalton (p55) and 75-kilodalton (p75) tumour necrosis factor receptors (TNFRs). Both TNFRs exist naturally in membrane-bound and soluble forms. Soluble TNFRs are thought to regulate TNF biological activity.

TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on cross-linking of cell surface TNFRs. Dimeric soluble receptors such as etanercept possess a higher affinity for TNF than monomeric receptors and are considerably more potent competitive inhibitors of TNF binding to its cellular receptors. In addition, use of an immunoglobulin Fc region as a fusion element in the construction of a dimeric receptor imparts a longer serum half-life.

Mechanism of action

Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin patholog plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controll TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF binding to cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept may also modulate biologic responses controlled by additional downstream molecules (e.g., cytokines, adhesion molecules, or proteinases) that are induced or regulated by TNF.

Clinical efficacy and safety … ........ … '.cr......

This section presents data from four randomised controlled trials in adults with rheumatoid arthritis, one study in adults with psoriatic arthritis, one study in adults with ankylosing spondylitis, one study in adults with non-radiographic axial spondyloarthritis, four studies in adults with plaque psoriasis, three studies in juvenile idiopathic arthritis and one study in paediatric patients with plaque psoriasis.

Adult patients with rheumatoid arthritis

The efficacy of LIFMIOR was assessed in a randomised study evaluated 234 adult patients with active rheumato

one but no more than four disease-modifying antirheumatic drugs (DMARDs). Doses of 10 mg or 25 mg LIFMIOR or placebo were administered subcutaneously twice a week for 6 consecutive months. The results of this controlled trial were expressed in percentage improvement in rheumatoid arthritis using American College of Rheu gy (ACR) response criteria.

ACR 20 and 50 responses were higher i atients treated with LIFMIOR at 3 and 6 months than in : LIFMIOR 62% and 59%, placebo 23% and 11% at 3 and R 41% and 40%, placebo 8% and 5% at months 3 and 6, cebo at all timepoints for both ACR 20 and ACR 50 responses).

s who received LIFMIOR achieved an ACR 70 response at month 3 and an 5% of subjects in the placebo arm. Among patients receiving ses generally appeared within 1 to 2 weeks after initiation of therapy and

nearly always occurred by 3 months. A dose response was seen; results with 10 mg were intermediate between placebo and 25 mg. LIFMIOR was significantly better than placebo in all components of the ACR criteria as well as other measures of rheumatoid arthritis disease activity not included in the ACR teria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), which ed disability, vitality, mental health, general health status, and arthritis-associated health status ins, was administered every 3 months during the trial. All subdomains of the HAQ were ved in patients treated with LIFMIOR compared to controls at 3 and 6 months.

After discontinuation of LIFMIOR, symptoms of arthritis generally returned within a month. Re-introduction of treatment with LIFMIOR after discontinuation of up to 24 months resulted in the same magnitudes of responses as patients who received LIFMIOR without interruption of therapy based on results of open-label studies. Continued durable responses have been seen for up to 10 years in open-label extension treatment trials when patients received LIFMIOR without interruption.

The efficacy of LIFMIOR was compared to methotrexate in a randomised, active-controlled study with blinded radiographic evaluations as a primary endpoint in 632 adult patients with active rheumatoid arthritis (<3 years duration) who had never received treatment with methotrexate. Doses of 10 mg or 25 mg LIFMIOR were administered SC twice a week for up to 24 months. Methotrexate doses were escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial and continued for up to 24 months. Clinical improvement including onset of action within

2 weeks with LIFMIOR 25 mg was similar to that seen in the previous trials, and was maintained for up to 24 months. At baseline, patients had a moderate degree of disability, with mean HAQ scores of 1.4 to 1.5. Treatment with LIFMIOR 25 mg resulted in substantial improvement at 12 months, with about 44% of patients achieving a normal HAQ score (less than 0.5). This benefit was maintained in Year 2 of this study.

In this study, structural joint damage was assessed radiographically and expressed as change in Tota Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score. Radiographs of hands/wrists and feet were read at baseline and 6, 12, and 24 months. The 10 mg LIFMIOR dose had consistently less effect on structural damage than the 25 mg dose. LIFMI 25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. differences in TSS and JSN were not statistically significant between methotrexate an 25 mg. The results are shown in the figure below.

, double-blind, randomised study, clinical efficacy, safety, and in RA patients treated with LIFMIOR alone (25 mg twice weekly),

7.5 to 20 mg weekly, median dose 20 mg), and of the combination of LIFMIOR tiated concurrently were compared in 682 adult patients with active rheumatoid s to 20 years duration (median 5 years) who had a less than satisfactory response to ase-modifying antirheumatic drug (DMARD) other than methotrexate.

aCtiRents in the LIFMIOR in combination with methotrexate therapy group had significantly higher 20, ACR 50, ACR 70 responses and improvement for DAS and HAQ scores at both 24 and eeks than patients in either of the single therapy groups (results shown in table below).

ignificant advantages for LIFMIOR in combination with methotrexate compared with LIFMIOR monotherapy and methotrexate monotherapy were also observed after 24 months.

Clinical Efficacy Results at 12 Months: Comparison of LIFMIOR vs Methotrexate vs LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration

Endpoint

ACR Responsesa

ACR 20

ACR 50

ACR 70

DAS

Baseline scoreb

Week 52 scoreb Remissionc

HAQ

Baseline

Week 52

a: Patients who did not complete 12 months in the study were considere b: Values for Disease Activity Score (DAS) are means.

c: Remission is defined as DAS <1.6

Pairwise comparison p-values: f = p < 0.05 for comparisons of LIF

methotrexate and fo = p < 0.05 for comparisons of LIFMIOR + m

Radiographic progression at 12 months was significantly methotrexate group, while the combination was significa slowing radiographic progression (see figure below).

Radiographic Progression: Comparison of LIFMIOR vs Methotrexate vs LIFMIOR in Combination with Methotrexate i ents with RA of 6 Months To 20 Years Duration lOnth Results)

Methotrexate

LIFMIOR

LI FMI OR + Methotrexate

Pairwise comparison p-values: * = p < 0.05 for comparisons of LIFMIOR vs methotrexate, f = p < 0.05 for comparisons of LIFMIOR + methotrexate vs methotrexate and 0 = p < 0.05 for comparisons of LIFMIOR + methotrexate vs LIFMIOR

Significant advantages for LIFMIOR in combination with methotrexate compared with LIFMIOR monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for LIFMIOR monotherapy compared with methotrexate monotherapy were also observed after 24 months.

In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, the percentage of patients without progression (TSS change < 0.5) at 24 months was higher in the LIFMIOR in combination with methotrexate group compared with the LIFMIOR alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p<0.05). The difference between LIFMIOR alone and methotrexate alone was also significant (p<0.05). Among patients who completed a full 24 months of therapy in the study, the non-progression rates were 78%, 70%, and 61%, respectively.

♦ (

The safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly were evaluated in a double-blind, placebo-controlled study of 420 patients with active RA. In this study, 53 patients received placebo, 214 patients received 50 mg LIFMIOR once weekly and 153 patients received 25 mg LIFMIOR twice weekly. The safety and efficacy profiles of the two LIFMIOR treatment regimens were comparable at week 8 in their effect on signs and symptoms of RA; data at week 16 did not show comparability (non-inferiority) between the two regimens. A single 50 mg/ml injection of LIFMIOR was found to be bioequivalent to two simultaneous injections of 25 mg/ml.

Adult patients with psoriatic arthritis

The efficacy of LIFMIOR was assessed in a randomised, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (> 3 swollen joints and > 3 tender joints) in atjeOstWg^lf the following forms: (1) distal interphalangeal (DIP) involvement; (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or (5) spondylitislike ankylosis. Patients also had plaque psoriasis with a qualifying target lesion > 2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on methotrexate therapy (stable for > 2 months) could continue at a stable dose of < 25 mg/week methotrexate. Doses of 25^igof LIFMIOR (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months. At the end of the double-blind study, patients could enter a long-term open-label extension study for a total duration of up to 2 years.

Clinical responses were expressed as percentages of patients achieving the ACR 20, 50, and 70 response and percentages w are summarised in the table

Mean (SE) Annualized Change from Baseline in Total Sharp Score

No study has been performed in patients with psoriatic arthritis using the 50 mg once weekly dosing regimen. Evidence of efficacy for the once weekly dosing regimen in this patient population has been based on data from the study in patients with ankylosing spondylitis.

Adult patients with ankylosing spondylitis

The efficacy of LIFMIOR in ankylosing spondylitis was assessed in 3 randomised, double-blind studies comparing twice weekly administration of 25 mg LIFMIOR with placebo. A total of 401 patients were enrolled from which 203 were treated with LIFMIOR. The largest of these trials (n= 277) enrolled patients who were between 18 and 70 years of age and had active ankylosing spondylitis defined as visual analog scale (VAS) scores of > 30 for average of duration and intensity of morning stiffness plus VAS scores of > 30 for at least 2 of the following 3 parameters: patient global assessment; average of VAS values for nocturnal back pain and total back pain; average of 10 questions on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients receiving DMARDs, NSAIDS, or corticosteroids could continue them on stable doses. Patients wi ankylosis of the spine were not included in the study. Doses of 25 mg of LIFMIOR (b dose-finding studies in patients with rheumatoid arthritis) or placebo were administere subcutaneously twice a week for 6 months in 138 patients.

Compared to placebo, treatment with LIFMIOR resulted in significant improvements in the ASAS 20, ASAS 50 and ASAS 70 as early as 2 weeks after the initiation of therapy.

Among patients with ankylosing spondylitis who received LIFMIOR, the clinical responses were apparent at the time of the first visit (2 weeks) and were maintained through 6 months of therapy. Responses were similar in patients who were or were not receiving concomitant therapies at baseline.

Similar results were obtained in the 2 smaller ankylosing spondylitis trials.

In a fourth study, the safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly vs 25 mg LIFMIOR administered twice weekly were evaluated in a double-blind, placebo-controlled study of 356 patients with active ankylosing spondylitis. The safety and efficacy profiles of the 50 mg once weekly and 25 mg twice weekly regimens were similar.

Adult patients with non-radiographic axial spondyloarthritis

The efficacy of LIFMIOR in patients with non-radiographic axial spondyloarthritis (nr-AxSpa) was assessed in a randomised, 12-week double-blind, placebo-controlled study. The study evaluated 215 adult patients (modified intent-to-treat population) with active nr-AxSpa (18 to 49 years of age), defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meet the modified New York criteria for AS. Patients were also required to have an inadequate response or intolerance to two or more NSAIDs. In the double-blind period, patients received LIFMIOR 50 mg weekly or placebo for 12 weeks. The primary measure of efficacy (ASAS 4 40% improvement in at least three of the four ASAS domains and absence of deterioration in remaining domain. The double-blind period was followed by an open-label period duri patients receive LIFMIOR 50 mg weekly for up to an additional 92 weeks. MRIs of the and spine were obtained to assess inflammation at baseline and at weeks 12 and 104.

Compared to placebo, treatment with LIFMIOR resulted in statistically significant improvement in the ASAS 40, ASAS 20 and ASAS 5/6. Significant improvement was also observed for the ASAS partial remission and BASDAI 50. Week 12 results are shown in the table below.

Efficacy Response in Placebo-Controlled nr-AxSpa Study:

Adult patients with plaque psoriasis

LIFMIOR is recommended for use in patients as defined in section 4.1. Patients who “failed to respond to” in the target population is defined by insufficient response (PASI<50 or PGA less than good), or worsening of the disease while on treatment, and who were adequately dosed for a sufficiently long duration to assess response with at least each of the three major systemic therapies as available.

The efficacy of LIFMIOR versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing LIFMIOR with other systemic therapies. Instead, the safety and efficacy of LIFMIOR were assesse in four randomised, double-blind, placebo-controlled studies. The primary efficacy endpoint in a studies was the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at a 75% improvement in the Psoriasis Area and Severity Index score from baseline) at 12 weeks.

Study 1 was a Phase 2 study in patients with active but clinically stable plaque psoriasi 10% of the body surface area that were > 18 years old. One hundred and twelve (112) p randomised to receive a dose of 25 mg of LIFMIOR (n=57) or placebo (n=55) twice a 24 weeks.

Study 3 evaluated 583 patients and had the same inclusion criteria as study 2. Patients in this study received a dose of 25 mg or 50 mg LIFMIOR, or placebo twice a week for 12 weeks and then all patients received open-label 25 mg LIFMIOR twice weekly for an additional 24 weeks.

ilar inclusion criteria to studies 2 and 3. Patients in this or placebo once weekly for 12 weeks and then all patients ce weekly for an additional 12 weeks.

In study 1, the LIFMIOR-treated group had a significantly higher proportion of patients with a PASI ) compared to the placebo-treated group (2%) (p<0.0001). At 24 weeks,

OR-treated group had achieved the PASI 75 compared to 5% of ey results of studies 2, 3 and 4 are shown below.

Responses of Patients with Psoriasis in Studies 2, 3 And 4

In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of anti-etanercept antibodies were approximately 6% of subjects with rheumatoid arthritis, 7.5% of subjects with psoriatic arthritis, 2% of subjects with ankylosing spondylitis, 7% of subjects with psoriasis, 9.7% of subjects with paediatric psoriasis, and 4.8% of subjects with juvenile idiopathic arthritis.

demonstrated clinical improvement in secondary endpoints such as number of tender joints and physician global assessment. The safety profile was consistent with that observed in other JIA studies.

Studies have not been done in patients with juvenile idiopathic arthritis to assess the effects of continued LIFMIOR therapy in patients who do not respond within 3 months of initiating LIFMIOR therapy. Additionally, studies have not been conducted to assess the effects of discontinuing or reducing the recommended dose of LIFMIOR following its long-term use in patients with JIA.

Paediatric patients with plaque psoriasis

The efficacy of LIFMIOR was assessed in a randomised, double-blind, placebo-controlled study in 211 paediatric patients aged 4 to 17 years with moderate to severe plaque psoriasis (as defined by sPGA score > 3, involving > 10% of the BSA, and PASI > 12). Eligible patients had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy.

maximum serum concentration observed in healthy volunteers was 1.65 ± 0.66 ^g/ml. and the area under the curve was 235 ± 96.6 p.g^hr/ml.

Mean serum concentration profiles at steady state in treated RA patients were Cmax of 2.4 mg/l vs.

2.6 mg/l, Cmin of 1.2 mg/l vs. 1.4 mg/l, and partial AUC of 297 mgh/l vs. 316 mgh/l for 50 mg LIFMIOR once weekly (n=21) vs. 25 mg LIFMIOR twice weekly (n=16), respectively. In an openlabel, single-dose, two-treatment, crossover study in healthy volunteers, etanercept administered as a single 50 mg/ml injection was found to be bioequivalent to two simultaneous injections of 25 mg/ml.

In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady state AUCs were 466 |Jg^hr/ml and 474 ^g^hr/ml for 50 mg LIFMIOR once weekly (N = 154) and 25 mg twice weekly (N = 148), respectively.

♦ <

Distribution

A biexponential curve is required to describe the concentration time curve of etanercept. The central volume of distribution of etanercept is 7.6 l, while the volume of distribution at steady-state is 10.4 l.

Elimination

Etanercept is cleared slowly from the body. The half-life is long, approximately 70 hours. Clearance is approximately 0.066 l/hr in patients with rheumatoid arthritis, somewhat lower than the value of 0.11 l/hr observed in healthy volunteers. Additionally, the pharmacokinetics of LIFMIOR in rheumatoid arthritis patients, ankylosing spondylitis and plaque psoriasis patients are similar.

There is no apparent pharmacokinetic difference between males and females.

Linearity

Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.

Special populations

Renal impairment

Although there is elimination of radioactivity in urine after administration of radiolabelled etanercept

oncentrations were not observed in patients with

acute renal failure. The presence of renal impairment should not require a change in dosage.

Hepatic impairment

Increased etanercept concentrations were not observed in patients with acute hepatic failure. The presence of hepatic impairment should not require a change in dosage.

Elderly

The impact of advanced age was studied in the population pharmacokinetic analysis of etanercept serum concentrations. Clearance and volume estimates in patients aged 65 to 87 years were similar to estimates in patients less than 65 years of age.

PaedigtrC^Opu­lation

Paediatric patients with juvenile idiopathic arthritis

In a polyarticular-course juvenile idiopathic arthritis trial with LIFMIOR, 69 patients (aged 4 to 17 years) were administered 0.4 mg LIFMIOR/kg twice weekly for three months. Serum concentration profiles were similar to those seen in adult rheumatoid arthritis patients. The youngest children (4 years of age) had reduced clearance (increased clearance when normalised by weight) compared with older children (12 years of age) and adults. Simulation of dosing suggests that while older children (10–17 years of age) will have serum levels close to those seen in adults, younger children will have appreciably lower levels.

Paediatric patients with plaque psoriasis

Patients with paediatric plaque psoriasis (aged 4 to 17 years) were administered 0.8 mg/kg (up to a maximum dose of 50 mg per week) of etanercept once weekly for up to 48 weeks. The mean serum steady state trough concentrations ranged from 1.6 to 2.1 mcg/ml at weeks 12, 24, and 48. These mean concentrations in patients with paediatric plaque psoriasis were similar to the concentrations observed in patients with juvenile idiopathic arthritis (treated with 0.4 mg/kg etanercept twice weekly, up to maximum dose of 50 mg per week). These mean concentrations were similar to those seen in adult patients with plaque psoriasis treated with 25 mg etanercept twice weekly.

5.3 Preclinical safety data

In the toxicological studies with LIFMIOR, no dose-limiting or target organ toxicity was evident. LIFMIOR was considered to be non-genotoxic from a battery of in vitro and in vivo studies. Carcinogenicity studies, and standard assessments of fertility and postnatal toxicity, were not performed with LIFMIOR due to the development of neutralising antibodies in rodents.

LIFMIOR did not induce lethality or notable signs of toxicity in mice or rats following a subcutaneous dose of 2000 mg/kg or a single intravenous dose of 1000 mg/kg. LIFMIOR dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneous administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AUC-based serum drug concentrations that were over 27-fold higher than that obtained in humans recommended dose of 25 mg.

6. PHARMACEUTICAL PARTICULARS

Sucrose

Sodium chloride

L-Arginine hydrochloride

Sodium phosphate monobasic dihydrate

Sodium phosphate dibasic dihydrate

Water for injections

6.3 Shelf life

6.4

Storejn^^cfri­gerator (2°C – 8°C). eze.

LIFMIOR may be stored at temperatures up to a maximum of 25°C for a single period of up to four weeks; after which, it should not be refrigerated again. LIFMIOR should be discarded if not used within four weeks of removal from refrigeration.

Keep the pre-filled pens in the outer carton in order to protect from light.

6.5 Nature and contents of container

Pre-filled pen (MYCLIC) containing a pre-filled syringe of LIFMIOR. The syringe inside the pen is made from clear type 1 glass with a stainless steel 27 gauge needle, rubber needle cover, and plastic plunger. The needle cap of the pre-filled pen contains dry natural rubber (a derivative of latex). See section 4.4.

Cartons contain 2, 4 or 12 pre-filled pens of LIFMIOR with 2, 4 or 12 alcohol swabs. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Instructions for use and handling

Before injection, LIFMIOR single-use pre-filled pens should be allowed to reach room temperature (approximately 15 to 30 minutes). The needle cover should not be removed while allowing the prefilled pen to reach room temperature. By looking though the inspection window, the solution sho be clear to slightly opalescent, colourless to pale yellow or pale brown, and may contain small translucent or white particles of protein.

Comprehensive instructions for administration are given in the package leaflet, sectio MYCLIC pre-filled pen to inject LIFMIOR."

Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles

Belgium

8. MARKETING AUTHORISATION N

1. NAME OF THE MEDICINAL PRODUCT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

4.1 Therapeutic indicati

4.2 Posology and method of administration

LIFMIOR treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of juvenile idiopathic arthritis or paediatric plaque psoriasis. Patients treated with LIFMIOR should be given the Patient Alert Card.

Posology

Special populations

Renal and hepatic impairment No dose adjustment is required.

Paediatric population

The 10 mg presentation is for paediatric patients prescribed a dose of 10 mg or l LIFMIOR 10 mg should be used on a single occasion in a single patient, and the r should be discarded.

Juvenile idiopathic arthritis

The recommended dose is 0.4 mg/kg (up to a maximum of 25 mg per dose) given twice weekly as a subcutaneous injection with an interval of 3–4 days between doses or 0.8 mg/kg (up to a maximum of 50 mg per dose) given once weekly. Discontinuation of treatment should be considered in patients who show no response after 4 months.

No formal clinical trials have been conducted in children aged 2 to 3 years. However, limited safety data from a patient registry suggest that the safety profile in children from 2 to 3 years of age is similar to that seen in adults and children aged 4 years and subcutaneously (see section 5.1).

4.3 Contraindications

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

Sepsis or risk of sepsis.

4.4 Special warnings and precautions for use

s is diagnosed, LIFMIOR therapy must not be initiated. If inactive (‘latent’) iagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis the initiation of LIFMIOR, and in accordance with local recommendations. In this e benefit/risk balance of LIFMIOR therapy should be very carefully considered.

ll patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis.g., persistent cough, wasting/weight loss, low-grade fever) appear during or after LIFMIOR treatment.

Hepatitis B reactivation

Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant TNF-antagonists, including LIFMIOR, has been reported. This includes reports of reactivation of hepatitis B in patients who were anti-HBc positive but HBsAg negative. Patients should be tested for HBV infection before initiating treatment with LIFMIOR. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when administering LIFMIOR in patients

previously infected with HBV. These patients should be monitored for signs and symptoms of active HBV infection throughout therapy and for several weeks following termination of therapy. Adequate data from treating patients infected with HBV with anti-viral therapy in conjunction with TNF-antagonist therapy are not available. In patients who develop HBV infection, LIFMIOR should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

Solid and haematopoietic malignancies (excluding skin cancers)

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the postmarketing period (see section 4.8).

In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. In the postmarketing setting, cases of leukaemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.

Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded.

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 a 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), including LIFMIOR, in the postmarketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies typically associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.

Skin cancers

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF-antagonists, including LIFMIOR. Postmarketing cases of Merkel cell carcinoma have be reported very infrequently in patients treated with LIFMIOR. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Combining the results of controlled clinical trials, more cases of NMSC were obser receiving LIFMIOR compared with control patients, particularly in patients wit

Vaccinations

Live vaccines should not be given concurrently with LIFMIOR. No dat secondary transmission of infection by live vaccines in patients receivi double-blind, placebo-controlled, randomised clinical study in adul 184 patients also received a multivalent pneumococcal polysac most psoriatic arthritis patients receiving LIFMIOR were ab response to pneumococcal polysaccharide vaccine, but t few patients had two-fold rises in titres compared to pat significance of this is unknown.

Autoantibody formation

Treatment with LIFMIOR may result in the formation of autoimmune antibodies (see section 4.8).

ases of aplastic anaemia, some with fatal outcome, have MIOR. Caution should be exercised in patients being treated istory of blood dyscrasias. All patients and parents/caregivers

atient develops signs and symptoms suggestive of blood dyscrasias or ver, sore throat, bruising, bleeding, paleness) whilst on LIFMIOR, they

medical advice. Such patients should be investigated urgently, including full yscrasias are confirmed, LIFMIOR should be discontinued.

;rs

rare reports of CNS demyelinating disorders in patients treated with LIFMIOR (see section 4 dditionally, there have been rare reports of peripheral demyelinating polyneuropathies g Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, ating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have performed evaluating LIFMIOR therapy in patients with multiple sclerosis, clinical trials of other F antagonists in patients with multiple sclerosis have shown increases in disease activity. A careful risk/benefit evaluation, including a neurologic assessment, is recommended when prescribing LIFMIOR to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.

Combination therapy

In a controlled clinical trial of two years duration in adult rheumatoid arthritis patients, the combination of LIFMIOR and methotrexate did not result in unexpected safety findings, and the safety profile of LIFMIOR when given in combination with methotrexate was similar to the profiles reported in studies of LIFMIOR and methotrexate alone. Long-term studies to assess the safety of the combination are ongoing. The long-term safety of LIFMIOR in combination with other disease-modifying antirheumatic drugs (DMARD) has not been established.

The use of LIFMIOR in combination with other systemic therapies or phototherapy for the treatment of psoriasis has not been studied.

Renal and hepatic impairment

Based on pharmacokinetic data (see section 5.2), no dose adjustment is needed in patients with renal or hepatic impairment; clinical experience in such patients is limited.

Congestive heart failure (Cardiac failure congestive)

Physicians should use caution when using LIFMIOR in patients who have congestive heart failur (CHF). There have been postmarketing reports of worsening of CHF, with and without identifiab precipitating factors, in patients taking LIFMIOR. There have also been rare (< 0.1%) reports of

onset CHF, including CHF in patients without known pre-existing cardiovascular dise these patients have been under 50 years of age. Two large clinical trials evaluating the LIFMIOR in the treatment of CHF were terminated early due to lack of efficacy. Altho conclusive, data from one of these trials suggest a possible tendency toward wor patients assigned to LIFMIOR treatment.

Alcoholic hepatitis

In a phase II randomised placebo-controlled study of 48 hospitalised

placebo for moderate to severe alcoholic hepatitis, LIFMIOR was not efficacious, and the mortality rate in patients treated with LIFMIOR was significantly hig LIFMIOR should not be used in patients for the treatment o caution when using LIFMIOR in patients who also have mo

Wegener's gra­nulomatosis

A placebo-controlled trial, in which 89 adult patient e treated with LIFMIOR in addition to standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median duration of 25 months, has not shown LIFMIOR to be an effective treatment for Wegener’s gra­nulomatosis. The incidence of non-cutaneous malignancies of various types was significantly higher in patients treated with LIFMIOR than in the control group. LIFMIOR is not recommended for the treatment of Wegener’s gra­nulo tosis.

oglycaemia following initiation of LIFMIOR in patients receiving ssitating a reduction in anti-diabetic medication in some of these patients.

Special populati

Elderly

In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no overall differences in adverse events, serious adverse events, and serious infections in patients age 65 or older eceived LIFMIOR were observed compared with younger patients. However, caution should be sed when treating the elderly and particular attention paid with respect to occurrence of ons.

It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating LIFMIOR therapy (see

Vaccinations, above).

Inflammatory bowel disease (IBD) and uveitis in patients with juvenile idiopathic arthritis (JIA) There have been reports of IBD and uveitis in JIA patients being treated with LIFMIOR (see section 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent treatment with anakinra

Adult patients treated with LIFMIOR and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either LIFMIOR or anakinra alone (historical data).

In addition, in a double-blind, placebo-controlled trial in adult patients receiving background methotrexate, patients treated with LIFMIOR and anakinra were observed to have a higher rat serious infections (7%) and neutropenia than patients treated with LIFMIOR (see sections 4.4 4.8). The combination LIFMIOR and anakinra has not demonstrated increased clinical benefit therefore not recommended.

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and LIFMIOR resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see section 4.4).

Concurrent treatment with sulfasalazine

In a clinical study of adult patients who were receiving established f sulfasalazine, to which LIFMIOR was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with LIFMIOR or sulfasalazine alone. The clinical significance of this interaction is unknown. Physicians should use caution when considering combination therapy wit

Non-interactions X

In clinical trials, no interactions have been observed when LIFMIOR was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or methotrexate. See section 4.4 for vaccination advice.

No clinically significant pharmaco methotrexate, digoxin or wa

Women of childbear: tential

Women of childbearing potential should consider the use of appropriate contraception to avoid becoming pregnant during LIFMIOR therapy and for three weeks after discontinuation of therapy.

ental toxicity studies performed in rats and rabbits have revealed no evidence of harm to the neonatal rat due to etanercept. The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. A higher rate of major birth defects was observed in one observational study comparing pregnancies exposed to etanercept (n=370) during the first trimester with pregnancies not exposed to etanercept or other TNF-antagonists (n=164) (adjusted odds ratio 2.4, 95% CI: 1.0–5.5). The types of major birth defects were consistent with those most commonly reported in the general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. In another observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept during the first 90 days of pregnancy (n=425) to those exposed to non-biologic drugs (n=3497), there was no observed increased risk of major birth defects (crude odds ratio [OR]= 1.22, 95% CI: 0.79–1.90; adjusted OR = 0.96, 95% CI: 0.58–1.60 after adjusting for country, maternal disease, parity, maternal age and smoking in early pregnancy). This study also

showed no increased risks of minor birth defects, preterm birth, stillbirth, or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. LIFMIOR should only be used during pregnancy if clearly needed.

Etanercept crosses the placenta and has been detected in the serum of infants born to female patients treated with LIFMIOR during pregnancy. The clinical impact of this is unknown, however, infants may be at increased risk of infection. Administration of live vaccines to infants for 16 weeks after the mother’s last dose of LIFMIOR is generally not recommended.

Breast-feeding

Etanercept has been reported to be excreted in human milk following subcutaneous administration lactating rats following subcutaneous administration, etanercept was excreted in the milk and in the serum of pups. Because immunoglobulins, in common with many medicinal products, c excreted in human milk, a decision must be made whether to discontinue breast-feeding or t discontinue LIFMIOR therapy, taking into account the benefit of breast-feeding for the child benefit of therapy for the woman.

Fertility

Preclinical data about peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machin

Summary of the safety profile

Undesirable effects in paediatric patient In general, the adverse events in paedi frequency and type to those seen i Differences from adults and other

nical trials in juvenile idiopathic arthritis patients aged 2 to 18 years rate and consistent with those commonly seen in outpatient paediatric events reported included varicella with signs and symptoms of aseptic without sequelae (see also section 4.4), appendicitis, gastroenteritis, ity disorder, cutaneous ulcer, oesophagitis/gas­tritis, group A streptococcal septic es mellitus, and soft tissue and post-operative wound infection.

In one study in children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 (62%) children experienced an infection while receiving LIFMIOR during 3 months of the study (part 1, open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of LIFMIOR in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile idiopathic arthritis patients receiving 3 months of LIFMIOR compared to the 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 event per patient year), abdominal pain (19%, 0.74 events per patient year), and vomiting (13%, 0.74 events per patient year).

There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.

There have been reports of inflammatory bowel disease and uveitis in JIA patients being treated with LIFMIOR from post-marketing sources, including a very small number of cases indicating a positive rechallenge (see section 4.4).

Undesirable effects in paediatric patients with plaque psoriasis

In a 48-week study in 211 children aged 4 to 17 years with paediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.

Adult population

Undesirable effects in adults

The most commonly reported adverse reactions are injection site reactions (such as pain, swellin itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infecti bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibo itching, and fever.

Serious adverse reactions have also been reported for LIFMIOR. TNF-antagonists, such as LIFMIOR, affect the immune system and their use may affect the body’s defenses against infection and cancer.

Serious infections affect fewer than 1 in 100 patients treated with LIFMIOR. Reports have included

fatal and life-threatening infections and sepsis. Various malignancies h of LIFMIOR, including cancers of the breast, lung, skin and lymph gla

Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia and very rare reports of ap naemia. Central and peripheral

demyelinating events have been seen rarely and very rarely, tively, with LIFMIOR use. There have been rare reports of lupus, lupus-related conditions, a vasculitis.

Tabulated list of adverse reactions

The following list of adverse reactions is based postmarketing experience.

Within the organ system classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (>1/10); common (>1/100 to <1/10 J>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare

(<1/10,000); not known (c ated from the available data).

infection, skin ulcer, urinary tract infection, vasculitis, and wound infection. In the 2-year active-controlled study where patients were treated with either LIFMIOR alone, methotrexate alone or LIFMIOR in combination with methotrexate, the rates of serious infections were similar among the treatment groups. However, it cannot be excluded that the combination of LIFMIOR with methotrexate could be associated with an increase in the rate of infections.

There were no differences in rates of infection among patients treated with LIFMIOR and those treated with placebo for plaque psoriasis in placebo-controlled trials of up to 24 weeks duration. Serious infections experienced by LIFMIOR-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis, gastritis, appendicitis, Streptococcal fasciitis, myositis, sept shock, diverticulitis and abscess. In the double-blind and open-label psoriatic arthritis trials, 1 patient reported a serious infection (pneumonia).

Serious and fatal infections have been reported during use of LIFMIOR; reported pathogens i bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred withi weeks after initiating treatment with LIFMIOR in patients who have underlying conditions (e diabetes, congestive heart failure, history of active or chronic infections) in addition to their rheumatoid arthritis (see section 4.4). LIFMIOR treatment may increase mortality in patients with established sepsis.

ve been rare reports of patients, including rheumatoid factor positive patients, who have d other autoantibodies in conjunction with a lupus-like syndrome or rashes that are le with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.

Pancytopenia and aplastic anaemia

There have been postmarketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes (see section 4.4).

Interstitial lung disease

In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of interstitial lung disease in patients receiving etanercept without concomitant methotrexate was 0.06% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of interstitial lung disease was 0.47%

(frequency uncommon). There have been postmarketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.

Concurrent treatment with anakinra

In studies when adult patients received concurrent treatment with LIFMIOR plus anakinra, a higher rate of serious infections compared to LIFMIOR alone was observed and 2% of patients (3/139)

developed neutropenia (absolute neutrophil count < 1000/mm3). While neutropenic, one patient developed cellulitis that resolved after hospitalisation (see sections 4.4 and 4.5).

Elevated liver enzymes

In the double-blind periods of controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of adverse events of elevated liver enzymes in patients receivin etanercept without concomitant methotrexate was 0.54% (frequency uncommon). In the double-b periods of controlled clinical trials that allowed concomitant treatment with etanercept and

methotrexate, the frequency (incidence proportion) of adverse events of elevated liver 4.18% (frequency common).

Autoimmune hepatitis

In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of autoimmune hepatitis in patients receiving etanercept without concomitant methotrexate was 0.02% (frequency rare). In the controlled clinical trials that allowed concomita atment with etanercept and methotrexate, the frequency (incidence proportion) of autoimm itis was 0.24%

(frequency uncommon).

Paediatric population

See Summary of the safety profile, above.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authori

allows continued monitoring of the benefit/risk^ba­lance of the medicinal product. Healthcare professionals are asked to report any susp idVerse reactions via the national reporting system

listed in Appendix V.

4.9 Overdose

No dose-limiting toxicities were observed during clinical trials of rheumatoid arthritis patients. The highest dose level evaluated has been an intravenous loading dose of 32 mg/m2 followed by subcutaneous doses of 16 mg/m2 administered twice weekly. One rheumatoid arthritis patient mistakenly self-administered 62 mg LIFMIOR subcutaneously twice weekly for 3 weeks without experiencing undesirable effects. There is no known antidote to LIFMIOR.

acotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-a) inhibitors, C code: L04AB01

Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of rheumatoid arthritis. Elevated levels of TNF are also found in the synovium and psoriatic plaques of patients with psoriatic arthritis and in serum and synovial tissue of patients with ankylosing spondylitis. In plaque psoriasis, infiltration by inflammatory cells, including T-cells, leads to increased TNF levels in psoriatic lesions compared with levels in uninvolved skin. Etanercept is a competitive inhibitor of TNF binding to its cell surface receptors, and thereby inhibits the biological activity of TNF. TNF and lymphotoxin are pro-inflammatory cytokines that bind to two distinct cell surface receptors: the 55-kilodalton (p55) and 75-kilodalton (p75) tumour necrosis factor receptors (TNFRs). Both TNFRs exist naturally in membrane-bound and soluble forms. Soluble TNFRs are thought to regulate TNF biological activity.

TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on cross-linking of cell surface TNFRs. Dimeric soluble receptors, such as etanercept, possess a higher affinity for TNF than monomeric receptors and are considerably more potent competitive inhibitors of TNF binding to its cellular receptors. In addition, use of an immunoglobulin Fc region as a fusion element in the construction of a dimeric receptor imparts a longer serum half-life.

Mechanism of action

Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin patholog plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controll TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF binding to cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept may also modulate biologic responses controlled by additional downstream molecules (e.g., cytokines, adhesion molecules, or proteinases) that are induced or regulated by TNF.

Long-term safety of LIFMIOR monotherapy (n=103), LIFMIOR plus methotrexate (n=294), or methotrexate monotherapy (n=197) were assessed for up to 3 years in a registry of 594 children aged 2 to 18 years with juvenile idiopathic arthritis, 39 of whom were 2 to 3 years of age. Overall, infections

Placebo

Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate in Patients with RA of <3 Years Duration

0.8

2.2

*p < 0.05

Endpoint

Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate vs. LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration (12 Month Results)

Pairwise comparison p-values: * = p < 0.05 for com methotrexate, f = p < 0.05 for comparisons of LI methotrexate and 0 = p < 0.05 for comparisons LIFMIOR.

Significant advantages for LIFMIOR in combination with methotrexate compared with LIFMIOR monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for LIFMIOR monotherapy red with methotrexate monotherapy were also observed after 24 months.

opped out of the study for any reason were considered to ^Without progression (TSS change < 0.5) at 24 months was th methotrexate group compared with the LIFMIOR alone , and 36%, respectively; p<0.05). The difference between

ne was also significant (p<0.05). Among patients who completed dy, the non-progression rates were 78%, 70%, and 61%,

mg LIFMIOR (two 25 mg SC injections) administered once weekly lind, placebo-controlled study of 420 patients with active RA. In this

ceived placebo, 214 patients received 50 mg LIFMIOR once weekly and 153 mg LIFMIOR twice weekly. The safety and efficacy profiles of the two ent regimens were comparable at week 8 in their effect on signs and symptoms of eek 16 did not show comparability (non-inferiority) between the two regimens.

atients with plaque psoriasis

OR is recommended for use in patients as defined in section 4.1. Patients who “failed to

d to” in the target population is defined by insufficient response (PASI<50 or PGA less than good), or worsening of the disease while on treatment, and who were adequately dosed for a sufficiently long duration to assess response with at least each of the three major systemic therapies as available.

The efficacy of LIFMIOR versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing LIFMIOR with other systemic therapies. Instead, the safety and efficacy of LIFMIOR were assessed in four randomised, double-blind, placebo-controlled studies. The primary efficacy endpoint in all four studies was the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at least a 75% improvement in the Psoriasis Area and Severity Index score from baseline) at 12 weeks.

Study 1 was a Phase 2 study in patients with active, but clinically stable, plaque psoriasis involving > 10% of the body surface area who were > 18 years old. One hundred and twelve (112) patients were randomised to receive a dose of 25 mg of LIFMIOR (n=57) or placebo (n=55) twice a week for 24 weeks.

Study 2 evaluated 652 patients with chronic plaque psoriasis using the same inclusion criteria as study 1 with the addition of a minimum psoriasis area and severity index (PASI) of 10 at screening.

LIFMIOR was administered at doses of 25 mg once a week, 25 mg twice a week or 50 mg twice a week for 6 consecutive months. During the first 12 weeks of the double-blind treatment period, patients received placebo or one of the above three LIFMIOR doses. After 12 weeks of treatm patients in the placebo group began treatment with blinded LIFMIOR (25 mg twice a week) in the active treatment groups continued to week 24 on the dose to which they were origi randomised.

Study 3 evaluated 583 patients and had the same inclusion criteria as study 2. Pati received a dose of 25 mg or 50 mg LIFMIOR, or placebo twice a week for 12 patients received open-label 25 mg LIFMIOR twice weekly for an additional

Study 4 evaluated 142 patients and had similar inclusion criteria to stud nd 3. Patients in this

study received a dose of 50 mg LIFMIOR or placebo once weekly for 12 weeks and then all patients received open-label 50 mg LIFMIOR once weekly for an additional 12 weeks.

In study 1, the LIFMIOR-treated group had a significantly higher proportion of patients with a PASI 75 response at week 12 (30%) compared to the placebo-treated group (2%) (p<0.0001). At 24 weeks, 56% of patients in the LIFMIOR-treated group had achieved the PASI 75 compared to 5% of placebo-treated patients. Key results of studies 2, 3 and 4 are shown below.

Among patients with plaque psoriasis who received LIFMIOR, significant responses relative to placebo were apparent at the time of the first visit (2 weeks) and were maintained through 24 weeks of therapy.

Study 2 also had a drug withdrawal period during which patients who achieved a PASI improvement of at least 50% at week 24 had treatment stopped. Patients were observed off treatment for the

occurrence of rebound (PASI >150% of baseline) and for the time to relapse (defined as a loss of at least half of the improvement achieved between baseline and week 24). During the withdrawal period, symptoms of psoriasis gradually returned, with a median time to disease relapse of 3 months. No rebound flare of disease and no psoriasis-related serious adverse events were observed. There was some evidence to support a benefit of re-treatment with LIFMIOR in patients initially responding to treatment.

In study 3, the majority of patients (77%) who were initially randomised to 50 mg twice weekly and had their LIFMIOR dose decreased at week 12 to 25 mg twice weekly maintained their PASI 75 response through week 36. For patients who received 25 mg twice weekly throughout the study, the PASI 75 response continued to improve between weeks 12 and 36.

In study 4, the LIFMIOR-treated group had a higher proportion of patients with PASI 75 at we (38%) compared to the placebo-treated group (2%) (p<0.0001). For patients who received 5 weekly throughout the study, the efficacy responses continued to improve with 71% a 75 at week 24.

In long-term (up to 34 months) open-label studies where LIFMIOR was given w clinical responses were sustained and safety was comparable to shorter-term stud

An analysis of clinical trial data did not reveal any baseline disease characteristics that would assist clinicians in selecting the most appropriate dosing option (intermittent or continuous). Consequently, the choice of intermittent or continuous therapy should be based upon physician judgment and individual patient needs.

Antibodies to LIFMIOR w........ .

Antibodies to etanercept have been detected in the sera of some subjects treated with etanercept.

These antibodies have all been non-neutral correlation between antibody development

In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of anti-etanercept antibodies were approximately 6% of subjects with rheumatoid arthritis, 7.5% of subjects with psoriatic arthritis, 2% of subjects with ankylosing spondylitis, 7% of subjects with psoriasis, 9.7% of subjects with atric psoriasis, and 4.8% of subjects with juvenile idiopathic arthritis.

veloped antibodies to etanercept in longer-term trials (of up to e, as expected. However, due to their transient nature, the incidence of assessment point was typically less than 7% in rheumatoid arthritis ects.

asis study in which patients received 50 mg twice weekly for 96 weeks, the ibodies observed at each assessment point was up to approximately 9%.

tanercept serum values were determined by an Enzyme-Linked Immunosorbent Assay (ELISA) ethod, which may detect ELISA-reactive degradation products as well as the parent compound.

Renal impairment

Although there is elimination of radioactivity in urine after administration of radiolabelled etanercept to patients and volunteers, increased etanercept concentrations were not observed in patients with acute renal failure. The presence of renal impairment should not require a change in dosage.

Linearity

Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.

5.3 Preclinical safety data

In the toxicological studies with LIFMIOR, no dose-limiting or target organ toxicity was evident. LIFMIOR was considered to be non-genotoxic from a battery of in vitro and in vivo studies. Carcinogenicity studies, and standard assessments of fertility and postnatal toxicity, were not performed with LIFMIOR due to the development of neutralising antibodies in rodents.

LIFMIOR did not induce lethality or notable signs of toxicity in mice or rats following a single subcutaneous dose of 2000 mg/kg or a single intravenous dose of 1000 mg/kg. LIFMIOR did not dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneo administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AU drug concentrations that were over 27-fold higher than that obtained in humans at the dose of 25 mg.

6. PHARMACEUTICAL PARTICULARS

Powder

Mannitol (E421)

Sucrose

Trometamol

Solvent

Water for injections

In the absence of compatibility products.

From a microbiological point of view, the reconstituted medicinal product should be used immediately. Chemical and physical in-use stability has been demonstrated for 6 hours at temperatures not above 25°C after reconstitution.

in a refrigerator (2°C – 8°C). Do not freeze.

IFMIOR may be stored at temperatures up to a maximum of 25° C for a single period of up to four weeks; after which, it should not be refrigerated again. LIFMIOR should be discarded if not used within four weeks of removal from refrigeration.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

6.6 Special precautions for disposal and other handling

7. MARKETING AUTHORISATION HOLDER

8. MARKETING AUTHORIS

9. DATE OF FIR

ORISATION/RENEWAL OF THE AUTHORISATION

OF REVISION OF THE TEXT

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers of the biological active substance

Boehringer Ingelheim Pharma KG

Birkendorfer Strasse 65

D-88397 Biberach an der Riss Germany

Pfizer Ireland Pharmaceuticals Grange Castle Business Park Clondalkin

Dublin 22

Ireland

Name and address of the manufacturers responsible for batch release Wyeth Pharmaceuticals New Lane Havant Hampshire, PO9 2NG United Kingdom

Pfizer Manufacturing Belgium NV Rijksweg 12, 2870 Puurs

Belgium

The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.

dical prescription (see Annex I: Summary of Product

Periodi

AND REQUIREMENTS OF THE MARKETING

Update Reports

nts for submission of periodic safety update reports for this medicinal product are set f Union reference dates (EURD list) provided for under Article 107c(7) of Directive d any subsequent updates published on the European medicines web-portal.

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

Additional risk minimisation measures

Prior to launch in each Member State, the MAH shall agree the final educational material with the competent authority in that Member State comprising of information provided to all healthcare professionals expected to prescribe the product on the correct and safe use of the pre-filled pen an Patient Alert Card which is to be given to patients using LIFMIOR.

The healthcare professional’s e­ducational material should contain the following key eleme

• Teaching guide to facilitate training of the patients in the safe use of the pre-filled pe
• A needle-free demonstration device
• Instructional materials to share with patients

The Patient’s Alert Card should contain the following key elements for patients treated with LIFMIOR:

• The risk of opportunistic infections and tuberculosis
• The risk of Congestive Heart Failure (CHF).

CARTON TEXT - EU/1/16/1165/002–004

| 1. NAME OF THE MEDICINAL PRODUCT

LIFMIOR 25 mg powder and solvent for solution for injection etanercept

| 2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial of LIFMIOR contains 25 mg etanercept.

| 3. LIST OF EXCIPIENTS

The other ingredients in LIFMIOR are:

Powder: Mannitol, sucrose and trometamol.

Solvent: Water for injections

| 4.  PHARMACEUTICAL FORM AND CONTENTS^/                       |

Powder and solvent for solution for injection

8 alcohol swabs

8 vials of powder

8 pre-filled syringes of 1 ml solvent

8 stainless steel injection needles

8 vial adaptors

16 alcohol swabs

24 vials of powder

24 pre-filled syringes of 1 ml solvent

24 stainless steel injection needles

24 vial adaptors

48 alcohol swabs

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Subcutaneous use

| 14. GENERAL CLASSIFICATION FOR SUPPLY

LIFMIOR 25 mg

2D barcode carrying the unique identifier included.

PC:

SN:

NN:

I 16. INFORMATION IN BRAILLE

I 17. UNIQUE IDENTIFIER-2D BARCODE

I 18. UNIQUE IDENTIFIER-HUMAN READABLE DATA

CARTON TEXT – (25 mg Pre-filled Syringe) - EU/1/16/1165/005–007

The other ingredients in LIFMIOR are:

Sucrose, sodium chloride, L-arginine hydrochloride, sodium phosp phosphate dibasic dihydrate and water for injections.

vice:

the solution after it has reached room temperature (15 to 30 minutes after taking the product the refrigerator).

ect slowly, at an angle of 45° to 90° to the skin.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

| 8. EXPIRY DATE

CARTON TEXT – (50 mg Pre-filled Syringe) - EU/1/16/1165/008–010

I 1. NAME OF THE MEDICINAL PRODUCT

LIFMIOR 50 mg solution for injection in pre-filled syringe etanercept

I 2. STATEMENT OF ACTIVE SUBSTANCE(S)

The other ingredients in LIFMIOR are:

Sucrose, sodium chloride, L-arginine hydrochloride, sodium phosphate phosphate dibasic dihydrate and water for injections.

[T PHARMACEUTICAL FORM AND CONTENTS

4 pre-filled syringes

4 alcohol swabs

Read the package leaflet before use. Subcutaneous use.

tion after it has reached room temperature (15 to 30 minutes after taking the product efrigerator).

lowly, at an angle of 45° to 90° to the skin.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

| 8. EXPIRY DATE

I 17. UNIQUE IDENTIFIER-2D BARCODE

CARTON TEXT – (50 mg Pre-filled Pen) - EU/1/16/1165/011–013

The other ingredients in LIFMIOR are:

Sucrose, sodium chloride, L-arginine hydrochloride, sodium phosphate phosphate dibasic dihydrate and water for injections.

12 MYCLIC pre-filled pens

12 alcohol swabs