Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
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
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
4.1Therapeutic 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
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
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
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 of peripheral joint damage as measured by
Axial spondyloarthritis
Ankylosing spondylitis (AS)
Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Treatment of adults with severe
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
Paediatric plaque psoriasis
Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.
4.2Posology and method of administration
LIFMIOR treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis,
LIFMIOR is available in strengths of 10, 25 and 50 mg.
Posology
Rheumatoid arthritis
25 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
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
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 adults
Paediatric population
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
The 10 mg vial strength may be more appropriate for administration to children with JIA below the 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).
There is generally no applicable use of LIFMIOR in children aged below 2 years in the indication juvenile idiopathic arthritis.
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
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. 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."
4.3Contraindications
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.
4.4Special 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
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 in delay of appropriate treatment and 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.
Tuberculosis
Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with
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
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
All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g., persistent cough, wasting/weight loss,
Hepatitis B reactivation
Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant
Worsening of hepatitis C
There have been reports of worsening of hepatitis C in patients receiving LIFMIOR. LIFMIOR should 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 use of 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).
Allergic reactions
Allergic reactions associated with LIFMIOR administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, LIFMIOR therapy should be discontinued immediately and appropriate therapy initiated.
Immunosuppression
The possibility exists for
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
Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with
Skin cancers
Melanoma and
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 with LIFMIOR. No data are available on the secondary transmission of infection by live vaccines in patients receiving LIFMIOR. In a
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 very rare reports of peripheral demyelinating polyneuropathies (including
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.
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
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
Alcoholic hepatitis
In a phase II randomised
Wegener's granulomatosis
A
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
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 juvenile idiopathic arthritis (JIA) There have been reports of IBD and uveitis in JIA patients being treated with LIFMIOR (see section 4.8).
4.5Interaction 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
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 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.
In clinical trials, no interactions have been observed when LIFMIOR was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal
No clinically significant pharmacokinetic
4.6Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should be advised to use appropriate contraception to avoid becoming 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. A higher rate of major birth defects was observed in an observational study comparing pregnancies exposed to etanercept during the first trimester, with pregnancies not exposed to etanercept or other
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.
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 medicinal products, can be excreted in human milk, a decision must be made whether to discontinue
Fertility
Preclinical data about peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available.
4.7Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever.
Serious adverse reactions have also been reported for LIFMIOR.
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,
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); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Infections and infestations:
Very common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin
| infections)* |
Uncommon: | Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis and parasitic |
| infection)* |
Rare: | Tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial, |
| atypical mycobacterial, viral infections, and Legionella)* |
Not known: | Listeria, hepatitis B reactivation |
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Uncommon: | |
Rare: | Lymphoma, melanoma (see section 4.4) |
Not known: | Leukaemia, Merkel cell carcinoma (see section 4.4) |
Blood and lymphatic system disorders: | |
Uncommon: | Thrombocytopenia |
Rare: | Anaemia, leukopenia, neutropenia, pancytopenia* |
Very rare: | Aplastic anaemia* |
Immune system disorders: | |
Common: | Allergic reactions (see Skin and subcutaneous tissue disorders), autoantibody |
| formation* |
Uncommon: | Systemic vasculitis (including |
Rare: | Serious allergic/anaphylactic reactions (including angioedema, bronchospasm), |
| sarcoidosis |
Not known: | Macrophage activation syndrome*, worsening of symptoms of dermatomyositis |
Nervous system disorders: | |
Rare: | Seizures |
| CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating |
| conditions, such as optic neuritis and transverse myelitis (see section 4.4) |
Very rare: | Peripheral demyelinating events, including |
| inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and |
| multifocal motor neuropathy (see section 4.4) |
Eye disorders: |
|
Uncommon: | Uveitis, scleritis |
Cardiac disorders:
Rare: | Congestive heart failure (see section 4.4) |
Respiratory, thoracic and mediastinal disorders: | |
Uncommon: | Interstitial lung disease (including pneumonitis and pulmonary fibrosis)* |
Hepatobiliary disorders: | |
Rare: | Elevated liver enzymes, autoimmune hepatitis |
Skin and subcutaneous tissue disorders: | |
Common: | Pruritus |
Uncommon: | Angioedema, urticaria, rash, psoriasiform rash, psoriasis (including new onset or |
| worsening and pustular, primarily palms and soles) |
Rare: | Cutaneous vasculitis (including leukocytoclastic vasculitis), |
| syndrome, erythema multiforme |
Very rare: | Toxic epidermal necrolysis |
Musculoskeletal and connective tissue disorders: | |
Rare: | Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, |
| syndrome |
General disorders and administration site conditions:
Very common: Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)*
Common: Fever
* see Description of selected adverse reactions, below.
Description of selected adverse reactions
Malignancies and lymphoproliferative disorders
One hundred and
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
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 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 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.
In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with LIFMIOR developed injection site reactions compared with 3.4% of
Serious infections
In
There were no differences in rates of infection among patients treated with LIFMIOR and those treated with placebo for plaque psoriasis in
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
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
There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a
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
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).
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
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,
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
Undesirable effects in paediatric patients with plaque psoriasis
In a
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9Overdose
No
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha
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
TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on
Mechanism of action
Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by
Clinical efficacy and safety
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
Adult patients with rheumatoid arthritis
The efficacy of LIFMIOR was assessed in a randomised,
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 Rheumatology (ACR) response criteria.
ACR 20 and 50 responses were higher in patients treated with LIFMIOR at 3 and 6 months than in patients treated with placebo (ACR 20: LIFMIOR 62% and 59%, placebo 23% and 11% at 3 and 6 months, respectively: ACR 50: LIFMIOR 41% and 40%, placebo 8% and 5% at months 3 and 6,
respectively; p<0.01 LIFMIOR vs. placebo at all timepoints for both ACR 20 and ACR 50 responses).
Approximately 15% of subjects who received LIFMIOR achieved an ACR 70 response at month 3 and month 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receiving LIFMIOR, the clinical responses 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 response criteria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), which included disability, vitality, mental health, general health status, and
After discontinuation of LIFMIOR, symptoms of arthritis generally returned within a month.
The efficacy of LIFMIOR was compared to methotrexate in a randomised,
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 Total 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. LIFMIOR
25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. The differences in TSS and JSN were not statistically significant between methotrexate and LIFMIOR 25 mg. The results are shown in the figure below.

Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate in Patients with RA of <3 Years Duration
Change from Baseline
2.5 |
| 12 Months |
| 2.5 | 2.2 | 24 Months |
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2.0 |
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| 2.0 |
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1.5 | 1.3 |
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| 1.5 | 1.2 | 1.3 |
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1.0 | 0.8 | 0.9 |
| 1.0 |
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| 0.9 |
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| 0.6* | 0.6 | |||
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| 0.4* | 0.4 0.4 |
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| ||
0.5 |
| 0.5 |
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| ||
0.0 |
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| 0.0 |
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| TSS | Erosions | JSN |
| TSS | Erosions | JSN |
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| MTX |
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| LIFMIOR 25 mg |
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| *p < 0.05 |
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|
In another
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. LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration
|
|
| LIFMIOR + |
Endpoint | Methotrexate | LIFMIOR | Methotrexate |
| (n = 228) | (n = 223) | (n = 231) |
ACR Responsesa |
|
| 74.5% †, |
ACR 20 | 58.8% | 65.5% | |
ACR 50 | 36.4% | 43.0% | 63.2% †, |
ACR 70 | 16.7% | 22.0% | 39.8% †, |
DAS |
|
|
|
Baseline scoreb | 5.5 | 5.7 | 5.5 |
Week 52 scoreb | 3.0 | 3.0 | 2.3†, |
Remissionc | 14% | 18% | 37%†, |
HAQ |
|
|
|
Baseline | 1.7 | 1.7 | 1.8 |
Week 52 | 1.1 | 1.0 | 0.8†, |
a:Patients who did not complete 12 months in the study were considered to be
b:Values for Disease Activity Score (DAS) are means.
c:Remission is defined as DAS <1.6.
Pairwise comparison
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
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
The safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly were evaluated in a
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
Adult patients with psoriatic arthritis
The efficacy of LIFMIOR was assessed in a randomised,
(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
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
| Percent of Patients | |
| Placebo | LIFMIORa |
Psoriatic Arthritis Response | n = 104 | n = 101 |
ACR 20 |
| 59b |
Month 3 | ||
Month 6 | 50b | |
ACR 50 |
| 38b |
Month 3 | ||
Month 6 | 37b | |
ACR 70 |
| 11b |
Month 3 | ||
Month 6 | 9c | |
PsARC |
| 72b |
Month 3 | ||
Month 6 | 70b |
a:25 mg LIFMIOR SC twice weekly
b:p < 0.001, LIFMIOR vs. placebo
c:p < 0.01, LIFMIOR vs. placebo
Among patients with psoriatic arthritis who received LIFMIOR, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. LIFMIOR was significantly better than placebo in all measures of disease activity (p < 0.001), and responses were similar with and without concomitant methotrexate therapy. Quality of life in psoriatic arthritis patients was assessed at every timepoint using the disability index of the HAQ. The disability index score was significantly improved at all timepoints in psoriatic arthritis patients treated with LIFMIOR, relative to placebo (p < 0.001).
Radiographic changes were assessed in the psoriatic arthritis study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. The modified TSS at 12 months is presented in the table below. 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 12 months 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 Change from Baseline in Total Sharp Score
| Placebo | Etanercept |
Time | (n = 104) | (n = 101) |
Month 12 | 1.00 (0.29) |
SE = standard error. a. p = 0.0001.
LIFMIOR treatment resulted in improvement in physical function during the
There is insufficient evidence of the efficacy of LIFMIOR in patients with ankylosing
No study has been performed in patients with psoriatic arthritis using the 50 mg
Adult patients with ankylosing spondylitis
The efficacy of LIFMIOR in ankylosing spondylitis was assessed in 3 randomised,
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 with complete ankylosis of the spine were not included in the study. Doses of 25 mg of LIFMIOR (based on
The primary measure of efficacy (ASAS 20) was a 20% improvement in at least 3 of the
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 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.

Responses of Patients with Ankylosing Spondylitis in a
| Percent of Patients | |
Ankylosing Spondylitis | Placebo | LIFMIOR |
Response | N = 139 | N = 138 |
ASAS 20 |
|
|
2 weeks | 46a | |
3 months | 60a | |
6 months | 58a | |
|
|
|
ASAS 50 |
|
|
2 weeks | 24a | |
3 months | 45a | |
6 months | 42a | |
|
|
|
ASAS 70 |
|
|
2 weeks | 12b | |
3 months | 29b | |
6 months | 28b | |
|
|
|
a:p<0.001, LIFMIOR vs. placebo
b:p = 0.002, LIFMIOR vs. placebo
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
Adult patients with
The efficacy of LIFMIOR in patients with
215 adult patients (modified
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 | LIFMIOR | |
Responses at Week 12 | N=106 to 109* | N=103 to 105* |
ASAS** 40 | 15.7 | 32.4b |
ASAS 20 | 36.1 | 52.4c |
10.4 | 33.0a | |
ASAS partial remission | 11.9 | 24.8c |
BASDAI***50 | 23.9 | 43.8b |
*Some patients did not provide complete data for each endpoint **ASAS=Assessments in Spondyloarthritis International Society
***Bath Ankylosing Spondylitis Disease Activity Index
a: p<0.001, b:<0.01 and c:<0.05, respectively between LIFMIOR and placebo
At week 12, there was a statistically significant 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 SPARCC score measured on MRI for all
LIFMIOR showed statistically significantly greater improvement from baseline to week 12 compared to placebo in most
Clinical responses among
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 assessed in four randomised,
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
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
Study 4 evaluated 142 patients and had similar inclusion criteria to studies 2 and 3. Patients in this study received a dose of 50 mg LIFMIOR or placebo once weekly for 12 weeks and then all patients received
In study 1, the
Responses of Patients with Psoriasis in Studies 2, 3 and 4
|
| Study 2 |
|
|
| Study 3 |
|
| Study 4 |
| |
|
|
|
| ||||||||
|
| 25 mg | 50 mg |
| 25 mg | 50 mg |
| 50 mg | 50 mg | ||
| Placebo | BIW | BIW | Placebo | BIW | BIW | Placebo | QW | QW | ||
| n = 166 | n = | n = | n = | n = | n = 193 | n = 196 | n = 196 | n = 46 | n = 96 | n = 90 |
| wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk 24a | ||||
Respons |
| wk | wk | wk | wk |
|
|
|
|
|
|
e (%) |
| 24a | 24a |
|
|
|
|
|
| ||
PASI 50 | 58* | 74* | 64* | 77* | 69* | ||||||
PASI 75 | 34* | 49* | 34* | 49* | 38* | ||||||
DSGA b, |
|
|
|
|
|
|
|
|
|
|
|
clear or |
|
|
|
|
|
|
|
|
|
|
|
almost |
|
|
|
|
|
|
|
|
|
|
|
clear | 34* | 49* | 39* | 57* | 39* |
*p 0.0001 compared with placebo
a.No statistical comparisons to placebo were made at week 24 in studies 2 and 4 because the original placebo group began receiving LIFMIOR 25 mg BIW or 50 mg once weekly from week 13 to week 24.
b.Dermatologist Static Global Assessment. Clear or almost clear defined as 0 or 1 on a 0 to 5 scale.
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
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
In
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 etanercept. These antibodies have all been
In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of
The proportion of subjects who developed antibodies to etanercept in
In a
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
The safety and efficacy of LIFMIOR were assessed in a
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
In another
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
Paediatric patients with plaque psoriasis
The efficacy of LIFMIOR was assessed in a randomised,
Patients received LIFMIOR 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomised to LIFMIOR had positive efficacy responses (e.g., PASI 75) than those randomised to placebo.
Paediatric Plaque Psoriasis Outcomes at 12 Weeks
| LIFMIOR |
|
| 0.8 mg/kg Once |
|
| Weekly | Placebo |
| (N = 106) | (N = 105) |
PASI 75, n (%) | 60 (57%)a | 12 (11%) |
PASI 50, n (%) | 79 (75%)a | 24 (23%) |
sPGA “clear” or “minimal”, n (%) | 56 (53%)a | 14 (13%) |
Abbreviation:
After the
During a randomised withdrawal period, significantly more patients
The
5.2Pharmacokinetic properties
Etanercept serum values were determined by an
Absorption
Etanercept 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
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,
In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady state AUCs were 466 g 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
Elimination
Etanercept is cleared slowly from the body. The
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 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.
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.
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
In a
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
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
5.3Preclinical safety data
In the toxicological studies with LIFMIOR, no
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 elicit
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Powder
Mannitol (E421)
Sucrose
Trometamol
Solvent
Water for injections
6.2Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3Shelf life
4 years.
Chemical and physical
6.4Special 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.
6.5Nature and contents of container
Clear glass vial (4 ml, type I glass) with rubber stoppers, aluminium seals, and
6.6Special 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 subcutaneous injection. LIFMIOR contains no antibacterial preservative, and therefore solutions prepared with water 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, with no lumps, flakes or particles. Some white foam may remain in the vial – this is normal. LIFMIOR should not be used if 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 PREPARATION 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
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)
EU/1/16/1165/002
EU/1/16/1165/003
EU/1/16/1165/004
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: {DD month YYYY}
Date of last renewal: {DD month YYYY}
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
LIFMIOR 25 mg solution for injection in
LIFMIOR 50 mg solution for injection in
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
25 mg solution for injection in
50 mg solution for injection in
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
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
The solution is clear, and colourless or pale yellow.
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
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
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
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
Axial spondyloarthritis
Ankylosing spondylitis (AS)
Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Treatment of adults with severe
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
Paediatric plaque psoriasis
Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.
4.2 Posology and method of administration
LIFMIOR treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis,
LIFMIOR is available in strengths of 10, 25 and 50 mg.
Posology
Rheumatoid arthritis
25 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
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
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 adults
Paediatric population
The dosage of LIFMIOR is based on body weight for paediatric patients. Patients weighing less than 62.5 kg should be accurately dosed on a mg/kg basis using the powder and solvent for solution for injection presentations or the powder for solution for injection presentations (see below for dosing for specific indications). Patients weighing 62.5 kg or more, may be dosed using a
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
The 10 mg vial strength may be more appropriate for administration to children with JIA below the 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).
There is generally no applicable use of LIFMIOR in children aged below 2 years in the indication juvenile idiopathic arthritis.
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
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
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 in delay of appropriate treatment and 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.
Tuberculosis
Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with
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
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
All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g., persistent cough, wasting/weight loss,
Hepatitis B reactivation
Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant
Worsening of hepatitis C
There have been reports of worsening of hepatitis C in patients receiving LIFMIOR. LIFMIOR should 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 use of 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).
Allergic reactions
The needle cover of the
Allergic reactions associated with LIFMIOR administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, LIFMIOR therapy should be discontinued immediately and appropriate therapy initiated.
Immunosuppression
The possibility exists for
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
Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with
Skin cancers
Melanoma and
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 with LIFMIOR. No data are available on the secondary transmission of infection by live vaccines in patients receiving LIFMIOR. In a
Autoantibody formation
Treatment with LIFMIOR may result in the formation of autoimmune antibodies (see section 4.8).
Haematologic reactions
- Erelzi - etanercept
- Enbrel - etanercept
- Benepali - etanercept
Prescription drugs listed. Substance: "Etanercept"
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 very rare reports of peripheral demyelinating polyneuropathies (including
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.
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
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
Alcoholic hepatitis
In a phase II randomised
Wegener's granulomatosis
A
duration of 25 months, has not shown LIFMIOR to be an effective treatment for Wegener’s granulomatosis. The incidence of
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
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 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
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 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.
In clinical trials, no interactions have been observed when LIFMIOR was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal
No clinically significant pharmacokinetic
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should be advised to use appropriate contraception to avoid becoming 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. A higher rate of major birth defects was observed in an observational study comparing pregnancies exposed to etanercept during the first trimester, with pregnancies not exposed to etanercept or other
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.
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 medicinal products, can be excreted in human milk, a decision must be made whether to discontinue
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 machines have been performed.
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever.
Serious adverse reactions have also been reported for LIFMIOR.
fatal and
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,
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); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Infections and infestations:
Very common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin
| infections)* |
Uncommon: | Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis and parasitic |
| infection)* |
Rare: | Tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial, |
| atypical mycobacterial, viral infections, and Legionella)* |
Not known: | Listeria, hepatitis B reactivation |
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Uncommon: | |
Rare: | Lymphoma, melanoma (see section 4.4) |
Not known: | Leukaemia, Merkel cell carcinoma (see section 4.4) |
Blood and lymphatic system disorders: | |
Uncommon: | Thrombocytopenia |
Rare: | Anaemia, leukopenia, neutropenia, pancytopenia* |
Very rare: | Aplastic anaemia* |
Immune system disorders: | |
Common: | Allergic reactions (see Skin and subcutaneous tissue disorders), autoantibody |
| formation* |
Uncommon: | Systemic vasculitis (including |
Rare: | Serious allergic/anaphylactic reactions (including angioedema, bronchospasm), |
| sarcoidosis |
Not known: | Macrophage activation syndrome*, worsening of symptoms of dermatomyositis |
Nervous system disorders: | |
Rare: | Seizures |
| CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating |
| conditions, such as optic neuritis and transverse myelitis (see section 4.4) |
Very rare: | Peripheral demyelinating events, including |
| inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and |
| multifocal motor neuropathy (see section 4.4) |
Eye disorders:
Uncommon: Uveitis, scleritis
Cardiac disorders:
Rare: | Congestive heart failure (see section 4.4) |
Respiratory, thoracic and mediastinal disorders: | |
Uncommon: | Interstitial lung disease (including pneumonitis and pulmonary fibrosis)* |
Hepatobiliary disorders: | |
Rare: | Elevated liver enzymes, autoimmune hepatitis |
Skin and subcutaneous tissue disorders: | |
Common: | Pruritus |
Uncommon: | Angioedema, urticaria, rash, psoriasiform rash, psoriasis (including new onset or |
| worsening and pustular, primarily palms and soles) |
Rare: | Cutaneous vasculitis (including leukocytoclastic vasculitis), |
| syndrome, erythema multiforme |
Very rare: | Toxic epidermal necrolysis |
Musculoskeletal and connective tissue disorders: | |
Rare: | Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, |
| syndrome |
General disorders and administration site conditions:
Very common: Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)*
Common: Fever
*see Description of selected adverse reactions, below.
Description of selected adverse reactions
Malignancies and lymphoproliferative disorders
One hundred and
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 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 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.
In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with LIFMIOR developed injection site reactions compared with 3.4% of
Serious infections
In
There were no differences in rates of infection among patients treated with LIFMIOR and those treated with placebo for plaque psoriasis in
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
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
There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a
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
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).
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
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,
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
Undesirable effects in paediatric patients with plaque psoriasis
In a
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
No
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha
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
TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on
Mechanism of action
Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by
Clinical efficacy and safety
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
Adult patients with rheumatoid arthritis
The efficacy of LIFMIOR was assessed in a randomised,
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 Rheumatology (ACR) response criteria.
ACR 20 and 50 responses were higher in patients treated with LIFMIOR at 3 and 6 months than in patients treated with placebo (ACR 20: LIFMIOR 62% and 59%, placebo 23% and 11% at 3 and 6 months, respectively: ACR 50: LIFMIOR 41% and 40%, placebo 8% and 5% at months 3 and 6,
respectively; p<0.01 LIFMIOR vs. placebo at all timepoints for both ACR 20 and ACR 50 responses).
Approximately 15% of subjects who received LIFMIOR achieved an ACR 70 response at month 3 and month 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receiving LIFMIOR, the clinical responses 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 response criteria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), which included disability, vitality, mental health, general health status, and
After discontinuation of LIFMIOR, symptoms of arthritis generally returned within a month.
The efficacy of LIFMIOR was compared to methotrexate in a randomised,
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 Total 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. LIFMIOR
25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. The differences in TSS and JSN were not statistically significant between methotrexate and LIFMIOR 25 mg. The results are shown in the figure below.
Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate in Patients with RA of <3 Years Duration
Change from Baseline
2.5 |
| 12 Months |
| 2.5 | 2.2 | 24 Months |
|
|
|
|
|
|
|
| |
2.0 |
|
|
| 2.0 |
|
|
|
1.5 | 1.3 |
|
| 1.5 | 1.2 | 1.3 |
|
|
|
|
|
|
|
| |
1.0 | 0.8 | 0.9 |
| 1.0 |
|
| 0.9 |
|
|
| 0.6* | 0.6 | |||
|
| 0.4* | 0.4 0.4 |
|
| ||
0.5 |
| 0.5 |
|
|
| ||
0.0 |
|
|
| 0.0 |
|
|
|
| TSS | Erosions | JSN |
| TSS | Erosions | JSN |
|
|
|
| MTX |
|
|
|
|
|
|
| LIFMIOR 25 mg |
|
|
|
|
|
|
| *p < 0.05 |
|
|
|
In another
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. LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration
|
|
| LIFMIOR + |
Endpoint | Methotrexate | LIFMIOR | Methotrexate |
| (n = 228) | (n = 223) | (n = 231) |
ACR Responsesa |
|
| 74.5% †, |
ACR 20 | 58.8% | 65.5% | |
ACR 50 | 36.4% | 43.0% | 63.2% †, |
ACR 70 | 16.7% | 22.0% | 39.8% †, |
DAS |
|
|
|
Baseline scoreb | 5.5 | 5.7 | 5.5 |
Week 52 scoreb | 3.0 | 3.0 | 2.3†, |
Remissionc | 14% | 18% | 37%†, |
HAQ |
|
|
|
Baseline | 1.7 | 1.7 | 1.8 |
Week 52 | 1.1 | 1.0 | 0.8†, |
a:Patients who did not complete 12 months in the study were considered to be
b:Values for Disease Activity Score (DAS) are means.
c:Remission is defined as DAS <1.6.
Pairwise comparison
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
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
The safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly were evaluated in a
25 mg/ml.
Adult patients with psoriatic arthritis
The efficacy of LIFMIOR was assessed in a randomised,

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
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
| Percent of Patients | |
| Placebo | LIFMIORa |
Psoriatic Arthritis Response | n = 104 | n = 101 |
ACR 20 |
| 59b |
Month 3 | ||
Month 6 | 50b | |
ACR 50 |
| 38b |
Month 3 | ||
Month 6 | 37b | |
ACR 70 |
| 11b |
Month 3 | ||
Month 6 | 9c | |
PsARC |
| 72b |
Month 3 | ||
Month 6 | 70b |
a:25 mg LIFMIOR SC twice weekly
b:p < 0.001, LIFMIOR vs. placebo
c:p < 0.01, LIFMIOR vs. placebo
Among patients with psoriatic arthritis who received LIFMIOR, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. LIFMIOR was significantly better than placebo in all measures of disease activity (p < 0.001), and responses were similar with and without concomitant methotrexate therapy. Quality of life in psoriatic arthritis patients was assessed at every timepoint using the disability index of the HAQ. The disability index score was significantly improved at all timepoints in psoriatic arthritis patients treated with LIFMIOR, relative to placebo (p < 0.001).
Radiographic changes were assessed in the psoriatic arthritis study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. The modified TSS at 12 months is presented in the table below. 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 12 months 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 Change from Baseline in Total Sharp Score
| Placebo | Etanercept |
Time | (n = 104) | (n = 101) |
Month 12 | 1.00 (0.29) |
SE = standard error. a. p = 0.0001.
LIFMIOR treatment resulted in improvement in physical function during the
There is insufficient evidence of the efficacy of LIFMIOR in patients with ankylosing
No study has been performed in patients with psoriatic arthritis using the 50 mg
Adult patients with ankylosing spondylitis
The efficacy of LIFMIOR in ankylosing spondylitis was assessed in 3 randomised,
The primary measure of efficacy (ASAS 20) was a 20% improvement in at least 3 of the 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 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.

Responses of Patients with Ankylosing Spondylitis in a
| Percent of Patients | |
Ankylosing Spondylitis | Placebo | LIFMIOR |
Response | N = 139 | N = 138 |
ASAS 20 |
|
|
2 weeks | 46a | |
3 months | 60a | |
6 months | 58a | |
|
|
|
ASAS 50 |
|
|
2 weeks | 24a | |
3 months | 45a | |
6 months | 42a | |
|
|
|
ASAS 70 |
|
|
2 weeks | 12b | |
3 months | 29b | |
6 months | 28b | |
|
|
|
a:p <0.001, LIFMIOR vs. placebo
b:p = 0.002, LIFMIOR vs. placebo
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
Adult patients with
The efficacy of LIFMIOR in patients with
215 adult patients (modified
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 | LIFMIOR | |
Responses at Week 12 | N=106 to 109* | N=103 to 105* |
ASAS** 40 | 15.7 | 32.4b |
ASAS 20 | 36.1 | 52.4c |
10.4 | 33.0a | |
ASAS partial remission | 11.9 | 24.8c |
BASDAI***50 | 23.9 | 43.8b |
*Some patients did not provide complete data for each endpoint **ASAS=Assessments in Spondyloarthritis International Society
***Bath Ankylosing Spondylitis Disease Activity Index
a: p <0.001, b:<0.01 and c:<0.05, respectively between LIFMIOR and placebo
At week 12, there was a statistically significant 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 SPARCC score measured on MRI for all
LIFMIOR showed statistically significantly greater improvement from baseline to week 12 compared to placebo in most
Clinical responses among
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 assessed in four randomised,
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
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.
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
Study 4 evaluated 142 patients and had similar inclusion criteria to studies 2 and 3. Patients in this study received a dose of 50 mg LIFMIOR or placebo once weekly for 12 weeks and then all patients received
In study 1, the
Responses of Patients with Psoriasis in Studies 2, 3 and 4
|
| Study 2 |
|
|
| Study 3 |
|
| Study 4 |
| |
|
|
|
| ||||||||
|
| 25 mg | 50 mg |
| 25 mg | 50 mg |
| 50 mg | 50 mg | ||
| Placebo | BIW | BIW | Placebo | BIW | BIW | Placebo | QW | QW | ||
| n = 166 | n = | n = | n = | n = | n = 193 | n = 196 | n = 196 | n = 46 | n = 96 | n = 90 |
| wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk 24a | ||||
Respons |
| wk | wk | wk | wk |
|
|
|
|
|
|
e (%) |
| 24a | 24a |
|
|
|
|
|
| ||
PASI 50 | 58* | 74* | 64* | 77* | 69* | ||||||
PASI 75 | 34* | 49* | 34* | 49* | 38* | ||||||
DSGA b, |
|
|
|
|
|
|
|
|
|
|
|
clear or |
|
|
|
|
|
|
|
|
|
|
|
almost |
|
|
|
|
|
|
|
|
|
|
|
clear | 34* | 49* | 39* | 57* | 39* |
*p 0.0001 compared with placebo
a.No statistical comparisons to placebo were made at week 24 in studies 2 and 4 because the original placebo group began receiving LIFMIOR 25 mg BIW or 50 mg once weekly from week 13 to week 24.
b.Dermatologist Static Global Assessment. Clear or almost clear defined as 0 or 1 on a 0 to 5 scale.
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
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
In
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 etanercept. These antibodies have all been
In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of
The proportion of subjects who developed antibodies to etanercept in
In a
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
The safety and efficacy of LIFMIOR were assessed in a
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
In another
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
Paediatric patients with plaque psoriasis
The efficacy of LIFMIOR was assessed in a randomised,
Patients received LIFMIOR 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomised to LIFMIOR had positive efficacy responses (e.g., PASI 75) than those randomised to placebo.
Paediatric Plaque Psoriasis Outcomes at 12 Weeks
| LIFMIOR |
|
| 0.8 mg/kg Once |
|
| Weekly | Placebo |
| (N = 106) | (N = 105) |
PASI 75, n (%) | 60 (57%)a | 12 (11%) |
PASI 50, n (%) | 79 (75%)a | 24 (23%) |
sPGA “clear” or “minimal”, n (%) | 56 (53%)a | 14 (13%) |
Abbreviation:
After the
During a randomised withdrawal period, significantly more patients
The
5.2 Pharmacokinetic properties
Etanercept serum values were determined by an
Absorption
Etanercept 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
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,
In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady state AUCs were 466 g 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
Elimination
Etanercept is cleared slowly from the body. The
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 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.
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.
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
In a
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
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
5.3 Preclinical safety data
In the toxicological studies with LIFMIOR, no
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 elicit
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sucrose
Sodium chloride
Sodium phosphate monobasic dihydrate
Sodium phosphate dibasic dihydrate
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
30 months.
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 used within four weeks of removal from refrigeration.
Keep the
6.5 Nature and contents of container
25 mg solution for injection in
Clear glass syringe (type I glass) with stainless steel needle, rubber needle cover and plastic plunger. Cartons contain 4, 8 or 24
50 mg solution for injection in
Clear glass syringe (type I glass) with stainless steel needle, rubber needle cover and plastic plunger. Cartons contain 2, 4 or 12
6.6 Special precautions for disposal and other handling
Before injection, LIFMIOR
Comprehensive instructions for administration are given in the package leaflet, section 7, "Instructions for preparation 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
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)
25 mg solution for injection in
EU/1/16/1165/006
EU/1/16/1165/007
50 mg solution for injection in
EU/1/16/1165/009
EU/1/16/1165/010
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: {DD month YYYY}
Date of last renewal: {DD month YYYY}
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
LIFMIOR 50 mg solution for injection in
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each
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
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
The solution is clear, and colourless or pale yellow.
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
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
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
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 of peripheral joint damage as measured by
Axial spondyloarthritis
Ankylosing spondylitis (AS)
Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Treatment of adults with severe
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
Paediatric plaque psoriasis
Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.
4.2 Posology and method of administration
LIFMIOR treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis,
The LIFMIOR
Posology
Rheumatoid arthritis
25 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
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
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 adults
Paediatric population
The dosage of LIFMIOR is based on body weight for paediatric patients. Patients weighing less than 62.5 kg should be accurately dosed on a mg/kg basis using the powder and solvent for solution for injection presentations or the powder for solution for injection presentations (see below for dosing for specific indication). Patients weighing 62.5 kg or more, may be dosed using a
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
The 10 mg vial strength may be more appropriate for administration to children with JIA below the 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).
There is generally no applicable use of LIFMIOR in children aged below 2 years in the indication juvenile idiopathic arthritis.
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
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
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
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 in delay of appropriate treatment and 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.
Tuberculosis
Cases of active tuberculosis including miliary tuberculosis and tuberculosis with
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
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
All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g., persistent cough, wasting/weight loss,
Hepatitis B reactivation
Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant
Worsening of hepatitis C
There have been reports of worsening of hepatitis C in patients receiving LIFMIOR. LIFMIOR should 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 use of 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).
Allergic reactions
Allergic reactions associated with LIFMIOR administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, LIFMIOR therapy should be discontinued immediately and appropriate therapy initiated.
The needle cap of the
Immunosuppression
The possibility exists for
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
Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with
Skin cancers
Melanoma and
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 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
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 very rare reports of peripheral demyelinating polyneuropathies (including
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.
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
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
Alcoholic hepatitis
In a phase II randomised
Wegener's granulomatosis
A
duration of 25 months, has not shown LIFMIOR to be an effective treatment for Wegener’s granulomatosis. The incidence of
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
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 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
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 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.
In clinical trials, no interactions have been observed when LIFMIOR was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal
No clinically significant pharmacokinetic
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should be advised to use appropriate contraception to avoid becoming 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. A higher rate of major birth defects was observed in an observational study comparing pregnancies exposed to etanercept during the first trimester, with pregnancies not exposed to etanercept or other
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.
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 medicinal products, can be excreted in human milk, a decision must be made whether to discontinue
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 machines have been performed.
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever.
Serious adverse reactions have also been reported for LIFMIOR.
fatal and
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,
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); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Infections and infestations:
Very common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin
| infections)* |
Uncommon: | Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis and parasitic |
| infection)* |
Rare: | Tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial, |
| atypical mycobacterial, viral infections, and Legionella)* |
Not known: | Listeria, hepatitis B reactivation |
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Uncommon: | |
Rare: | Lymphoma, melanoma (see section 4.4) |
Not known: | Leukaemia, Merkel cell carcinoma (see section 4.4) |
Blood and lymphatic system disorders: | |
Uncommon: | Thrombocytopenia |
Rare: | Anaemia, leukopenia, neutropenia, pancytopenia* |
Very rare: | Aplastic anaemia* |
Immune system disorders: | |
Common: | Allergic reactions (see Skin and subcutaneous tissue disorders), autoantibody |
| formation* |
Uncommon: | Systemic vasculitis (including |
Rare: | Serious allergic/anaphylactic reactions (including angioedema, bronchospasm), |
| sarcoidosis |
Not known: | Macrophage activation syndrome*, worsening of symptoms of dermatomyositis |
Nervous system disorders: | |
Rare: | Seizures |
| CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating |
| conditions such as optic neuritis and transverse myelitis (see section 4.4) |
Very rare: | Peripheral demyelinating events, including |
| inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and |
| multifocal motor neuropathy (see section 4.4) |
Eye disorders:
Uncommon: Uveitis, scleritis
Cardiac disorders:
Rare: | Congestive heart failure (see section 4.4) |
Respiratory, thoracic and mediastinal disorders: | |
Uncommon: | Interstitial lung disease (including pneumonitis and pulmonary fibrosis)* |
Hepatobiliary disorders: | |
Rare: | Elevated liver enzymes, autoimmune hepatitis |
Skin and subcutaneous tissue disorders: | |
Common: | Pruritus |
Uncommon: | Angioedema, urticaria, rash, psoriasiform rash, psoriasis (including new onset or |
| worsening and pustular, primarily palms and soles) |
Rare: | Cutaneous vasculitis (including leukocytoclastic vasculitis), |
| syndrome, erythema multiforme |
Very rare: | Toxic epidermal necrolysis |
Musculoskeletal and connective tissue disorders: | |
Rare: | Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, |
| syndrome |
General disorders and administration site conditions:
Very common: Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)*
Common: Fever
*see Description of selected adverse reactions, below.
Description of selected adverse reactions
Malignancies and lymphoproliferative disorders
One hundred and
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 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 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.
In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with LIFMIOR developed injection site reactions compared with 3.4% of
Serious infections
In
There were no differences in rates of infection among patients treated with LIFMIOR and those treated with placebo for plaque psoriasis in
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
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
There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a
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
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).
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
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,
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
Undesirable effects in paediatric patients with plaque psoriasis
In a
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
No
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, Tumor Necrosis Factor alpha
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
TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on
- Benepali - L04AB01
- Enbrel - L04AB01
- Erelzi - L04AB01
Prescription drugs listed. ATC Code: "L04AB01"
Mechanism of action
Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by
Clinical efficacy and safety
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
Adult patients with rheumatoid arthritis
The efficacy of LIFMIOR was assessed in a randomised,
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 Rheumatology (ACR) response criteria.
ACR 20 and 50 responses were higher in patients treated with LIFMIOR at 3 and 6 months than in patients treated with placebo (ACR 20: LIFMIOR 62% and 59%, placebo 23% and 11% at 3 and 6 months respectively: ACR 50: LIFMIOR 41% and 40%, placebo 8% and 5% at months 3 and 6,
respectively; p<0.01 LIFMIOR vs placebo at all timepoints for both ACR 20 and ACR 50 responses).
Approximately 15% of subjects who received LIFMIOR achieved an ACR 70 response at month 3 and month 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receiving LIFMIOR, the clinical responses 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 response criteria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), which included disability, vitality, mental health, general health status, and
After discontinuation of LIFMIOR, symptoms of arthritis generally returned within a month.
The efficacy of LIFMIOR was compared to methotrexate in a randomised,
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 Total 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. LIFMIOR
25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. The differences in TSS and JSN were not statistically significant between methotrexate and LIFMIOR 25 mg. The results are shown in the figure below.

Radiographic Progression: Comparison of LIFMIOR vs Methotrexate in Patients with RA of <3 Years Duration
Change from Baseline
2.5 |
| 12 Months |
| 2.5 | 2.2 | 24 Months |
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1.0 | 0.8 | 0.9 |
| 1.0 |
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0.0 |
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| TSS | Erosions | JSN |
| TSS | Erosions | JSN |
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| LIFMIOR 25 mg |
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| *p < 0.05 |
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In another
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 LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration
|
|
| LIFMIOR + |
Endpoint | Methotrexate | LIFMIOR | Methotrexate |
| (n = 228) | (n = 223) | (n = 231) |
ACR Responsesa |
|
| 74.5% †, |
ACR 20 | 58.8% | 65.5% | |
ACR 50 | 36.4% | 43.0% | 63.2% †, |
ACR 70 | 16.7% | 22.0% | 39.8% †, |
DAS |
|
|
|
Baseline scoreb | 5.5 | 5.7 | 5.5 |
Week 52 scoreb | 3.0 | 3.0 | 2.3†, |
Remissionc | 14% | 18% | 37%†, |
HAQ |
|
|
|
Baseline | 1.7 | 1.7 | 1.8 |
Week 52 | 1.1 | 1.0 | 0.8†, |
a:Patients who did not complete 12 months in the study were considered to be
b:Values for Disease Activity Score (DAS) are means.
c:Remission is defined as DAS <1.6
Pairwise comparison
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 < 0.05 for comparisons of LIFMIOR + methotrexate vs methotrexate and = 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
The safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly were evaluated in a
25 mg/ml.
Adult patients with psoriatic arthritis
The efficacy of LIFMIOR was assessed in a randomised,

(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
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
| Percent of Patients | |
| Placebo | LIFMIORa |
Psoriatic Arthritis Response | n = 104 | n = 101 |
ACR 20 |
| 59b |
Month 3 | ||
Month 6 | 50b | |
ACR 50 |
| 38b |
Month 3 | ||
Month 6 | 37b | |
ACR 70 |
| 11b |
Month 3 | ||
Month 6 | 9c | |
PsARC |
| 72b |
Month 3 | ||
Month 6 | 70b |
a:25 mg LIFMIOR SC twice weekly
b:p < 0.001, LIFMIOR vs. placebo
c:p < 0.01, LIFMIOR vs. placebo
Among patients with psoriatic arthritis who received LIFMIOR, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. LIFMIOR was significantly better than placebo in all measures of disease activity (p < 0.001), and responses were similar with and without concomitant methotrexate therapy. Quality of life in psoriatic arthritis patients was assessed at every timepoint using the disability index of the HAQ. The disability index score was significantly improved at all timepoints in psoriatic arthritis patients treated with LIFMIOR, relative to placebo (p < 0.001).
Radiographic changes were assessed in the psoriatic arthritis study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. The modified TSS at 12 months is presented in the Table below. 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 12 months 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 Change from Baseline in Total Sharp Score
| Placebo | Etanercept |
Time | (n = 104) | (n = 101) |
Month 12 | 1.00 (0.29) |
SE = standard error. a. p = 0.0001.
LIFMIOR treatment resulted in improvement in physical function during the
There is insufficient evidence of the efficacy of LIFMIOR in patients with ankylosing
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,
The primary measure of efficacy (ASAS 20) was a 20% improvement in at least 3 of the 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 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.

Responses of Patients with Ankylosing Spondylitis in a
| Percent of Patients | |
| Placebo | LIFMIOR |
Ankylosing Spondylitis | N = 139 | N = 138 |
Response |
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ASAS 20 |
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2 weeks | 46a | |
3 months | 60a | |
6 months | 58a | |
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ASAS 50 |
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2 weeks | 24a | |
3 months | 45a | |
6 months | 42a | |
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ASAS 70: |
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2 weeks | 12b | |
3 months | 29b | |
6 months | 28b | |
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a:p <0.001, LIFMIOR vs. Placebo
b:p = 0.002, LIFMIOR vs. placebo
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
Adult patients with
The efficacy of LIFMIOR in patients with
215 adult patients (modified
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 | LIFMIOR | |
Responses at Week 12 | N=106 to 109* | N=103 to 105* |
ASAS** 40 | 15.7 | 32.4b |
ASAS 20 | 36.1 | 52.4c |
10.4 | 33.0a | |
ASAS partial remission | 11.9 | 24.8c |
BASDAI***50 | 23.9 | 43.8b |
*Some patients did not provide complete data for each endpoint **ASAS=Assessments in Spondyloarthritis International Society
***Bath Ankylosing Spondylitis Disease Activity Index
a: p<0.001, b:<0.01 and c:<0.05, respectively between LIFMIOR and placebo
At week 12, there was a statistically significant 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 SPARCC score measured on MRI for all
LIFMIOR showed statistically significantly greater improvement from baseline to week 12 compared to placebo in most
Clinical responses among
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 assessed in four randomised,
Study 1 was a Phase 2 study in patients with active but clinically stable plaque psoriasis involving 10% of the body surface area that 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
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.
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
Study 4 evaluated 142 patients and had similar inclusion criteria to studies 2 and 3. Patients in this study received a dose of 50 mg LIFMIOR or placebo once weekly for 12 weeks and then all patients received
In study 1, the
Responses of Patients with Psoriasis in Studies 2, 3 And 4
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| 25 mg | 50 mg |
| 25 mg | 50 mg |
| 50 mg | 50 mg | ||
| Placebo | BIW | BIW | Placebo | BIW | BIW | Placebo | QW | QW | ||
| n = 166 | n = | n = | n = | n = | n = 193 | n = 196 | n = 196 | n = 46 | n = 96 | n = 90 |
| wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk 24a | ||||
Respons |
| wk | wk | wk | wk |
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e (%) |
| 24a | 24a |
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PASI 50 | 58* | 74* | 64* | 77* | 69* | ||||||
PASI 75 | 34* | 49* | 34* | 49* | 38* | ||||||
DSGA b, |
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clear or |
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almost |
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clear | 34* | 49* | 39* | 57* | 39* |
*p 0.0001 compared with placebo
a.No statistical comparisons to placebo were made at week 24 in studies 2 and 4 because the original placebo group began receiving LIFMIOR 25 mg BIW or 50 mg once weekly from week 13 to week 24.
b.Dermatologist Static Global Assessment. Clear or almost clear defined as 0 or 1 on a 0 to 5 scale.
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
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
In
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 etanercept. These antibodies have all been
In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of
The proportion of subjects who developed antibodies to etanercept in
In a
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
The safety and efficacy of LIFMIOR were assessed in a
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
In another
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
Paediatric patients with plaque psoriasis
The efficacy of LIFMIOR was assessed in a randomised,
Patients received LIFMIOR 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomised to LIFMIOR had positive efficacy responses (e.g. PASI 75) than those randomised to placebo.
Paediatric Plaque Psoriasis Outcomes at 12 Weeks
| LIFMIOR |
|
| 0.8 mg/kg Once |
|
| Weekly | Placebo |
| (N = 106) | (N = 105) |
PASI 75, n (%) | 60 (57%)a | 12 (11%) |
PASI 50, n (%) | 79 (75%)a | 24 (23%) |
sPGA “clear” or “minimal”, n (%) | 56 (53%)a | 14 (13%) |
Abbreviation:
After the
During a randomised withdrawal period, significantly more patients
The
5.2 Pharmacokinetic properties
Etanercept serum values were determined by an
Absorption
Etanercept 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
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,
In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady state AUCs were 466 g 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
Elimination
Etanercept is cleared slowly from the body. The
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 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.
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.
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
In a
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
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 elicit
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sucrose
Sodium chloride
Sodium phosphate monobasic dihydrate
Sodium phosphate dibasic dihydrate
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
30 months.
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 used within four weeks of removal from refrigeration.
Keep the
6.5 Nature and contents of container
Cartons contain 2, 4 or 12
6.6 Special precautions for disposal and other handling
Instructions for use and handling
Before injection, LIFMIOR
Comprehensive instructions for administration are given in the package leaflet, section 7, "Using the MYCLIC
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)
EU/1/16/1165/011EU/1/16/1165/012
EU/1/16/1165/013
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: {DD month YYYY}
Date of last renewal: {DD month YYYY}
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
LIFMIOR 10 mg powder and solvent for solution for injection for paediatric use.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 10 mg of etanercept. When reconstituted, the solution contains 10 mg/ml 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
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
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
LIFMIOR has not been studied in children aged less than 2 years.
Paediatric plaque psoriasis
Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.
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 less. Each vial of LIFMIOR 10 mg should be used on a single occasion in a single patient, and the remainder of the vial 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
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).
There is generally no applicable use of LIFMIOR in children aged below 2 years in the indication juvenile idiopathic arthritis.
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
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. 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
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
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 in delay of appropriate treatment and 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.
Tuberculosis
Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with
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
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
All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g., persistent cough, wasting/weight loss,
Hepatitis B reactivation
Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant
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
Worsening of hepatitis C
There have been reports of worsening of hepatitis C in patients receiving LIFMIOR. LIFMIOR should 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 use of 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).
Allergic reactions
Allergic reactions associated with LIFMIOR administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, LIFMIOR therapy should be discontinued immediately and appropriate therapy initiated.
Immunosuppression
The possibility exists for
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
Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with
Skin cancers
Melanoma and
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 with LIFMIOR. No data are available on the secondary transmission of infection by live vaccines in patients receiving LIFMIOR. In a
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 very rare reports of peripheral demyelinating polyneuropathies (including
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.
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
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
Alcoholic hepatitis
In a phase II randomised
Wegener's granulomatosis
A
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
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 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
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 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.
In clinical trials, no interactions have been observed when LIFMIOR was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal
No clinically significant pharmacokinetic
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should be advised to use appropriate contraception to avoid becoming 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. A higher rate of major birth defects was observed in an observational study comparing pregnancies exposed to etanercept during the first trimester, with pregnancies not exposed to etanercept or other
general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. LIFMIOR is not recommended during pregnancy.
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.
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 medicinal products, can be excreted in human milk, a decision must be made whether to discontinue
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 machines have been performed.
4.8 Undesirable effects
Summary of the safety profile
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 (see below, Undesirable effects in adults). 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
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,
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
Undesirable effects in paediatric patients with plaque psoriasis
In a
Adult population
Undesirable effects in adults
The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever.
Serious adverse reactions have also been reported for LIFMIOR.
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,
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); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Infections and infestations:
Very common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin
| infections)* |
Uncommon: | Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis and parasitic |
| infection)* |
Rare: | Tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial, |
| atypical mycobacterial, viral infections, and Legionella)* |
Not known: | Listeria, hepatitis B reactivation |
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Uncommon: | |
Rare: | Lymphoma, melanoma (see section 4.4) |
Not known: | Leukaemia, Merkel cell carcinoma (see section 4.4) |
Blood and lymphatic system disorders: | |
Uncommon: | Thrombocytopenia |
Rare: | Anaemia, leukopenia, neutropenia, pancytopenia* |
Very rare: | Aplastic anaemia* |
Immune system disorders: | |
Common: | Allergic reactions (see Skin and subcutaneous tissue disorders), autoantibody |
| formation* |
Uncommon: | Systemic vasculitis (including |
Rare: | Serious allergic/anaphylactic reactions (including angioedema, bronchospasm), |
| sarcoidosis |
Not known: | Macrophage activation syndrome†, worsening of symptoms of dermatomyositis |
Nervous system disorders: | |
Rare: | Seizures |
| CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating |
| conditions, such as optic neuritis and transverse myelitis (see section 4.4) |
Very rare: | Peripheral demyelinating events, including |
| inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and |
| multifocal motor neuropathy (see section 4.4) |
Eye disorders: |
|
Uncommon: | Uveitis, scleritis |
Cardiac disorders:
Rare: | Congestive heart failure (see section 4.4) |
Respiratory, thoracic and mediastinal disorders: | |
Uncommon: | Interstitial lung disease (including pneumonitis and pulmonary fibrosis)* |
Hepatobiliary disorders: | |
Rare: | Elevated liver enzymes, autoimmune hepatitis |
Skin and subcutaneous tissue disorders: | |
Common: | Pruritus |
Uncommon: | Angioedema, urticaria, rash, psoriasiform rash, psoriasis (including new onset or |
| worsening and pustular, primarily palms and soles) |
Rare: | Cutaneous vasculitis (including leukocytoclastic vasculitis), |
| syndrome, erythema multiforme |
Very rare: | Toxic epidermal necrolysis |
Musculoskeletal and connective tissue disorders: | |
Rare: | Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, |
| syndrome |
General disorders and administration site conditions:
Very common: Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)*
Common: Fever
*see Description of selected adverse reactions, below.
† Please see
Description of selected adverse reactions
Malignancies and lymphoproliferative disorders
One hundred and
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 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 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.
In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with LIFMIOR developed injection site reactions compared with 3.4% of
Serious infections
In
There were no differences in rates of infection among patients treated with LIFMIOR and those treated with placebo for plaque psoriasis in
shock, diverticulitis and abscess. In the
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
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
There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a
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
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).
Paediatric population
See Summary of the safety profile, above.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
No
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha
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
TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on
Mechanism of action
Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by
Clinical efficacy and safety
This section presents data from three studies in juvenile idiopathic arthritis, one study in paediatric patients with plaque psoriasis, four studies in adults with rheumatoid arthritis, and four studies in adults with plaque psoriasis.
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
The safety and efficacy of LIFMIOR were assessed in a
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
In another
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
Paediatric patients with plaque psoriasis
The efficacy of LIFMIOR was assessed in a randomised,

Patients received LIFMIOR 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomised to LIFMIOR had positive efficacy responses (e.g., PASI 75) than those randomised to placebo.
Paediatric Plaque Psoriasis Outcomes at 12 Weeks
| LIFMIOR |
|
| 0.8 mg/kg Once |
|
| Weekly | Placebo |
| (N = 106) | (N = 105) |
PASI 75, n (%) | 60 (57%)a | 12 (11%) |
PASI 50, n (%) | 79 (75%)a | 24 (23%) |
sPGA “clear” or “minimal”, n (%) | 56 (53%)a | 14 (13%) |
Abbreviation:
After the
During a randomised withdrawal period, significantly more patients
The
Adult patients with rheumatoid arthritis
The efficacy of LIFMIOR was assessed in a randomised,
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 Rheumatology (ACR) response criteria.
ACR 20 and 50 responses were higher in patients treated with LIFMIOR at 3 and 6 months than in patients treated with placebo (ACR 20: LIFMIOR 62% and 59%, placebo 23% and 11% at 3 and 6 months, respectively: ACR 50: LIFMIOR 41% and 40%, placebo 8% and 5% at months 3 and 6,
respectively; p<0.01 LIFMIOR vs. placebo at all timepoints for both ACR 20 and ACR 50 responses).
Approximately 15% of subjects who received LIFMIOR achieved an ACR 70 response at month 3 and month 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receiving LIFMIOR, the clinical responses 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 response criteria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), which included disability, vitality, mental health, general health status, and
After discontinuation of LIFMIOR, symptoms of arthritis generally returned within a month.

same magnitudes of responses as patients who received LIFMIOR without interruption of therapy based on results of
The efficacy of LIFMIOR was compared to methotrexate in a randomised,
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 Total 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. LIFMIOR
25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. The differences in TSS and JSN were not statistically significant between methotrexate and LIFMIOR 25 mg. The results are shown in the figure below.
Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate in Patients with RA of <3 Years Duration
Change from Baseline
2.5 |
| 12 Months |
| 2.5 | 2.2 | 24 Months |
|
|
|
|
|
|
|
| |
2.0 |
|
|
| 2.0 |
|
|
|
1.5 | 1.3 |
|
| 1.5 | 1.2 | 1.3 |
|
|
|
|
|
|
|
| |
1.0 | 0.8 | 0.9 |
| 1.0 |
|
| 0.9 |
|
|
| 0.6* | 0.6 | |||
|
| 0.4* | 0.4 0.4 |
|
| ||
0.5 |
| 0.5 |
|
|
| ||
0.0 |
|
|
| 0.0 |
|
|
|
| TSS | Erosions | JSN |
| TSS | Erosions | JSN |
|
|
|
| MTX |
|
|
|
|
|
|
| LIFMIOR 25 mg |
|
|
|
|
|
|
| *p < 0.05 |
|
|
|
In another
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. LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration
|
|
| LIFMIOR + |
Endpoint | Methotrexate | LIFMIOR | Methotrexate |
| (n = 228) | (n = 223) | (n = 231) |
ACR Responsesa |
|
| 74.5% †, |
ACR 20 | 58.8% | 65.5% | |
ACR 50 | 36.4% | 43.0% | 63.2% †, |
ACR 70 | 16.7% | 22.0% | 39.8% †, |
DAS |
|
|
|
Baseline scoreb | 5.5 | 5.7 | 5.5 |
Week 52 scoreb | 3.0 | 3.0 | 2.3†, |
Remissionc | 14% | 18% | 37%†, |
HAQ |
|
|
|
Baseline | 1.7 | 1.7 | 1.8 |
Week 52 | 1.1 | 1.0 | 0.8†, |
a:Patients who did not complete 12 months in the study were considered to be non- responders.
b:Values for Disease Activity Score (DAS) are means.
c:Remission is defined as DAS <1.6.
Pairwise comparison
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
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
The safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly were evaluated in a
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 assessed in four randomised,
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
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
Study 4 evaluated 142 patients and had similar inclusion criteria to studies 2 and 3. Patients in this study received a dose of 50 mg LIFMIOR or placebo once weekly for 12 weeks and then all patients received
In study 1, the
Responses of Patients with Psoriasis in Studies 2, 3 and 4
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| Placebo | BIW | BIW | Placebo | BIW | BIW | Placebo | QW | QW | ||
| n = 166 | n = | n = | n = | n = | n = 193 | n = 196 | n = 196 | n = 46 | n = 96 | n = 90 |
| wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk 24a | ||||
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PASI 50 | 58* | 74* | 64* | 77* | 69* | ||||||
PASI 75 | 34* | 49* | 34* | 49* | 38* | ||||||
DSGA b, |
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clear or |
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almost |
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clear | 34* | 49* | 39* | 57* | 39* |
*p 0.0001 compared with placebo
a.No statistical comparisons to placebo were made at week 24 in studies 2 and 4 because the original placebo group began receiving LIFMIOR 25 mg BIW or 50 mg once weekly from week 13 to week 24.
b.Dermatologist Static Global Assessment. Clear or almost clear defined as 0 or 1 on a 0 to 5 scale.
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
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
In
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 etanercept. These antibodies have all been
In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of
The proportion of subjects who developed antibodies to etanercept in
In a
5.2 Pharmacokinetic properties
Etanercept serum values were determined by an
Special populations
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.
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
In a
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
Adults
Absorption
Etanercept 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
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
In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady state AUCs were 466 g 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
Elimination
Etanercept is cleared slowly from the body. The
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.
5.3 Preclinical safety data
In the toxicological studies with LIFMIOR, no
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 elicit
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Powder
Mannitol (E421)
Sucrose
Trometamol
Solvent
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
3 years.
From a microbiological point of view, the reconstituted medicinal product should be used immediately. Chemical and physical
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 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 stopper, aluminium seal, and
Cartons contain 4 vials of LIFMIOR, 4
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 subcutaneous injection. The solution should be clear and colourless to pale yellow, with no lumps, flakes or particles. Some white foam may remain in the vial – this is normal. LIFMIOR should not be used if all the powder in the vial is not dissolved within 10 minutes. 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 preparation 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
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/16/1165/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: {DD month YYYY}
Date of last renewal: {DD month YYYY}
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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