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
- 5.1 Pharmacodynamic properties
- 1.3
- 0.8
- 0.9
- 0.4*
- 0.4
- 0.4
- 2.80
- 1.68
- 1.12
- 0.52*
- 0.21*
- 0.32
- 0.8 mg/kg Once
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. PHARMACEUTICAL PARTICULARS
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal
- 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
- 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
- 5.1 Pharmacodynamic properties
- 1.3
- 0.8
- 0.9
- 0.4*
- 0.4
- 0.4
- 2.80
- 1.68
- 1.12
- 0.52*
- 0.21*
- 0.32
- 0.8 mg/kg Once
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. PHARMACEUTICAL PARTICULARS
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal
- 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
Benepali 25 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 (injection).
The solution is clear to slightly opalescent, colourless or pale yellow, and is formulated at pH 6.2 ± 0.3. The osmolality of the solution is 325 ± 35 mOsm/kg.
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Rheumatoid arthritis
Benepali in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to
Benepali can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
Benepali is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.
Benepali, 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
Etanercept 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. Etanercept 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
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
Benepali 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,
Benepali is available in strengths of 25 and 50 mg.
Posology
Rheumatoid arthritis
25 mg etanercept 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 etanercept 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 etanercept 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 a dose of 50 mg once weekly. Treatment with Benepali 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
Benepali is only available as 25 mg
Thus, it is not possible to administer Benepali to paediatric patients that require less than a full 25 mg or 50 mg dose. Paediatric patients who require a dose other than a full 25 mg or 50 mg should not receive Benepali. If an alternate dose is required, other etanercept products offering such an option should be used.
The dosage of etanercept 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 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
A 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 etanercept 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 etanercept in children aged below 6 years in the indication plaque psoriasis.
Method of administration
Benepali is for subcutaneous use (see section 6.6).
Comprehensive instructions for administration are given in the package leaflet, section 7, “Instructions for use”.
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 Benepali 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 Benepali, 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 etanercept (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 Benepali should be monitored closely. Administration of Benepali should be discontinued if a patient develops a serious infection. The safety and efficacy of etanercept in patients with chronic infections have not been evaluated. Physicians should exercise caution when considering the use of Benepali 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 Benepali, 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, Benepali 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
Patients should be tested for HBV infection before initiating treatment with Benepali. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when administering Benepali 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 etanercept. Benepali should be used with caution in patients with a history of hepatitis C.
Concurrent treatment with anakinra
Concurrent administration of etanercept and anakinra has been associated with an increased risk of serious infections and neutropenia compared to etanercept alone. This combination has not demonstrated increased clinical benefit. Thus, the combined use of Benepali and anakinra is not recommended (see sections 4.5 and 4.8).
Concurrent treatment with abatacept
In clinical studies, concurrent administration of abatacept and etanercept 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 etanercept administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, Benepali 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 Benepali therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin.
The safety and efficacy of etanercept 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 etanercept compared with control patients, particularly in patients with psoriasis.
Vaccinations
Live vaccines should not be given concurrently with Benepali. No data are available on the secondary transmission of infection by live vaccines in patients receiving etanercept. In a
arthritis patients receiving etanercept were able to mount effective
Autoantibody formation
Treatment with Benepali 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 etanercept. Caution should be exercised in patients being treated with Benepali 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, and paleness) whilst on Benepali, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, Benepali should be discontinued.
Neurological disorders
There have been rare reports of CNS demyelinating disorders in patients treated with etanercept (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 etanercept and methotrexate did not result in unexpected safety findings, and the safety profile of etanercept when given in combination with methotrexate was similar to the profiles reported in studies of etanercept and methotrexate alone.
The use of etanercept 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 Benepali in patients who have congestive heart failure (CHF). There have been
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 etanercept in patients receiving medicinal products 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 etanercept 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 etanercept 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 etanercept (see section 4.8).
Benepali contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially
4.5Interaction with other medicinal products and other forms of interaction
Concurrent treatment with anakinra
Adult patients treated with etanercept and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either etanercept or anakinra alone (historical data).
In addition, in a
Concurrent treatment with abatacept
In clinical studies, concurrent administration of abatacept and etanercept 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 etanercept was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with etanercept 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 etanercept 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 Benepali 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 etanercept 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 Benepali 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 etanercept.
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 etanercept 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 System Organ Class, 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 |
| antibody positive vasculitis) |
|

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 cases 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 |
| syndrome, chronic 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: | Elevated liver enzymes* |
Uncommon: | |
Rare: | 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), |
| |
Very rare: | Toxic epidermal necrolysis |
Musculoskeletal and connective tissue disorders: | |
Rare: | Subacute cutaneous lupus erythematosus, discoid lupus |
| erythematosus, |
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 etanercept 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 etanercept 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 etanercept 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 etanercept developed injection site reactions compared with 3.4% of
Serious infections
In
There were no differences in rates of infection among patients treated with etanercept and those treated with placebo for plaque psoriasis in
Serious and fatal infections have been reported during use of etanercept; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks after initiating treatment with etanercept 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). Benepali treatment may increase mortality in patients with established sepsis.
Opportunistic infections have been reported in association with etanercept, 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 etanercept. The
Pneumocystis, Aspergillus, and Histoplasma. Invasive fungal infections accounted for more than half of the fatalities amongst patients who developed opportunistic infections. The majority of the reports with a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, and aspergillosis (see section 4.4).
Autoantibodies
Adult patients had serum samples tested for autoantibodies at multiple timepoints. Of the rheumatoid arthritis patients evaluated for antinuclear antibodies (ANA), the percentage of patients who developed new positive ANA (≥ 1:40) was higher in patients treated with etanercept (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 etanercept plus anakinra, a higher rate of serious infections compared to etanercept alone was observed and 2% of patients (3/139) developed neutropenia (absolute neutrophil count < 1,000/mm3). While neutropenic, one patient developed cellulitis that resolved after hospitalisation (see sections 4.4 and 4.5).
Elevated liver enzymes
In the
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 etanercept 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 etanercept 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
Benepali is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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
lymphotoxin are
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 etanercept was assessed in a randomised,
25 mg etanercept 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 etanercept at 3 and 6 months than in patients treated with placebo (ACR 20: etanercept 62% and 59%, placebo 23% and 11% at 3 and 6 months, respectively: ACR 50: etanercept 41% and 40%, placebo 8% and 5% at months 3 and 6,
respectively; p < 0.01 etanercept vs. placebo at all timepoints for both ACR 20 and ACR 50 responses).
Approximately 15% of subjects who received etanercept 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 etanercept, 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. Etanercept 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 etanercept, symptoms of arthritis generally returned within a month. Reintroduction of treatment with etanercept after discontinuation of up to 24 months resulted in the same magnitudes of responses as patients who received etanercept without interruption of therapy

based on results of
The efficacy of etanercept was compared to methotrexate in a randomised,
24 months. Methotrexate doses were escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial and continued for up to 24 months. Clinical improvement, including onset of action within 2 weeks with etanercept 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 etanercept 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 etanercept dose had consistently less effect on structural damage than the 25 mg dose. Etanercept 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 etanercept 25 mg. The results are shown in the figure below.
Radiographic progression: Comparison of etanercept vs. methotrexate in patients with RA of < 3 years duration
| 2.5 |
| 12 Months |
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| 2.5 |
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Baseline | 2.0 |
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| 2.0 |
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1.5 | 1.3 |
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| 1.5 | |
from |
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1.0 | 0.8 | 0.9 |
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| 1.0 | |
Change |
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0.5 |
| 0.4* | 0.4 | 0.4 | 0.5 | |
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| 0.0 | TSS | Erosions | JSN | 0.0 | |
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|
24 Months
2.2
1.2 | 1.3 |
|
| 0.9 | |
|
| |
| 0.6* | 0.6 |
TSS | Erosions | JSN |
MTX
Etanercept 25 mg *p < 0.05
In another
Patients in the etanercept 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 etanercept in combination with methotrexate compared with etanercept monotherapy and methotrexate monotherapy were also observed after 24 months.
Clinical Efficacy results at 12 months: Comparison of etanercept vs. methotrexate vs. etanercept in combination with methotrexate in patients with RA of 6 months to 20 years duration
|
| Methotrexate | Etanercept | Etanercept + |
Endpoint |
| Methotrexate | ||
| (n = 228) | (n = 223) | ||
|
| (n = 231) | ||
|
|
|
| |
ACR | ACR 20 | 58.8% | 65.5% | 74.5%†, Φ |
Responsesa | ACR 50 | 36.4% | 43.0% | 63.2%†, Φ |
| ACR 70 | 16.7% | 22.0% | 39.8%†, Φ |
DAS | (Scoreb) Baseline | 5.5 | 5.7 | 5.5 |
| (Scoreb) Week 52 | 3.0 | 3.0 | 2.3†, Φ |
| Remissionc | 14% | 18% | 37%†, Φ |
HAQ | Baseline | 1.7 | 1.7 | 1.8 |
| Week 52 | 1.1 | 1.0 | 0.8†, Φ |
a Patients who did not complete 12 months in the study were considered to be
c Remission is defined as DAS <1.6.
Pairwise comparison
Radiographic progression at 12 months was significantly less in the etanercept 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 etanercept vs. methotrexate vs. etanercept in combination with methotrexate in patients with RA of 6 months to 20 years duration (12 month results)
Change from Baseline
3.0 |
| 2.80 |
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| Methotrexate | |
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| Etanercept | |||
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2.5 |
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2.0 |
| 1.68 |
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1.5 |
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1.0 |
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0.5 | 0.52* | 0.21* | 0.32 | |
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0.0 |
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| † | |||
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TSS | Erosions | JSN | ||
|
Pairwise comparison
Significant advantages for etanercept in combination with methotrexate compared with etanercept monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for etanercept 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 etanercept in combination with methotrexate group compared with the etanercept alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p < 0.05). The difference between etanercept 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 etanercept (two 25 mg SC injections) administered once weekly were evaluated in a
etanercept 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 etanercept was assessed in a randomised,
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 etanercept (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 |
|
Psoriatic Arthritis Response |
| Placebo | Etanercepta |
|
| n = 104 | n = 101 |
ACR 20 | Month 3 | 59b | |
| Month 6 | 50b | |
ACR 50 | Month 3 | 38b | |
| Month 6 | 37b | |
ACR 70 | Month 3 | 11b | |
| Month 6 | 9c | |
PsARC | Month 3 | 72b | |
| Month 6 | 70b | |
a 25 mg etanercept SC twice | weekly |
|
|
b p < 0.001, etanercept vs. placebo |
|
| |
|
|
|
c p < 0.01, etanercept vs. placebo
Among patients with psoriatic arthritis who received etanercept, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. Etanercept 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 etanercept, 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 etanercept group compared with the placebo group (73% vs. 47%, respectively, p ≤ 0.001). The effect of etanercept 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
Time | Placebo | Etanercept | |
(n = 104) | (n = 101) | ||
| |||
Month 12 | 1.00 (0.29) | ||
SE = standard error |
|
| |
a p = 0.0001 |
|
|
Etanercept treatment resulted in improvement in physical function during the
There is insufficient evidence of the efficacy of etanercept 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 etanercept in ankylosing spondylitis was assessed in 3 randomised,
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
- Lifmior - etanercept
- Erelzi - etanercept
- Enbrel - etanercept
Prescription drugs listed. Substance: "Etanercept"
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 etanercept (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 etanercept 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 Response | Placebo | Etanercept | |
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, etanercept vs. placebo |
|
| |
b p = 0.002, etanercept vs. placebo |
|
|
Among patients with ankylosing spondylitis who received etanercept, 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 etanercept (two 25 mg SC injections) administered once weekly vs. 25 mg etanercept administered twice weekly were evaluated in a
Adult patients with
The efficacy of etanercept in patients with
defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meet the modified New York criteria for AS. Patients were also required to have an inadequate response or intolerance to two or more NSAIDs. In the
Compared to placebo, treatment with etanercept 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 | Etanercept | |
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 etanercept 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 etanercept. Adjusted mean change from baseline was 3.8 for etanercept 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
Etanercept showed statistically significantly greater improvement from baseline to week 12 compared to placebo in most
Clinical responses among
Adult patients with plaque psoriasis
Etanercept 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 etanercept versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing etanercept with other systemic therapies. Instead, the safety and efficacy of etanercept 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 etanercept (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.

Etanercept 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 etanercept, 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 etanercept 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 |
| |
| Placebo |
| Etanercept |
| Placebo | Etanercept | Placebo | Etanercept | |||
| 25 mg | 50 mg BIW | 25 mg | 50 mg | 50 mg | 50 mg | |||||
Response |
| BIW |
|
| BIW | BIW |
| QW | QW | ||
|
|
|
|
|
| ||||||
(%) | n = 166 | n = | n = | n = | n = | n = 193 | n = | n = | n = 46 | n = | n = |
| |||||||||||
| wk 12 | wk | wk | wk | wk | wk 12 | wk 12 | wk 12 | wk 12 | wk 12 | wk |
| 24a | 24a | 24a | ||||||||
PASI 50 | 58* | 74* | 64* | 77* | 69* | ||||||
PASI 75 | 34* | 49* | 34* | 49* | 38* |
DSGAb,
clear or 5 34* 39 49* 55 4 39* 57* 4 39* 64 almost
clear
* 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 etanercept 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 etanercept, 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 etanercept 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
PASI 75 at week 24.
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 etanercept
Antibodies to etanercept have been detected in the sera of some subjects treated with etanercept. These antibodies have generally been
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
The safety and efficacy of etanercept 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 etanercept 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 etanercept 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 etanercept 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 etanercept therapy in patients who do not respond within 3 months of initiating etanercept therapy. Additionally, studies have not been conducted to assess the effects of discontinuing or reducing the recommended dose of etanercept following its
Paediatric patients with plaque psoriasis
The efficacy of etanercept was assessed in a randomised,
Patients received etanercept 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At
week 12, more patients randomised to etanercept had positive efficacy responses (e.g., PASI 75) than those randomised to placebo.
Paediatric Plaque Psoriasis Outcomes at 12 Weeks
| Etanercept |
|
| 0.8 mg/kg Once | Placebo |
| Weekly | (N = 105) |
| (N = 106) |
|
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
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 mg × hr/l vs. 316 mg × hr/l for 50 mg etanercept once weekly (n = 21) vs. 25 mg etanercept
twice weekly (n = 16), respectively. In an
In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady state AUCs were 466 μg × hr/ml and 474 μg × hr/ml for 50 mg etanercept 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 etanercept 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 etanercept/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 etanercept, no
Etanercept did not induce lethality or notable signs of toxicity in mice or rats following a single subcutaneous dose of 2,000 mg/kg or a single intravenous dose of 1,000 mg/kg. Etanercept did not elicit
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Sucrose
Sodium chloride
Sodium dihydrogen phosphate monohydrate
Disodium hydrogen phosphate heptahydrate
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
30 months.
6.4Special precautions for storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep the
After taking a syringe from the refrigerator, wait approximately 30 minutes to allow the Benepali solution in the syringe to reach room temperature. Do not warm in any other way. Immediate use is then recommended.
Benepali 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. Benepali should be discarded if not used within four weeks of removal from refrigeration.
6.5Nature and contents of container
Clear glass (type I)
Benepali is available in packs containing 4
6.6Special precautions for disposal
Before injection, Benepali
Comprehensive instructions for administration are given in the package leaflet, section 7, ”Instructions for use”.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Samsung Bioepis UK Limited 5th floor
Profile West
950 Great West Road Brentford Middlesex TW8 9ES United Kingdom
8.MARKETING AUTHORISATION NUMBER(S)
EU/1/15/1074/005
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 14 January 2016
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
Benepali 50 mg solution for injection in
Benepali 50 mg solution for injection in
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
50 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 (injection).
The solution is clear to slightly opalescent, colourless or pale yellow, and is formulated at pH 6.2 ± 0.3. The osmolality of the solution is 325 ± 35 mOsm/kg.
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Rheumatoid arthritis
Benepali in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to
Benepali can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
Benepali is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.
Benepali, 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
Etanercept 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. Etanercept 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
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
Benepali 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,
Benepali is available in strengths of 25 and 50 mg.
Posology
Rheumatoid arthritis
The recommended dose is 50 mg etanercept administered once weekly (see section 5.1).
Psoriatic arthritis, ankylosing spondylitis and
The recommended dose is 50 mg etanercept 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 etanercept is 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 50 mg once weekly. Treatment with Benepali 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
Benepali is only available as 25 mg
Thus, it is not possible to administer Benepali to paediatric patients that require less than a full 25 mg or 50 mg dose. Paediatric patients who require a dose other than a full 25 mg or 50 mg should not receive Benepali. If an alternate dose is required, other etanercept products offering such an option should be used.
The dosage of etanercept 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 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
A 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 etanercept 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 etanercept in children aged below 6 years in the indication plaque psoriasis.
Method of administration
Benepali is for subcutaneous use (see section 6.6).
Comprehensive instructions for administration are given in the package leaflet, section 7, “Instructions for use”.
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 Benepali 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 Benepali, 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 etanercept (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 Benepali should be monitored closely. Administration of Benepali should be discontinued if a patient develops a serious infection. The safety and efficacy of etanercept in patients with chronic infections have not been evaluated. Physicians should exercise caution when considering the use of Benepali 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 Benepali, 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, Benepali 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
Patients should be tested for HBV infection before initiating treatment with Benepali. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when administering Benepali 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 etanercept. Benepali should be used with caution in patients with a history of hepatitis C.
Concurrent treatment with anakinra
Concurrent administration of etanercept and anakinra has been associated with an increased risk of serious infections and neutropenia compared to etanercept alone. This combination has not demonstrated increased clinical benefit. Thus, the combined use of Benepali and anakinra is not recommended (see sections 4.5 and 4.8).
Concurrent treatment with abatacept
In clinical studies, concurrent administration of abatacept and etanercept 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 etanercept administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious
allergic or anaphylactic reaction occurs, Benepali 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 Benepali therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin.
The safety and efficacy of etanercept 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 etanercept compared with control patients, particularly in patients with psoriasis.
Vaccinations
Live vaccines should not be given concurrently with Benepali. No data are available on the secondary transmission of infection by live vaccines in patients receiving etanercept. In a
Autoantibody formation
Treatment with Benepali 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 etanercept. Caution should be exercised in patients being treated with Benepali 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, and paleness) whilst on Benepali, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, Benepali should be discontinued.
Neurological disorders
There have been rare reports of CNS demyelinating disorders in patients treated with etanercept (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 etanercept and methotrexate did not result in unexpected safety findings, and the safety profile of etanercept when given in combination with methotrexate was similar to the profiles reported in studies of etanercept and methotrexate alone.
The use of etanercept 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 Benepali in patients who have congestive heart failure (CHF). There have been
conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to etanercept treatment.
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 etanercept in patients receiving medicinal products 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 etanercept 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 etanercept 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 etanercept (see section 4.8).
Benepali contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially
- Lifmior - L04AB01
- Erelzi - L04AB01
- Enbrel - L04AB01
Prescription drugs listed. ATC Code: "L04AB01"
4.5Interaction with other medicinal products and other forms of interaction
Concurrent treatment with anakinra
Adult patients treated with etanercept and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either etanercept or anakinra alone (historical data).
In addition, in a
Concurrent treatment with abatacept
In clinical studies, concurrent administration of abatacept and etanercept 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 etanercept was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with etanercept 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 etanercept 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 Benepali 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 etanercept 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 Benepali 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 etanercept.
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 etanercept 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 System Organ Class, 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 |
| antibody positive vasculitis) |
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 cases 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 |
| syndrome, chronic 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: | Elevated liver enzymes* |
Uncommon: | |
Rare: | 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), |
| |
Very rare: | Toxic epidermal necrolysis |
Musculoskeletal and connective tissue disorders: | |
Rare: | Subacute cutaneous lupus erythematosus, discoid lupus |
| erythematosus, |
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
studies conducted for more than 2 years with 351 ankylosing spondylitis patients, 6 malignancies were reported in
In a group of 7,416 patients treated with etanercept 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 etanercept 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 etanercept 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 etanercept developed injection site reactions compared with 3.4% of
Serious infections
In
There were no differences in rates of infection among patients treated with etanercept and those treated with placebo for plaque psoriasis in
Serious and fatal infections have been reported during use of etanercept; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks after initiating treatment with etanercept 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). Benepali treatment may increase mortality in patients with established sepsis.
Opportunistic infections have been reported in association with etanercept, 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 etanercept. 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 etanercept (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 etanercept plus anakinra, a higher rate of serious infections compared to etanercept alone was observed and 2% of patients (3/139) developed neutropenia (absolute neutrophil count < 1,000/mm3). While neutropenic, one patient developed cellulitis that resolved after hospitalisation (see sections 4.4 and 4.5).
Elevated liver enzymes
In the
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 etanercept 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 etanercept 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
Benepali is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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 etanercept was assessed in a randomised,
25 mg etanercept 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 etanercept at 3 and 6 months than in patients treated with placebo (ACR 20: etanercept 62% and 59%, placebo 23% and 11% at 3 and 6 months, respectively: ACR 50: etanercept 41% and 40%, placebo 8% and 5% at months 3 and 6,
respectively; p < 0.01 etanercept vs. placebo at all timepoints for both ACR 20 and ACR 50 responses).
Approximately 15% of subjects who received etanercept 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 etanercept, 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. Etanercept 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

subdomains, was administered every 3 months during the trial. All subdomains of the HAQ were improved in patients treated with etanercept compared to controls at 3 and 6 months.
After discontinuation of etanercept, symptoms of arthritis generally returned within a month. Reintroduction of treatment with etanercept after discontinuation of up to 24 months resulted in the same magnitudes of responses as patients who received etanercept without interruption of therapy based on results of
The efficacy of etanercept was compared to methotrexate in a randomised,
24 months. Methotrexate doses were escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial and continued for up to 24 months. Clinical improvement, including onset of action within 2 weeks with etanercept 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 etanercept 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 etanercept dose had consistently less effect on structural damage than the 25 mg dose. Etanercept 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 etanercept 25 mg. The results are shown in the figure below.
Radiographic progression: Comparison of etanercept vs. methotrexate in patients with RA of < 3 years duration
| 2.5 |
| 12 Months |
|
| 2.5 |
|
|
|
|
|
| |
Baseline | 2.0 |
|
|
|
| 2.0 |
|
|
|
|
| ||
1.5 | 1.3 |
|
|
| 1.5 | |
from |
|
|
|
| ||
1.0 | 0.8 | 0.9 |
|
| 1.0 | |
Change |
|
|
|
| ||
0.5 |
| 0.4* | 0.4 | 0.4 | 0.5 | |
|
|
|
|
|
| |
| 0.0 | TSS | Erosions | JSN | 0.0 | |
|
|
|
24 Months
2.2
1.2 | 1.3 |
|
| 0.9 | |
|
| |
| 0.6* | 0.6 |
TSS | Erosions | JSN |
MTX
Etanercept 25 mg *p < 0.05
In another

arthritis of 6 months to 20 years duration (median 5 years) who had a less than satisfactory response to at least 1
Patients in the etanercept 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 etanercept in combination with methotrexate compared with etanercept monotherapy and methotrexate monotherapy were also observed after 24 months.
Clinical Efficacy results at 12 months: Comparison of etanercept vs. methotrexate vs. etanercept in combination with methotrexate in patients with RA of 6 months to 20 years duration
|
| Methotrexate | Etanercept | Etanercept + |
Endpoint |
| Methotrexate | ||
| (n = 228) | (n = 223) | ||
|
| (n = 231) | ||
|
|
|
| |
ACR | ACR 20 | 58.8% | 65.5% | 74.5%†, Φ |
Responsesa | ACR 50 | 36.4% | 43.0% | 63.2%†, Φ |
| ACR 70 | 16.7% | 22.0% | 39.8%†, Φ |
DAS | (Scoreb) Baseline | 5.5 | 5.7 | 5.5 |
| (Scoreb) Week 52 | 3.0 | 3.0 | 2.3†, Φ |
| Remissionc | 14% | 18% | 37%†, Φ |
HAQ | Baseline | 1.7 | 1.7 | 1.8 |
| Week 52 | 1.1 | 1.0 | 0.8†, Φ |
a Patients who did not complete 12 months in the study were considered to be
c Remission is defined as DAS <1.6.
Pairwise comparison
Radiographic progression at 12 months was significantly less in the etanercept 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 etanercept vs. methotrexate vs. etanercept in combination with methotrexate in patients with RA of 6 months to 20 years duration (12 month results)
Change from Baseline
3.0 |
| 2.80 |
|
| Methotrexate | |
|
|
| ||||
|
|
| Etanercept | |||
|
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| ||||
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| |
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| |||
2.5 |
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| Etanercept + |
|
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| ||
|
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| ||||
|
|
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|
|
| Methotrexate |
2.0 |
| 1.68 |
| |
|
|
| ||
1.5 |
|
| 1.12 | |
|
|
| ||
1.0 |
|
|
| |
0.5 | 0.52* | 0.21* | 0.32 | |
| ||||
|
|
| ||
0.0 |
|
|
| |
| † | |||
| ||||
|
| |||
TSS | Erosions | JSN | ||
| ||||
|
|
|
Pairwise comparison
Significant advantages for etanercept in combination with methotrexate compared with etanercept monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for etanercept 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 etanercept in combination with methotrexate group compared with the etanercept alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p < 0.05). The difference between etanercept 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 etanercept (two 25 mg SC injections) administered once weekly were evaluated in a
etanercept treatment regimens were comparable at week 8 in their effect on signs and symptoms of RA; data at week 16 did not show comparability
25 mg/ml.
Adult patients with psoriatic arthritis
The efficacy of etanercept was assessed in a randomised,
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 etanercept (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
Psoriatic Arthritis Response |
| Percent of Patients |
|
| Placebo | Etanercepta | |
|
| n = 104 | n = 101 |
ACR 20 | Month 3 | 59b | |
| Month 6 | 50b | |
|
|
|

ACR 50 | Month 3 | 38b | |
| Month 6 | 37b | |
ACR 70 | Month 3 | 11b | |
| Month 6 | 9c | |
PsARC | Month 3 | 72b | |
| Month 6 | 70b |
a 25 mg etanercept SC twice weekly b p < 0.001, etanercept vs. placebo c p < 0.01, etanercept vs. placebo
Among patients with psoriatic arthritis who received etanercept, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. Etanercept 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 etanercept, 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 etanercept group compared with the placebo group (73% vs. 47%, respectively, p ≤ 0.001). The effect of etanercept 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
Time | Placebo | Etanercept | |
(n = 104) | (n = 101) | ||
| |||
Month 12 | 1.00 (0.29) | ||
SE = standard error |
|
| |
a p = 0.0001 |
|
|
Etanercept treatment resulted in improvement in physical function during the
There is insufficient evidence of the efficacy of etanercept 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 etanercept in ankylosing spondylitis was assessed in 3 randomised,
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 etanercept (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 etanercept 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 Response | Placebo | Etanercept | |
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, etanercept vs. placebo |
|
| |
b p = 0.002, etanercept vs. placebo |
|
|
Among patients with ankylosing spondylitis who received etanercept, 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 etanercept (two 25 mg SC injections) administered once weekly vs. 25 mg etanercept administered twice weekly were evaluated in a
Adult patients with
The efficacy of etanercept in patients with
defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meet the modified New York criteria for AS. Patients were also required to have an inadequate response or intolerance to two or more NSAIDs. In the

and spine were obtained to assess inflammation at baseline and at weeks 12 and 104.
Compared to placebo, treatment with etanercept 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 | Etanercept | |
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 etanercept 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 etanercept. Adjusted mean change from baseline was 3.8 for etanercept 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
Etanercept showed statistically significantly greater improvement from baseline to week 12 compared to placebo in most
Clinical responses among
Adult patients with plaque psoriasis
Etanercept 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 etanercept versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing etanercept with other systemic therapies. Instead, the safety and efficacy of etanercept 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 etanercept (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. Etanercept 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 etanercept, 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 etanercept 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 |
| |||
| Placeb |
| Etanercept |
|
|
| Etanercept |
|
| Etanercept | |||
| 25 mg |
| 50 mg BIW | Placebo |
| 25 m | 50 m | Placebo |
| 50 m | 50 m | ||
Response | o | BIW |
|
|
| g | g |
|
| g | g | ||
|
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|
| BIW | BIW |
|
| QW | QW | ||
(%) |
|
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|
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n = | n = | n = | n = | n = | n = 193 |
| n = | n = | n = 46 |
| n = | n = | |
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| |||||||||||
| |||||||||||||
|
|
| |||||||||||
| wk 12 | wk | wk | wk | wk | wk 12 |
| wk 12 | wk 12 | wk 12 |
| wk | wk |
| 24a | 24a |
| 24a | |||||||||
PASI 50 | 58* | 74* | 64* | 77* | 69* | ||||||||
PASI 75 | 34* | 49* | 34* | 49* | 38* | ||||||||
DSGAb, |
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|
clear or | 34* | 49* | 39* | 57* | 39* | ||||||||
almost |
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clear |
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* 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 etanercept 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 etanercept, 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 etanercept 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
PASI 75 at week 24.
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 etanercept
Antibodies to etanercept have been detected in the sera of some subjects treated with etanercept. These antibodies have generally been
Paediatric population
Paediatric patients with juvenile idiopathic arthritis
The safety and efficacy of etanercept 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 etanercept 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 etanercept 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 etanercept 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 etanercept therapy in patients who do not respond within 3 months of initiating etanercept therapy. Additionally, studies have not been conducted to assess the effects of discontinuing or reducing the recommended dose of etanercept following its
Paediatric patients with plaque psoriasis
The efficacy of etanercept was assessed in a randomised,
Patients received etanercept 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At
week 12, more patients randomised to etanercept had positive efficacy responses (e.g., PASI 75) than those randomised to placebo.
Paediatric Plaque Psoriasis Outcomes at 12 Weeks
| Etanercept |
|
| 0.8 mg/kg Once | Placebo |
| Weekly | (N = 105) |
| (N = 106) |
|
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
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 mg × hr/l vs. 316 mg × hr/l for 50 mg etanercept once weekly (n = 21) vs. 25 mg etanercept
twice weekly (n = 16), respectively. In an
In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady state AUCs were 466 μg × hr/ml and 474 μg × hr/ml for 50 mg etanercept 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 etanercept 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 etanercept/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 etanercept, no
Etanercept did not induce lethality or notable signs of toxicity in mice or rats following a single subcutaneous dose of 2,000 mg/kg or a single intravenous dose of 1,000 mg/kg. Etanercept did not elicit
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Sucrose
Sodium chloride
Sodium dihydrogen phosphate monohydrate
Disodium hydrogen phosphate heptahydrate
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
30 months.
6.4Special precautions for storage
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep the
After taking a syringe or a pen from the refrigerator, wait approximately 30 minutes to allow the Benepali solution in the syringe or the pen to reach room temperature. Do not warm in any other way. Immediate use is then recommended.
Benepali 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. Benepali should be discarded if not used within four weeks of removal from refrigeration.
6.5Nature and contents of container
50 mg solution for injection in
Clear glass (type I)
Benepali is available in packs containing 4
50 mg solution for injection in
6.6Special precautions for disposal
50 mg solution for injection in
Before injection, Benepali
Comprehensive instructions for administration are given in the package leaflet, section 7, ”Instructions for use”.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
50 mg solution for injection in
Before injection, Benepali
Comprehensive instructions for administration are given in the package leaflet, section 7, “Instructions for use”.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Samsung Bioepis UK Limited 5th floor
Profile West
950 Great West Road Brentford Middlesex TW8 9ES United Kingdom
8.MARKETING AUTHORISATION NUMBER(S)
EU/1/15/1074/001
EU/1/15/1074/002
EU/1/15/1074/003
EU/1/15/1074/004
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 14 January 2016
10.DATE OF REVISION OF THE TEXT
- Duloxetine boehringer ingelheim
- Pegintron
- Lemtrada
- Kuvan
- Oprymea
- Docetaxel teva pharma
Prescription drugs listed:
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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