Source: https://rxed.eu/en/e/Erelzi/2/
Timestamp: 2019-06-25 06:02:04
Document Index: 192137759

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Erelzi (etanercept) – Summary of product characteristics - L04AB01 – RXed.eu | EN
Erelzi (etanercept) – Summary of product characteristics - L04AB01
Medication name Erelzi
Erelzi: Summary of product characteristics
Erelzi: Conditions or restrictions regarding supply and use
Erelzi: Labelling
Erelzi: Package leaflet
▼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.
Erelzi 25 mg solution for injection in pre-filled syringe.
Erelzi 50 mg solution for injection in pre-filled syringe.
Erelzi 50 mg solution for injection in pre-filled pen.
Erelzi 25 mg solution for injection in pre-filled syringe
Erelzi 50 mg solution for injection in pre-filled syringe
Erelzi 50 mg solution for injection in pre-filled pen
The solution is clear or slightly opalescent, colourless to slightly yellowish.
Erelzi in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate.
Etanercept, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.
Treatment of adults with severe non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence, who have had an inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs).
Erelzi 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, non-radiographic axial spondyloarthritis, plaque psoriasis or paediatric plaque psoriasis. Patients treated with Erelzi should be given the Patient Alert Card.
Erelzi is available in strengths of 25 mg and 50 mg.
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 50 mg once weekly. Treatment with etanercept should continue until remission is achieved, for up to 24 weeks. Continuous therapy beyond 24 weeks may be appropriate for some adult patients (see section 5.1). Treatment should be discontinued in patients who show no response after 12 weeks. If re-treatment with etanercept is indicated, the same guidance on treatment duration should be followed. The dose should be 25 mg twice weekly or 50 mg once weekly.
No dose adjustment is required. Posology and administration are the same as for adults 18–64 years of age.
Erelzi is only available as 25 mg pre-filled syringe and 50 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to administer Erelzi 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 Erelzi. 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 the powder for solution for injection presentations (see below for dosing for specific indications). Patients weighing 62.5 kg or more may be dosed using a fixed-dose pre-filled syringe or pre-filled pen.
The recommended dose is 0.4 mg/kg (up to a maximum of 25 mg per dose), given twice weekly as a subcutaneous injection with an interval of 3–4 days between doses or 0.8 mg/kg (up to a maximum of 50 mg per dose) given once weekly. Discontinuation of treatment should be considered in patients who show no response after 4 months.
If re-treatment with etanercept is indicated, the above guidance on treatment duration should be followed. The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.
Erelzi is for subcutaneous use (see section 6.6).
Comprehensive instructions for administration are given in the package leaflet, section 7, "Instructions for use of the Erelzi pre-filled syringe” or “Instructions for use of the Erelzi SensoReady pen”.
Treatment with Erelzi should not be initiated in patients with active infections, including chronic or localised infections.
Patients should be evaluated for infections before, during, and after treatment with Erelzi, taking into consideration that the mean elimination half-life of etanercept is approximately 70 hours (range 7 to 300 hours).
Patients who develop a new infection while undergoing treatment with Erelzi should be monitored closely. Administration of Erelzi 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 Erelzi 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.
Before starting treatment with Erelzi, all patients must be evaluated for both active and inactive (‘latent’) tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e., tuberculin skin test and chest X-ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the Patient’s Alert Card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.
If active tuberculosis is diagnosed, Erelzi therapy must not be initiated. If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before the initiation of Erelzi, and in accordance with local recommendations. In this situation, the benefit/risk balance of Erelzi therapy should be very carefully considered.
All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g., persistent cough, wasting/weight loss, low-grade fever) appear during or after Erelzi treatment.
Patients should be tested for HBV infection before initiating treatment with Erelzi. 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 Erelzi in patients previously infected with HBV. These patients should be monitored for signs and symptoms of active HBV infection throughout therapy and for several weeks following termination of therapy. Adequate data from treating patients infected with HBV with anti-viral therapy in conjunction with TNF-antagonist therapy are not available. In patients who develop HBV infection, Erelzi should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
There have been reports of worsening of hepatitis C in patients receiving etanercept. Erelzi should be used with caution in patients with a history of hepatitis C.
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 Erelzi and anakinra is not recommended (see sections 4.5 and 4.8).
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, Erelzi therapy should be discontinued immediately and appropriate therapy initiated.
The possibility exists for TNF-antagonists, including Erelzi, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 adult patients with rheumatoid arthritis treated with etanercept, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations.
Two juvenile idiopathic arthritis patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. Patients with a significant exposure to varicella virus should temporarily discontinue Erelzi therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin.
Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the post-marketing period (see section 4.8).
In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. In the post-marketing setting, cases of leukaemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), including etanercept, in the post-marketing setting. Approximately half the cases were lymphomas. The other
cases represented a variety of different malignancies and included rare malignancies typically associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.
Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF-antagonists, including etanercept. Post-marketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with etanercept. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Live vaccines should not be given concurrently with Erelzi. No data are available on the secondary transmission of infection by live vaccines in patients receiving etanercept. In a double-blind, placebo-controlled, randomised clinical study in adult patients with psoriatic arthritis, 184 patients also received a multivalent pneumococcal polysaccharide vaccine at week 4. In this study, most psoriatic arthritis patients receiving etanercept were able to mount effective B-cell immune response to
pneumococcal polysaccharide vaccine, but titres in aggregate were moderately lower, and few patients had two-fold rises in titres compared to patients not receiving etanercept. The clinical significance of this is unknown.
Treatment with Erelzi may result in the formation of autoimmune antibodies (see section 4.8).
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 Erelzi who have a previous history of blood dyscrasias. All patients and parents/caregivers should be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias or infections (e.g., persistent fever, sore throat, bruising, bleeding, paleness) whilst on Erelzi, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, Erelzi should be discontinued.
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 Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have been performed evaluating etanercept therapy in patients with multiple sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have shown increases in disease activity. A careful risk/benefit evaluation, including a neurologic assessment, is recommended when prescribing Erelzi to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.
Physicians should use caution when using Erelzi in patients who have congestive heart failure (CHF). There have been post-marketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking etanercept. There have also been rare (< 0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Two large clinical trials evaluating the use of etanercept in the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to etanercept treatment.
In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with etanercept or placebo for moderate to severe alcoholic hepatitis, etanercept was not efficacious, and the mortality rate in patients treated with etanercept was significantly higher after 6 months. Consequently, Erelzi should
not be used in patients for the treatment of alcoholic hepatitis. Physicians should use caution when using Erelzi in patients who also have moderate to severe alcoholic hepatitis.
A placebo-controlled trial, in which 89 adult patients were treated with etanercept in addition to standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median duration of 25 months, has not shown etanercept to be an effective treatment for Wegener’s granulomatosis. The incidence of non-cutaneous malignancies of various types was significantly higher in patients treated with etanercept than in the control group. Erelzi is not recommended for the treatment of Wegener’s granulomatosis.
There have been reports of hypoglycaemia following initiation of etanercept in patients receiving medicinal product for diabetes, necessitating a reduction in anti-diabetic medicinal products in some of these patients.
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 Erelzi therapy (see Vaccinations, above).
Erelzi contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per 25mg or 50 mg, i.e. essentially ‘sodium-free’.
In clinical trials, no interactions have been observed when etanercept was administered with glucocorticoids, salicylates (except sulfasalazine), non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, or methotrexate. See section 4.4 for vaccination advice.
Women of childbearing potential should be advised to use appropriate contraception to avoid becoming pregnant during Erelzi therapy and for three weeks after discontinuation of therapy.
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 TNF-antagonists (adjusted odds ratio 2.4, 95% CI: 1.0-5.5). The types of major birth defects were consistent with those most commonly reported in the general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. Erelzi is not recommended during pregnancy.
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 Erelzi 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 breast-feeding or to discontinue Erelzi therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Serious adverse reactions have also been reported for etanercept. TNF-antagonists, such as etanercept, affect the immune system and their use may affect the body’s defences against infection and cancer. Serious infections affect fewer than 1 in 100 patients treated with etanercept. Reports have included fatal and life-threatening infections and sepsis. Various malignancies have also been reported with use of etanercept, including cancers of the breast, lung, skin and lymph glands (lymphoma).
The following list of adverse reactions is based on experience from clinical trials in adults and on post-marketing experience.
Infections (including upper respiratory tract infections, bronchitis,
cystitis, skin infections)*
Serious infections (including pneumonia, cellulitis, septic arthritis,
sepsis and parasitic infection)*
protozoal, bacterial, atypical mycobacterial, viral infections, and
CNS demyelinating events suggestive of multiple sclerosis or
One hundred and twenty-nine (129) new malignancies of various types were observed in
4,114 rheumatoid arthritis patients treated in clinical trials with etanercept for up to approximately 6 years, including 231 patients treated with etanercept in combination with methotrexate in a 2-year
active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. A total of 2 malignancies were reported in clinical studies of approximately 2 years duration involving 240 etanercept-treated psoriatic arthritis patients. In clinical studies conducted for more than 2 years with 351 ankylosing spondylitis patients, 6 malignancies were reported in etanercept-treated patients. In a group of 2,711 plaque psoriasis patients treated with etanercept in double-blind and open-label studies of up to 2.5 years, 30 malignancies and
43 non-melanoma skin cancers were reported.
Reports of various malignancies (including breast and lung carcinoma and lymphoma) have also been received in the post-marketing period (see section 4.4).
In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, or requiring hospitalisation or intravenous antibiotics) was observed. Serious infections occurred in 6.3% of rheumatoid arthritis patients treated with etanercept for up to 48 months. These included abscess (at various sites), bacteraemia, bronchitis, bursitis, cellulitis, cholecystitis, diarrhoea, diverticulitis, endocarditis (suspected), gastroenteritis, hepatitis B, herpes zoster, leg ulcer, mouth infection, osteomyelitis, otitis, peritonitis, pneumonia, pyelonephritis, sepsis, septic arthritis, sinusitis, skin infection, skin ulcer, urinary tract infection, vasculitis, and wound infection. In a 2-year
active-controlled study where patients were treated with either etanercept alone, methotrexate alone or etanercept in combination with methotrexate, the rates of serious infections were similar among the treatment groups. However, it cannot be excluded that the combination of etanercept with methotrexate could be associated with an increase in the rate of infections.
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). Etanercept 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 exposure-adjusted rate was 0.06 events per 100 patient-years. In post-marketing experience, approximately half of all of the case reports of opportunistic infections worldwide were invasive fungal infections. The most commonly reported invasive fungal infections included Candida, Pneumocystis, Aspergillus and Histoplasma. Invasive fungal infections accounted for more than half of the fatalities amongst patients who developed opportunistic infections. The majority of the reports with a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, and aspergillosis (see section 4.4).
There have been post-marketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes (see section 4.4).
There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
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).
Erelzi is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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 arthritis-associated health status 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. Re-introduction 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 open-label studies. Continued durable responses have been seen for up to 10 years in open-label extension treatment trials when patients received etanercept without interruption.
The efficacy of etanercept was compared to methotrexate in a randomised, active-controlled study with blinded radiographic evaluations as a primary endpoint in 632 adult patients with active rheumatoid arthritis (< 3 years duration) who had never received treatment with methotrexate. Doses of 10 mg or 25 mg etanercept were administered subcutaneously (SC) twice a week for up to 24 months. Methotrexate doses were escalated from 7.5 mg/week to a maximum of 20 mg/week over the first
8 weeks of the trial and continued for up to 24 months. Clinical improvement, including onset of action within 2 weeks with 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 another active-controlled, double-blind, randomised study, clinical efficacy, safety, and radiographic progression in RA patients treated with etanercept alone (25 mg twice weekly), methotrexate alone (7.5
to 20 mg weekly, median dose 20 mg), and the combination of etanercept and methotrexate initiated concurrently were compared in 682 adult patients with active rheumatoid arthritis of 6 months to 20 years duration (median 5 years) who had a less than satisfactory response to at least 1 disease-modifying antirheumatic drug (DMARD) other than methotrexate.
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.
a:Patients who did not complete 12 months in the study were considered to be non-responders.
b:Values for Disease Activity Score (DAS) are means.
c:Remission is defined as DAS < 1.6.
Pairwise comparison p-values: † = p < 0.05 for comparisons of etanercept + methotrexate vs. methotrexate and ϕ = p < 0.05 for comparisons of etanercept + methotrexate vs. etanercept.
Pairwise comparison p-values: * = p < 0.05 for comparisons of etanercept vs. methotrexate, † = p < 0.05 for comparisons of etanercept + methotrexate vs. methotrexate and ϕ = p < 0.05 for comparisons of etanercept + methotrexate vs. etanercept.
The safety and efficacy of 50 mg etanercept (two 25 mg SC injections) administered once weekly were evaluated in a double-blind, placebo-controlled study of 420 patients with active RA. In this study,
53 patients received placebo, 214 patients received 50 mg etanercept once weekly and 153 patients received 25 mg etanercept twice weekly. The safety and efficacy profiles of the two 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 (non-inferiority) between the two regimens. A single 50 mg/ml injection of etanercept was found to be bioequivalent to two simultaneous injections of 25 mg/ml.
The efficacy of etanercept was assessed in a randomised, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (≥ 3 swollen joints and ≥ 3 tender joints) in at least one of the following forms: (1) distal interphalangeal (DIP) involvement; (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or (5) spondylitis-like ankylosis. Patients also had plaque psoriasis with a qualifying target lesion ≥ 2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on methotrexate therapy (stable for ≥ 2 months) could continue at a stable dose of
a:25 mg etanercept SC twice weekly
b:p < 0.001, etanercept vs. placebo
c:p < 0.01, etanercept vs. placebo
The efficacy of etanercept in ankylosing spondylitis was assessed in 3 randomised, double-blind studies comparing twice-weekly administration of 25 mg etanercept with placebo. A total of 401 patients were enrolled, from which 203 were treated with etanercept. The largest of these trials (n = 277) enrolled patients who were between 18 and 70 years of age and had active ankylosing spondylitis defined as visual analog scale (VAS) scores of ≥ 30 for average of duration and intensity of morning stiffness plus VAS scores of ≥ 30 for at least 2 of the following 3 parameters: patient global assessment; average of VAS values for nocturnal back pain and total back pain; average of 10 questions on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients receiving DMARDs, NSAIDS, or corticosteroids could continue them on stable doses. Patients with complete ankylosis of the spine were not included in the study. Doses of 25 mg of etanercept (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered subcutaneously twice a week for 6 months in
138 patients.
a:p < 0.001, etanercept vs. placebo
b:p = 0.002, etanercept vs. placebo
defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meet the modified New York criteria for AS. Patients were also required to have an inadequate response or intolerance to two or more NSAIDs. In the double-blind period, patients received etanercept 50 mg weekly or placebo for 12 weeks. The primary measure of efficacy (ASAS 40) was a 40% improvement in at least three of the four ASAS domains and absence of deterioration in the remaining domain. The double-blind period was followed by an open-label period during which all patients received etanercept 50 mg weekly for up to an additional 92 weeks. MRIs of the sacroiliac joint and spine were obtained to assess inflammation at baseline and at week 12 and 104.
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-treated subjects was 4.64 for the SIJ (n = 153) and 1.40 the spine (n = 154).
≥ 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
--------Etanercept-------
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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.
In study 4, the etanercept-treated group had a higher proportion of patients with PASI 75 at week 12 (38%) compared to the placebo-treated group (2%) (p < 0.0001). For patients who received 50 mg once weekly throughout the study, the efficacy responses continued to improve with 71% achieving PASI 75 at week 24.
The safety and efficacy of etanercept were assessed in a two-part study in 69 children with polyarticular-course juvenile idiopathic arthritis who had a variety of juvenile idiopathic arthritis onset types (polyarthritis, pauciarthritis, systemic onset). Patients aged 4 to 17 years with moderately to severely active polyarticular-course juvenile idiopathic arthritis refractory to, or intolerant of, methotrexate were enrolled; patients remained on a stable dose of a single non-steroidal anti-inflammatory drug and/or prednisone (< 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) etanercept subcutaneously twice weekly. In part 2, patients with a clinical response at day 90 were randomised to remain on etanercept or receive placebo for four months and assessed for disease flare. Responses were measured using the ACR Pedi 30, defined as ≥ 30% improvement in at least three of six and ≥ 30% worsening in no more than one of six JRA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and erythrocyte sedimentation rate (ESR). Disease flare was defined as a ≥ 30% worsening in three of six JRA core set criteria and ≥ 30% improvement in not more than one of the six JRA core set criteria and a minimum of two active joints.
In part 1 of the study, 51 of 69 (74%) patients demonstrated a clinical response and entered part 2. In part 2, 6 of 25 (24%) patients remaining on 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 open-label, safety extension study, 58 paediatric patients from the above study (from the age of
4 years at time of enrolment) continued to receive etanercept for up to 10 years. Rates of serious adverse events and serious infections did not increase with long-term exposure.
Abbreviation: sPGA-static Physician Global Assessment a. p < 0.0001 compared with placebo
Etanercept is slowly absorbed from the site of subcutaneous injection, reaching maximum concentration approximately 48 hours after a single dose. The absolute bioavailability is 76%. With twice-weekly doses, it is anticipated that steady-state concentrations are approximately twice as high as those observed after single doses. After a single subcutaneous dose of 25 mg etanercept, the average maximum serum concentration observed in healthy volunteers was 1.65 ± 0.66 µg/ml, and the area
under the curve was 235 ± 96.6 µg•hr/ml.
Mean serum concentration profiles at steady state in treated RA patients were Cmax of 2.4 mg/l vs.
2.6 mg/l, Cmin of 1.2 mg/l vs. 1.4 mg/l, and partial AUC of 297 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
open-label, single-dose, two-treatment, crossover study in healthy volunteers, etanercept administered as a single 50 mg/ml injection was found to be bioequivalent to two simultaneous injections of
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.
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 (10–
17 years of age) will have serum levels close to those seen in adults, younger children will have appreciably lower levels.
Patients with paediatric plaque psoriasis (aged 4 to 17 years) were administered 0.8 mg/kg (up to a maximum dose of 50 mg per week) of etanercept once weekly for up to 48 weeks. The mean serum steady-state trough concentrations ranged from 1.6 to 2.1 mcg/ml at weeks 12, 24, and 48. These mean concentrations in patients with paediatric plaque psoriasis were similar to the concentrations observed in patients with juvenile idiopathic arthritis (treated with 0.4 mg/kg etanercept twice weekly, up to
maximum dose of 50 mg per week). These mean concentrations were similar to those seen in adult patients with plaque psoriasis treated with 25 mg etanercept twice-weekly.
Keep the pre-filled syringes and the pre-filled pens in the outer carton in order to protect from light.
After taking a syringe from the refrigerator, wait approximately 15-30 minutes to allow the Erelzi solution in the syringe to reach room temperature. Do not warm in any other way. Immediate use is then recommended.
Erelzi 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. Erelzi should be discarded if not used within four weeks of removal from refrigeration.
Erelzi solution for injection in pre-filled syringe
Clear type I glass syringe with a stainless steel 27 gauge ½ inch needle with a needle guard with finger flange, rubber needle cap and plastic plunger, containing 0.5 ml or 1.0 ml of solution.
Erelzi is supplied in a single-use pre-filled syringe assembled into a triangular-shaped pen with transparent window and label (SensoReady pen). The syringe inside the pen is made from clear type I glass with a stainless steel 27 gauge ½ inch needle and an inner rubber needle cap, containing 1.0 ml of solution.
Cartons contain 1, 2 or 4 pre-filled syringes or pre-filled pens of Erelzi. Multipacks contain 12 (3 packs of 4) pre-filled syringes or pre-filled pens of Erelzi. Not all pack sizes may be marketed.
Instructions for use and handling of the Erelzi pre-filled syringe
Before injection, Erelzi single-use pre-filled syringe should be allowed to reach room temperature (approximately 15 to 30 minutes). The needle cap should not be removed while allowing the pre-filled syringe to reach room temperature. The solution should be clear to slightly opalescent, colourless to slightly yellowish and may contain small translucent or white particles of protein.
Comprehensive instructions for administration are given in the package leaflet, section 7, "Instructions for use of the Erelzi pre-filled syringe".
Instructions for use and handling of the Erelzi pre-filled SensoReady pen
Before injection, Erelzi single-use pre-filled pens should be allowed to reach room temperature (approximately 15 to 30 minutes). The needle cap should not be removed while allowing the pre-filled pen to reach room temperature. By looking through the viewing window, the solution should be clear to slightly opalescent, colourless to slightly yellowish and may contain small translucent or white particles of protein.
Comprehensive instructions for administration are given in the package leaflet, section 7, "Instructions for use of the Erelzi SensoReady pen".