ERELZI 50mg injectible solution medication leaflet

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

Each pre-filled syringe contains 25 mg of etanercept.

Erelzi 50 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 50 mg of etanercept.

Erelzi 50 mg solution for injection in pre-filled pen

Each pre-filled pen contains 50 mg of etanercept.

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

DNA technology in a Chinese hamster ovary (CHO) mammalian expression system.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Solution for injection (injection) in pre-filled pen (SensoReady 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 activerheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, includingmethotrexate (unless contraindicated), has been inadequate.

Erelzi can be given as monotherapy in case of intolerance to methotrexate or when continued treatmentwith methotrexate is inappropriate.

Erelzi is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adultsnot previously treated with methotrexate.

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

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

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

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

Treatment of active and progressive psoriatic arthritis in adults when the response to previousdisease-modifying antirheumatic drug therapy has been inadequate. Etanercept has been shown toimprove physical function in patients with psoriatic arthritis, and to reduce the rate of progression ofperipheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of thedisease.

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

Non-radiographic axial spondyloarthritis

Treatment of adults with severe non-radiographic axial spondyloarthritis with objective signs ofinflammation 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).

Plaque psoriasis

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

Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years whoare inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

Erelzi treatment should be initiated and supervised by specialist physicians experienced in the diagnosisand treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosingspondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis or paediatric plaque psoriasis.

Patients treated with Erelzi should be given the Patient Card.

Erelzi is available in strengths of 25 mg and 50 mg.

Rheumatoid arthritis25 mg etanercept administered twice weekly is the recommended dose. Alternatively, 50 mgadministered once weekly has been shown to be safe and effective (see section 5.1).

Psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis

The recommended dose is 25 mg etanercept administered twice weekly, or 50 mg administered onceweekly.

For all of the above indications, available data suggest that a clinical response is usually achieved within12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not respondingwithin this time period.

Plaque psoriasis

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

No dose adjustment is required.

No dose adjustment is required. Posology and administration are the same as for adults 18-64 years ofage.

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 or50 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 dose of etanercept is based on body weight for paediatric patients. Patients weighing less than62.5 kg should be accurately dosed on a mg/kg basis using the powder and solvent for solution forinjection presentations or the powder for solution for injection presentation (see below for dosing forspecific indications). Patients weighing 62.5 kg or more may be dosed using a fixed-dose pre-filledsyringe or pre-filled pen.

The safety and efficacy of Erelzi in children aged less than 2 years has not been established.

No data are available.

The recommended dose is 0.4 mg/kg (up to a maximum of 25 mg per dose), given twice weekly as asubcutaneous injection with an interval of 3-4 days between doses or 0.8 mg/kg (up to a maximum of50 mg per dose) given once weekly. Discontinuation of treatment should be considered in patients whoshow no response after 4 months.

A 10 mg vial strength may be more appropriate for administration to children with JIA below theweight of 25 kg.

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

There is generally no applicable use of etanercept in children aged below 2 years in the indicationjuvenile 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 to24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks.

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

There is generally no applicable use of etanercept in children aged below 6 years in the indicationplaque psoriasis.

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

Comprehensive instructions for administration are given in the package leaflet, section 7, 'Instructionsfor use of the Erelzi pre-filled syringe” or “Instructions for use of the Erelzi pre-filled pen”. Detailedinstructions on unintentional dosing or scheduling variations, including missed doses, are provided insection 3 of the package leaflet.

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

Sepsis or risk of sepsis.

Treatment with Erelzi should not be initiated in patients with active infections, including chronic orlocalised infections.

In order to improve the traceability of biological medicinal products, the name and the batch number ofthe administered product should be clearly recorded.

Patients should be evaluated for infections before, during, and after treatment with Erelzi, taking intoconsideration that the mean elimination half-life of etanercept is approximately 70 hours (range 7 to300 hours).

Serious infections, sepsis, tuberculosis, and opportunistic infections, including invasive fungalinfections, 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 indelay of appropriate treatment and sometimes death. In evaluating patients for infections, the patient’srisk for relevant opportunistic infections (e.g., exposure to endemic mycoses) should be considered.

Patients who develop a new infection while undergoing treatment with Erelzi should be monitoredclosely. Administration of Erelzi should be discontinued if a patient develops a serious infection. Thesafety and efficacy of etanercept in patients with chronic infections have not been evaluated. Physiciansshould exercise caution when considering the use of Erelzi in patients with a history of recurring orchronic infections or with underlying conditions that may predispose patients to infections, such asadvanced or poorly controlled diabetes.

Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with extra-pulmonarylocation, have been reported in patients treated with etanercept.

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 oftuberculosis or possible previous contact with tuberculosis and previous and/or currentimmunosuppressive 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 theconduct of these tests should be recorded in the Patient Card. Prescribers are reminded of the risk offalse negative tuberculin skin test results, especially in patients who are severely ill orimmunocompromised.

If active tuberculosis is diagnosed, Erelzi therapy must not be initiated. If inactive (‘latent’) tuberculosisis diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before theinitiation of Erelzi, and in accordance with local recommendations. In this situation, the benefit/riskbalance 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.

Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV)and had received concomitant TNF-antagonists, including etanercept, has been reported. This includesreports of reactivation of hepatitis B in patients who were anti-HBc positive but HBsAg negative.

Patients should be tested for HBV infection before initiating treatment with Erelzi. For patients who testpositive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis Bis recommended. Caution should be exercised when administering Erelzi in patients previously infectedwith HBV. These patients should be monitored for signs and symptoms of active HBV infectionthroughout therapy and for several weeks following termination of therapy. Adequate data from treatingpatients infected with HBV with anti-viral therapy in conjunction with TNF-antagonist therapy are notavailable. In patients who develop HBV infection, Erelzi should be stopped and effective anti-viraltherapy with appropriate supportive treatment should be initiated.

Worsening of hepatitis C

There have been reports of worsening of hepatitis C in patients receiving etanercept. Erelzi should beused 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 ofserious infections and neutropenia compared to etanercept alone. This combination has notdemonstrated increased clinical benefit. Thus, the combined use of Erelzi and anakinra is notrecommended (see sections 4.5 and 4.8).

Concurrent treatment with abatacept

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

Allergic reactions associated with etanercept administration have been reported commonly. Allergicreactions have included angioedema and urticaria; serious reactions have occurred. If any seriousallergic or anaphylactic reaction occurs, Erelzi therapy should be discontinued immediately andappropriate therapy initiated.

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

Two juvenile idiopathic arthritis patients developed varicella infection and signs and symptoms ofaseptic meningitis, which resolved without sequelae. Patients with a significant exposure to varicellavirus should temporarily discontinue Erelzi 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.

Solid and haematopoietic malignancies (excluding skin cancers)

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have beenreceived in the post-marketing period (see section 4.8).

In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have beenobserved among patients receiving a TNF-antagonist compared with control patients. However, theoccurrence 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 inpatients treated with TNF-antagonists. There is an increased background risk for lymphoma andleukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease,which complicates risk estimation.

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

Caution should be exercised when considering TNF-antagonist therapy for patients with a history ofmalignancy or when considering continuing treatment in patients who develop a malignancy.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), includingetanercept, in the post-marketing setting. Approximately half the cases were lymphomas. The othercases represented a variety of different malignancies and included rare malignancies typically associatedwith immunosuppression. A risk for the development of malignancies in children and adolescentstreated with TNF-antagonists cannot be excluded.

Skin cancers

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

TNF-antagonists, including etanercept. Post-marketing cases of Merkel cell carcinoma have beenreported very infrequently in patients treated with etanercept. Periodic skin examination isrecommended for all patients, particularly those with risk factors for skin cancer.

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

Live vaccines should not be given concurrently with Erelzi. No data are available on the secondarytransmission 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 alsoreceived a multivalent pneumococcal polysaccharide vaccine at week 4. In this study, most psoriaticarthritis patients receiving etanercept were able to mount effective B-cell immune response topneumococcal polysaccharide vaccine, but titres in aggregate were moderately lower, and few patientshad two-fold rises in titres compared to patients not receiving etanercept. The clinical significance ofthis is unknown.

Autoantibody formation

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 beenreported 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 beadvised 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 seekimmediate medical advice. Such patients should be investigated urgently, including full blood count; ifblood dyscrasias are confirmed, Erelzi should be discontinued.

Neurological disorders

There have been rare reports of CNS demyelinating disorders in patients treated with etanercept (seesection 4.8). Additionally, there have been 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 beenperformed evaluating etanercept therapy in patients with multiple sclerosis, clinical trials of other TNFantagonists in patients with multiple sclerosis have shown increases in disease activity. A carefulrisk/benefit evaluation, including a neurologic assessment, is recommended when prescribing Erelzi topatients with pre-existing or recent onset of demyelinating disease, or to those who are considered tohave an increased risk of developing demyelinating disease.

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

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

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

Congestive heart failure (Cardiac failure congestive)

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 identifiableprecipitating factors, in patients taking etanercept. There have also been rare (< 0.1%) reports of newonset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some ofthese patients have been under 50 years of age. Two large clinical trials evaluating the use of etanerceptin the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, datafrom one of these trials suggest a possible tendency toward worsening CHF in those patients assigned toetanercept treatment.

Alcoholic hepatitis

In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with etanercept orplacebo for moderate to severe alcoholic hepatitis, etanercept was not efficacious, and the mortality ratein patients treated with etanercept was significantly higher after 6 months. Consequently, Erelzi shouldnot 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.

Wegener's granulomatosis

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

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of etanercept in patients receivingmedicinal product for diabetes, necessitating a reduction in anti-diabetic medicinal products in some ofthese patients.

In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no overalldifferences in adverse events, serious adverse events, and serious infections in patients age 65 or olderwho received etanercept were observed compared with younger patients. However, caution should beexercised when treating the elderly and particular attention paid with respect to occurrence of infections.

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

This medicinal product contains less than 1 mmol sodium (23 mg) per 25 mg or 50 mg, that is to sayessentially ‘sodium-free’.

Concurrent treatment with anakinra

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

In addition, in a double-blind, placebo-controlled trial in adult patients receiving backgroundmethotrexate, patients treated with etanercept and anakinra were observed to have a higher rate ofserious infections (7%) and neutropenia than patients treated with etanercept (see sections 4.4 and 4.8).

The combination etanercept and anakinra has not demonstrated increased clinical benefit, and istherefore not recommended.

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and etanercept resulted in increasedincidences 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 whichetanercept was added, patients in the combination group experienced a statistically significant decreasein 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 consideringcombination therapy with sulfasalazine.

Non-interactions

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

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

Women of childbearing potential should consider the use of appropriate contraception to avoidbecoming 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 thefoetus or neonatal rat due to etanercept. The effects of etanercept on pregnancy outcomes have beeninvestigated in two observational cohort studies. A higher rate of major birth defects was observed inone observational study comparing pregnancies exposed to etanercept (n = 370) during the firsttrimester with pregnancies not exposed to etanercept or other TNF-antagonists (n = 164) (adjusted oddsratio 2.4, 95% CI: 1.0 - 5.5). The types of major birth defects were consistent with those mostcommonly 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. Inanother observational multi-country registry study comparing the risk of adverse pregnancy outcomes inwomen exposed to etanercept during the first 90 days of pregnancy (n = 425) to those exposed to non-biologic drugs (n = 3497), there was no observed increased risk of major birth defects (crude odds ratio[OR] = 1.22, 95% CI: 0.79 - 1.90; adjusted OR = 0.96, 95% CI: 0.58 - 1.60 after adjusting for country,maternal disease, parity, maternal age and smoking in early pregnancy). This study also showed noincreased risks of minor birth defects, preterm birth, stillbirth, or infections in the first year of life forinfants born to women exposed to etanercept during pregnancy. Erelzi should only be used duringpregnancy if clearly needed.

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

In lactating rats following subcutaneous administration, etanercept was excreted in the milk anddetected in the serum of pups. Limited information from the published literature indicates etanercepthas been detected at low levels in human milk. Etanercept could be considered for use duringbreast-feeding taking into account the benefit of breast-feeding for the child and the benefit of therapyfor the woman.

While systemic exposure in a breastfed infant is expected to be low because etanercept is largelydegraded in the gastrointestinal tract, limited data regarding systemic exposure in the breastfed infantare available. Therefore, the administration of live vaccines (e.g., BCG) to a breastfed infant when themother is receiving etanercept could be considered 16 weeks after stopping breast-feeding (or at anearlier timepoint if the infant etanercept serum levels are undetectable).

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

Erelzi has no or negligible influence on the ability to drive and use machines.

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), headache, allergic reactions, development ofautoantibodies, itching, and fever.

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 includedfatal and life-threatening infections and sepsis. Various malignancies have also been reported with useof etanercept, including cancers of the breast, lung, skin and lymph glands (lymphoma).

Serious haematological, neurological and autoimmune reactions have also been reported. These includerare reports of pancytopenia and very rare reports of aplastic anaemia. Central and peripheraldemyelinating events have been seen rarely and very rarely, respectively, with etanercept use. Therehave been rare reports of lupus, lupus-related conditions, and vasculitis.

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

Within the system organ classes, adverse reactions are listed under headings of frequency (number ofpatients 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); veryrare (< 1/10,000); not known (cannot be estimated from the available data).

System Organ Very Common Uncommon Rare Very Rare Not Known

Class Common ≥ 1/100 ≥ 1/1,000 to ≥ 1/10,000 to < 1/10,000 (Cannot be≥ 1/10 to < 1/10 < 1/100 < 1/1,000 Estimatedfrom Available

Data)

Infections and Infection Serious infections Tuberculosis, Hepatitis Binfestations (including (including opportunistic reactivation,upper pneumonia, infection listeriarespiratory cellulitis, arthritis (includingtract bacterial, sepsis invasive fungal,infection, and parasitic protozoal,bronchitis, infection)* bacterial,cystitis, skin atypicalinfection)* mycobacterial,viral infections,and Legionella)*

Neoplasms Non-melanoma Malignant Merkel cellbenign, skin cancers* (see melanoma (see carcinoma (seemalignant and section 4.4) section 4.4), section 4.4),unspecified lymphoma, Kaposi(including cysts leukaemia Sarcomaand polyps)

Blood and Thrombocytopenia, Pancytopenia* Aplastic Histiocytosislymphatic anaemia, anaemia* haematophagicsystem disorders leukopenia, (macrophageneutropenia activationsyndrome)*

Immune system Allergic Vasculitis Serious allergic/ Worsening ofdisorders reactions (see (including anti- anaphylactic symptoms of

Skin and neutrophilic reactions dermatomyositissubcutaneous cytoplasmic (includingtissue disorders), antibody positive angioedema,autoantibody vasculitis) bronchospasm),formation* sarcoidosis

Nervous system Headache CNSdisorders demyelinatingeventssuggestive ofmultiplesclerosis orlocaliseddemyelinatingconditions, suchas optic neuritisand transversemyelitis (seesection 4.4),peripheraldemyelinatingevents, including

Guillain-Barrésyndrome,chronicinflammatorydemyelinatingpolyneuropathy,

System Organ Very Common Uncommon Rare Very Rare Not Known

Class Common ≥ 1/100 ≥ 1/1,000 to ≥ 1/10,000 to < 1/10,000 (Cannot be≥ 1/10 to < 1/10 < 1/100 < 1/1,000 Estimatedfrom Available

Data)demyelinatingpolyneuropathy,and multifocalmotorneuropathy (seesection 4.4),seizure

Eye disorders Uveitis, scleritis

Cardiac Worsening of New onsetdisorders cardiac failure cardiac failurecongestive (see congestive (seesection 4.4) section 4.4)

Respiratory, Interstitial lungthoracic, and diseasemediastinal (includingdisorders pneumonitis andpulmonaryfibrosis)*

Gastrointestinal Inflammatorydisorders bowel disease

Hepatobiliary Elevated liver Autoimmunedisorders enzymes* hepatitis*

Skin and Pruritus, rash Angioedema, Stevens-Johnson Toxicsubcutaneous psoriasis (including syndrome, epidermaltissue disorders new onset or cutaneous necrolysisworsening and vasculitispustular, primarily (includingpalms and soles), hypersensitivityurticaria, vasculitis),psoriasiform rash erythemamultiforme,lichenoidreactions

Musculoskeletal Cutaneous lupusand connective erythematosus,tissue disorders subacutecutaneous lupuserythematosus,lupus-likesyndrome

Renal and Glomerulonephriurinary disorders tis

General Injection site Pyrexiadisorders and reactionsadministration (includingsite conditions bleeding,bruising,erythema,itching,pain,swelling)*

*see Description of selected adverse reactions, below.

One hundred and twenty-nine (129) new malignancies of various types were observed in4,114 rheumatoid arthritis patients treated in clinical trials with etanercept for up to approximately6 years, including 231 patients treated with etanercept in combination with methotrexate in a 2-yearactive-controlled study. The observed rates and incidences in these clinical trials were similar to thoseexpected for the population studied. A total of 2 malignancies were reported in clinical studies ofapproximately 2 years duration involving 240 etanercept-treated psoriatic arthritis patients. In clinicalstudies conducted for more than 2 years with 351 ankylosing spondylitis patients, 6 malignancies werereported in etanercept-treated patients. In a group of 2,711 plaque psoriasis patients treated withetanercept in double-blind and open-label studies of up to 2.5 years, 30 malignancies and43 non-melanoma skin cancers were reported.

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

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have also beenreceived in the post-marketing period (see section 4.4).

Compared to placebo, patients with rheumatic diseases treated with etanercept had a significantly higherincidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the firstmonth. Mean duration was approximately 3 to 5 days. No treatment was given for the majority ofinjection site reactions in the etanercept treatment groups, and the majority of patients who were giventreatment 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 recentsite of injection, along with the simultaneous appearance of injection site reactions at previous injectionsites. 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 withetanercept developed injection site reactions compared with 3.4% of placebo-treated patients during thefirst 12 weeks of treatment.

In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, orrequiring 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 (atvarious 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, skininfection, skin ulcer, urinary tract infection, vasculitis, and wound infection. In a 2-yearactive-controlled study where patients were treated with either etanercept alone, methotrexate alone oretanercept in combination with methotrexate, the rates of serious infections were similar among thetreatment groups. However, it cannot be excluded that the combination of etanercept with methotrexatecould be associated with an increase in the rate of infections.

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

Serious and fatal infections have been reported during use of etanercept; reported pathogens includebacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a fewweeks 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 rheumatoidarthritis (see section 4.4). Etanercept treatment may increase mortality in patients with establishedsepsis.

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 overallincidence of opportunistic infections was 0.09% for the 15,402 subjects who received etanercept. Theexposure-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 fungalinfections. The most commonly reported invasive fungal infections included Candida, Pneumocystis,

Aspergillus and Histoplasma. Invasive fungal infections accounted for more than half of the fatalitiesamongst patients who developed opportunistic infections. The majority of the reports with a fataloutcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, andaspergillosis (see section 4.4).

Adult patients had serum samples tested for autoantibodies at multiple timepoints. Of the rheumatoidarthritis patients evaluated for antinuclear antibodies (ANA), the percentage of patients who developednew positive ANA (≥ 1:40) was higher in patients treated with etanercept (11%) than in placebo-treatedpatients (5%). The percentage of patients who developed new positive anti-double-stranded DNAantibodies was also higher by radioimmunoassay (15% of patients treated with etanercept compared to4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with etanerceptcompared to none of placebo-treated patients). The proportion of patients treated with etanercept whodeveloped anticardiolipin antibodies was similarly increased compared to placebo-treated patients. Theimpact of long-term treatment with etanercept on the development of autoimmune diseases is unknown.

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

Pancytopenia and aplastic anaemia

There have been post-marketing reports of pancytopenia and aplastic anaemia, some of which had fataloutcomes (see section 4.4).

In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) ofinterstitial lung disease in patients receiving etanercept without concomitant methotrexate was 0.06%(frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept andmethotrexate, the frequency (incidence proportion) of interstitial lung disease was 0.47% (frequencyuncommon). There have been post-marketing reports of interstitial lung disease (including pneumonitisand 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 rateof serious infections compared to etanercept alone was observed and 2% of patients (3/139) developedneutropenia (absolute neutrophil count ˂ 1,000/mm3). While neutropenic, one patient developedcellulitis that resolved after hospitalisation (see sections 4.4 and 4.5).

In the double-blind periods of controlled clinical trials of etanercept across all indications, the frequency(incidence proportion) of adverse events of elevated liver enzymes in patients receiving etanerceptwithout concomitant methotrexate was 0.54% (frequency uncommon). In the double-blind periods ofcontrolled clinical trials that allowed concomitant treatment with etanercept and methotrexate, thefrequency (incidence proportion) of adverse events of elevated liver enzymes was 4.18% (frequencycommon).

Autoimmune hepatitis

In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) ofautoimmune hepatitis in patients receiving etanercept without concomitant methotrexate was 0.02%(frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept andmethotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0.24% (frequencyuncommon).

Undesirable effects in paediatric patients with juvenile idiopathic arthritis

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

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

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

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

Undesirable effects in paediatric patients with plaque psoriasis

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system listedin Appendix V.

No dose-limiting toxicities were observed during clinical trials of rheumatoid arthritis patients. Thehighest dose level evaluated has been an intravenous loading dose of 32 mg/m2 followed bysubcutaneous doses of 16 mg/m2 administered twice weekly. One rheumatoid arthritis patientmistakenly self-administered 62 mg etanercept subcutaneously twice weekly for 3 weeks withoutexperiencing undesirable effects. There is no known antidote to etanercept.

Pharmacotherapeutic group: Immunosuppressants, tumour necrosis factor alpha (TNF-α) inhibitors,

ATC code: L04AB01

Erelzi is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency https://www.ema.europa.eu.

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

TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent oncross-linking of cell surface TNFRs. Dimeric soluble receptors, such as etanercept, possess a higheraffinity for TNF than monomeric receptors and are considerably more potent competitive inhibitors of

TNF binding to its cellular receptors. In addition, use of an immunoglobulin Fc region as a fusionelement in the construction of a dimeric receptor imparts a longer serum half-life.

Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology inplaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controlled by

TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF bindingto cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNF biologicallyinactive. Etanercept may also modulate biologic responses controlled by additional downstreammolecules (e.g., cytokines, adhesion molecules, or proteinases) that are induced or regulated by TNF.

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

Adult patients with rheumatoid arthritis

The efficacy of etanercept was assessed in a randomised, double-blind, placebo-controlled study. Thestudy evaluated 234 adult patients with active rheumatoid arthritis who had failed therapy with at leastone but no more than four disease-modifying antirheumatic drugs (DMARDs). Doses of 10 mg or25 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 arthritisusing 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 inpatients treated with placebo (ACR 20: etanercept 62% and 59%, placebo 23% and 11% at 3 and6 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 andmonth 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receivingetanercept, the clinical responses generally appeared within 1 to 2 weeks after initiation of therapy andnearly always occurred by 3 months. A dose response was seen; results with 10 mg were intermediatebetween 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 ACRresponse criteria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), whichincluded disability, vitality, mental health, general health status, and arthritis-associated health statussubdomains, was administered every 3 months during the trial. All subdomains of the HAQ wereimproved 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 thesame magnitudes of responses as patients who received etanercept without interruption of therapy basedon results of open-label studies. Continued durable responses have been seen for up to 10 years inopen-label extension treatment trials when patients received etanercept without interruption.

The efficacy of etanercept was compared to methotrexate in a randomised, active-controlled study withblinded radiographic evaluations as a primary endpoint in 632 adult patients with active rheumatoidarthritis (< 3 years duration) who had never received treatment with methotrexate. Doses of 10 mg or25 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 first8 weeks of the trial and continued for up to 24 months. Clinical improvement, including onset of actionwithin 2 weeks with etanercept 25 mg, was similar to that seen in the previous trials and was maintainedfor up to 24 months. At baseline, patients had a moderate degree of disability, with mean HAQ scores of1.4 to 1.5. Treatment with etanercept 25 mg resulted in substantial improvement at 12 months, withabout 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 mgetanercept dose had consistently less effect on structural damage than the 25 mg dose. Etanercept 25 mgwas significantly superior to methotrexate for erosion scores at both 12 and 24 months. The differencesin TSS and JSN were not statistically significant between methotrexate and etanercept 25 mg. Theresults are shown in the figure below.

Radiographic progression: comparison of etanercept vs. methotrexate in patients with RA of < 3years duration

In another active-controlled, double-blind, randomised study, clinical efficacy, safety, and radiographicprogression in RA patients treated with etanercept alone (25 mg twice weekly), methotrexate alone (7.5to 20 mg weekly, median dose 20 mg), and the combination of etanercept and methotrexate initiatedconcurrently were compared in 682 adult patients with active rheumatoid arthritis of 6 months to20 years duration (median 5 years) who had a less than satisfactory response to at least 1disease-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 and52 weeks than patients in either of the single therapy groups (results shown in table below). Significantadvantages for etanercept in combination with methotrexate compared with etanercept monotherapy andmethotrexate monotherapy were also observed after 24 months.

Clinical efficacy results at 12 months: comparison of etanercept vs. methotrexate vs. etanercept incombination with methotrexate in patients with RA of 6 months to 20 years duration

Etanercept +

Endpoint Methotrexate Etanercept Methotrexate(n = 228) (n = 223) (n = 231)

ACR Responsesa ACR 20 58.8% 65.5% 74.5% †,ϕ

ACR 50 36.4% 43.0% 63.2% †, ϕ

ACR 70 16.7% 22.0% 39.8% †, ϕ

DAS Baseline scoreb 5.5 5.7 5.5

Week 52 scoreb 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 †, ϕa: 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.

Radiographic progression at 12 months was significantly less in the etanercept group than in themethotrexate group, while the combination was significantly better than either monotherapy at slowingradiographic progression (see figure below).

Radiographic progression: comparison of etanercept vs. methotrexate vs. etanercept incombination with methotrexate in patients with RA of 6 months to 20 years duration (12 monthresults)

Pairwise comparison p-values: * = p < 0.05 for comparisons of etanercept vs. methotrexate, † = p < 0.05for comparisons of etanercept + methotrexate vs. methotrexate and ϕ = p < 0.05 for comparisons ofetanercept + methotrexate vs. etanercept.

Significant advantages for etanercept in combination with methotrexate compared with etanerceptmonotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, thesignificant advantages for etanercept monotherapy compared with methotrexate monotherapy were alsoobserved after 24 months.

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

The safety and efficacy of 50 mg etanercept (two 25 mg SC injections) administered once weekly wereevaluated 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 patientsreceived 25 mg etanercept twice weekly. The safety and efficacy profiles of the two etanercepttreatment regimens were comparable at week 8 in their effect on signs and symptoms of RA; data atweek 16 did not show comparability (non-inferiority) between the two regimens. A single 50 mg/mlinjection of etanercept was found to be bioequivalent to two simultaneous injections of 25 mg/ml.

Adult patients with psoriatic arthritis

The efficacy of etanercept was assessed in a randomised, double-blind, placebo-controlled study in205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had activepsoriatic 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 andpresence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or (5) spondylitis-likeankylosis. Patients also had plaque psoriasis with a qualifying target lesion ≥ 2 cm in diameter. Patientshad previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patientscurrently 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 dose-finding studies in patientswith rheumatoid arthritis) or placebo were administered SC twice a week for 6 months. At the end ofthe double-blind study, patients could enter a long-term open-label extension study for a total durationof up to 2 years.

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

Responses of patients with psoriatic arthritis in a placebo-controlled trial

Percent of Patients

Psoriatic Arthritis Response Placebo Etanerceptan = 104 n = 101

ACR 20 Month 3 15 59b

Month 6 13 50b

ACR 50 Month 3 4 38b

Month 6 4 37b

ACR 70 Month 3 0 11b

Month 6 1 9c

PsARC Month 3 31 72b

Month 6 23 70ba: 25 mg etanercept SC twice weeklyb: p < 0.001, etanercept vs. placeboc: p < 0.01, etanercept vs. placebo

Among patients with psoriatic arthritis who received etanercept, the clinical responses were apparent atthe time of the first visit (4 weeks) and were maintained through 6 months of therapy. Etanercept wassignificantly better than placebo in all measures of disease activity (p < 0.001), and responses weresimilar with and without concomitant methotrexate therapy. Quality of life in psoriatic arthritis patientswas assessed at every timepoint using the disability index of the HAQ. The disability index score wassignificantly improved at all timepoints in psoriatic arthritis patients treated with etanercept, relative toplacebo (p < 0.001).

Radiographic changes were assessed in the psoriatic arthritis study. Radiographs of hands and wristswere obtained at baseline and months 6, 12, and 24. The modified TSS at 12 months is presented in thetable below. In an analysis in which all patients who dropped out of the study for any reason wereconsidered to have progressed, the percentage of patients without progression (TSS change ≤ 0.5) at12 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 inpatients who continued on treatment during the second year. The slowing of peripheral joint damagewas observed in patients with polyarticular symmetrical joint involvement.

Mean (SE) annualized change from baseline in total sharp score

Placebo Etanercept(n = 101)

Time (n = 104)

Month 12 1.00 (0.29) -0.03 (0.09)a

SE = standard error.

a. p = 0.0001.

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

There is insufficient evidence of the efficacy of etanercept in patients with ankylosing spondylitis-likeand arthritis mutilans psoriatic arthropathies due to the small number of patients studied.

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

Adult patients with ankylosing spondylitis

The efficacy of etanercept in ankylosing spondylitis was assessed in 3 randomised, double-blind studiescomparing twice-weekly administration of 25 mg etanercept with placebo. A total of 401 patients wereenrolled, from which 203 were treated with etanercept. The largest of these trials (n = 277) enrolledpatients who were between 18 and 70 years of age and had active ankylosing spondylitis defined asvisual 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, orcorticosteroids could continue them on stable doses. Patients with complete ankylosis of the spine werenot included in the study. Doses of 25 mg of etanercept (based on dose-finding studies in patients withrheumatoid arthritis) or placebo were administered subcutaneously twice a week for 6 months in138 patients.

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 responsesused 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 ina placebo-controlled trial

Percent of Patients

Ankylosing Spondylitis Placebo Etanercept

Response N = 139 N = 138

ASAS 202 weeks 22 46a3 months 27 60a6 months 23 58a

ASAS 502 weeks 7 24a3 months 13 45a6 months 10 42a

ASAS 702 weeks 2 12b3 months 7 29b6 months 5 28ba: p < 0.001, etanercept vs. placebob: p = 0.002, etanercept vs. placebo

Among patients with ankylosing spondylitis who received etanercept, the clinical responses wereapparent 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) administeredonce weekly vs. 25 mg etanercept administered twice weekly were evaluated in a double-blind,placebo-controlled study of 356 patients with active ankylosing spondylitis. The safety and efficacyprofiles of the 50 mg once-weekly and 25 mg twice-weekly regimens were similar.

Adult patients with non-radiographic axial spondyloarthritis

Study 1

The efficacy of etanercept in patients with non-radiographic axial spondyloarthritis (nr-AxSpa) wasassessed in a randomised, 12-week double-blind, placebo-controlled study. The study evaluated215 adult patients (modified intent-to-treat population) with active nr-AxSpa (18 to 49 years of age),defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did notmeet the modified New York criteria for AS. Patients were also required to have an inadequate responseor intolerance to two or more NSAIDs. In the double-blind period, patients received etanercept 50 mgweekly or placebo for 12 weeks. The primary measure of efficacy (ASAS 40) was a 40% improvementin at least three of the four ASAS domains and absence of deterioration in the remaining domain. Thedouble-blind period was followed by an open-label period during which all patients received etanercept50 mg weekly for up to an additional 92 weeks. MRIs of the sacroiliac joint and spine were obtained toassess 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 partialremission and BASDAI 50. Week 12 results are shown in the table below.

Efficacy response in placebo-controlled nr-AxSpa study: percent of patients achievingendpoints

Double-Blind Clinical 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

ASAS 5/6 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 Indexa: 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 patientsreceiving etanercept. Adjusted mean change from baseline was 3.8 for etanercept treated (n = 95) versus0.8 for placebo treated (n = 105) patients (p < 0.001). At week 104, the mean change from baseline inthe 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).

Etanercept showed statistically significantly greater improvement from baseline to week 12 compared toplacebo in most health-related quality of life and physical function assessments, including BASFI (Bath

Ankylosing Spondylitis Functional Index), EuroQol 5D Overall Health State Score and SF-36 Physical

Component Score.

Clinical responses among nr-AxSpa patients who received etanercept were apparent at the time of thefirst visit (2 weeks) and were maintained through 2 years of therapy. Improvements in health-relatedquality of life and physical function were also maintained through 2 years of therapy. The 2 year datadid not reveal any new safety findings. At week 104, 8 subjects had progressed to a score of bilateral

Grade 2 on spinal X-ray according to the modified New York Radiological Grade, indicative of axialspondyloarthropathy.

Study 2

This multi-center, open-label, phase 4, 3-period study evaluated the withdrawal and retreatment ofetanercept in patients with active nr-AxSpa who achieved an adequate response (inactive diseasedefined as Ankylosing Spondylitis Disease Activity Score (ASDAS) C-reactive protein (CRP) less than1.3) following 24 weeks of treatment.

209 adult patients with active nr-AxSpa (18 to 49 years of age), defined as those patients meeting the

Assessment of SpondyloArthritis International Society (ASAS) classification criteria of axialspondyloarthritis (but not meeting the modified New York criteria for AS), having positive MRIfindings (active inflammation on MRI highly suggestive of sacroiliitis associated with SpA) and/orpositive hsCRP (defined as high sensitivity C-reactive protein [hsCRP] >3 mg/l), and active symptomsdefined by an ASDAS CRP greater than or equal to 2.1 at the screening visit received open-labeletanercept 50 mg weekly plus stable background NSAID at the optimal tolerated anti inflammatorydosage for 24 weeks in Period 1. Patients were also required to have an inadequate response orintolerance to two or more NSAIDs. At week 24, 119 (57%) patients achieved inactive disease andentered into the Period 2 40-week withdrawal phase where subjects discontinued etanercept, yetmaintained the background NSAID. The primary measure of efficacy was the occurrence of flare(defined as an ASDAS erythrocyte sedimentation rate (ESR) greater than or equal to 2.1) within 40weeks following withdrawal of etanercept. Patients who flared were retreated with etanercept 50 mgweekly for 12 weeks (Period 3).

In Period 2, the proportion of patients experiencing ≥1 flare increased from 22% (25/112) at week 4 to67% (77/115) at week 40. Overall, 75% (86/115) patients experienced a flare at any time point within40 weeks following withdrawal of etanercept.

The key secondary objective of Study 2 was to estimate time to flare after withdrawal of etanercept andadditionally compare the time to flare to patients from Study 1 who met the Study 2 withdrawal phaseentry requirements and continued etanercept therapy.

The median time to flare following withdrawal of etanercept was 16 weeks (95% CI: 13-24 weeks).

Less than 25% of patients in Study 1 who did not have treatment withdrawn experienced a flare over theequivalent 40-weeks as in Period 2 Study 2. The time to flare was statistically significantly shorter insubjects who discontinued etanercept treatment (Study 2) compared to subjects who receivedcontinuous etanercept treatment (Study 1), p<0.0001.

Of the 87 patients who entered Period 3 and were retreated with etanercept 50 mg weekly for 12 weeks,62% (54/87) reachieved inactive disease, with 50% of them reachieving it within 5 weeks (95% CI: 4 8weeks).

Adult patients with plaque psoriasis

Etanercept is recommended for use in patients as defined in section 4.1. Patients who “failed to respondto” in the target population is defined by insufficient response (PASI < 50 or PGA less than good), orworsening of the disease while on treatment, and who were adequately dosed for a sufficiently longduration to assess response with at least one 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 etanerceptwith other systemic therapies. Instead, the safety and efficacy of etanercept were assessed in fourrandomised, double-blind, placebo-controlled studies. The primary efficacy endpoint in all four studieswas the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at least a 75%improvement in the Psoriasis Area and Severity Index score from baseline) at 12 weeks.

Study 1 was a Phase 2 study in patients with active, but clinically stable, plaque psoriasis involving≥ 10% of the body surface area who were ≥ 18 years old. One hundred and twelve (112) patients wererandomised to receive a dose of 25 mg of etanercept (n = 57) or placebo (n = 55) twice a week for24 weeks.

Study 2 evaluated 652 patients with chronic plaque psoriasis using the same inclusion criteria as study 1with the addition of a minimum psoriasis area and severity index (PASI) of 10 at screening. Etanerceptwas administered at doses of 25 mg once a week, 25 mg twice a week or 50 mg twice a week for 6consecutive months. During the first 12 weeks of the double-blind treatment period, patients receivedplacebo or one of the above three etanercept doses. After 12 weeks of treatment, patients in the placebogroup began treatment with blinded etanercept (25 mg twice a week); patients in the active treatmentgroups continued to week 24 on the dose to which they were originally randomised.

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

Study 4 evaluated 142 patients and had similar inclusion criteria to studies 2 and 3. Patients in this studyreceived a dose of 50 mg etanercept or placebo once weekly for 12 weeks and then all patients receivedopen-label 50 mg etanercept once weekly for an additional 12 weeks.

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

Responses of patients with psoriasis in studies 2, 3 and 4

Study 2 Study 3 Study 4

- -------Etanercept------- -----Etanercept----- -----Etanercept-----

Placebo 25 mg 50 mg Placebo 25 mg 50 mg Placebo 50 mg 50 mg

BIW BIW BIW BIW QW QWn = 166 n = n = n = n = n = 196 n = 196 n = 96 n = 90162 162 164 164 n = 193 n = 46

Response a(%) wk 12 wk wk wk wk12 24a 12 24a wk 12 wk 12 wk 12 wk 12 wk 12 wk 24

PASI 50 14 58* 70 74* 77 9 64* 77* 9 69* 83

PASI 75 4 34* 44 49* 59 3 34* 49* 2 38* 71

DSGAb,clear oralmostclear 5 34* 39 49* 55 4 39* 57* 4 39* 64

*p ≤ 0.0001 compared with placebo

a. No statistical comparisons to placebo were made at week 24 in studies 2 and 4 because the originalplacebo 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 placebowere 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 ofat least 50% at week 24 had treatment stopped. Patients were observed off treatment for the occurrenceof rebound (PASI ≥ 150% of baseline) and for the time to relapse (defined as a loss of at least half of theimprovement achieved between baseline and week 24). During the withdrawal period, symptoms ofpsoriasis gradually returned, with a median time to disease relapse of 3 months. No rebound flare ofdisease and no psoriasis-related serious adverse events were observed. There was some evidence tosupport a benefit of re-treatment with etanercept in patients initially responding to treatment.

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

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 onceweekly throughout the study, the efficacy responses continued to improve with 71% achieving PASI 75at week 24.

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

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

Antibodies to etanercept

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

Paediatric patients with juvenile idiopathic arthritis

The safety and efficacy of etanercept were assessed in a two-part study in 69 children with polyarticularcourse 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 severelyactive polyarticular-course juvenile idiopathic arthritis refractory to, or intolerant of, methotrexate wereenrolled; patients remained on a stable dose of a single non-steroidal anti-inflammatory drug and/orprednisone (< 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum25 mg per dose) etanercept subcutaneously twice weekly. In part 2, patients with a clinical response atday 90 were randomised to remain on etanercept or receive placebo for four months and assessed fordisease flare. Responses were measured using the ACR Pedi 30, defined as ≥ 30% improvement in atleast three of six and ≥ 30% worsening in no more than one of six JRA core set criteria, including activejoint count, limitation of motion, physician and patient/parent global assessments, functionalassessment, and erythrocyte sedimentation rate (ESR). Disease flare was defined as a ≥ 30% worseningin three of six JRA core set criteria and ≥ 30% improvement in not more than one of the six JRA coreset 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. Inpart 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. Ofpatients who demonstrated a clinical response at 90 days and entered part 2 of the study, some of thepatients remaining on etanercept continued to improve from month 3 through month 7, while those whoreceived placebo did not improve.

In an open-label, safety extension study, 58 paediatric patients from the above study (from the age of4 years at time of enrolment) continued to receive etanercept for up to 10 years. Rates of serious adverseevents and serious infections did not increase with long-term exposure.

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

In another open-label single-arm study (n=127), 60 patients with extended oligoarthritis (EO)(15 patients aged 2 to 4, 23 patients aged 5 to 11 and 22 patients aged 12 to 17 years old), 38 patientswith enthesitis-related arthritis (12 to 17 years old), and 29 patients with psoriatic arthritis (12 to17 years old) were treated with etanercept at a dose of 0.8 mg/kg (up to a maximum of 50 mg per dose)administered weekly for 12 weeks. In each of the JIA subtypes, the majority of patients met ACR

Pedi 30 criteria and demonstrated clinical improvement in secondary endpoints such as number oftender joints and physician global assessment. The safety profile was consistent with that observed inother JIA studies.

Of the 127 patients in the parent study, 109 participated in the open-label extension study and werefollowed for an additional 8 years for a total of up to 10 years. At the end of the extension study, 84/109(77%) patients had completed the study; 27 (25%) while actively taking etanercept, 7 (6%) hadwithdrawn from treatment due to low/inactive disease; 5 (5%) had re-started etanercept following anearlier withdrawal from treatment; and 45 (41%) had stopped etanercept (but remained underobservation); 25/109 (23%) patients permanently discontinued from the study. Improvements in clinicalstatus achieved in the parent study were generally maintained for all efficacy endpoints during the entirefollow-up period. Patients actively taking etanercept could enter an optional withdrawal-retreatmentperiod once during the extension study based on investigator’s judgement of clinical response.30 patients entered the withdrawal period. 17 patients were reported to have a flare (defined as ≥ 30%worsening in at least 3 of the 6 ACR Pedi components with ≥ 30% improvement in not more than 1 ofthe remaining 6 components and a minimum of 2 active joints); median time to flare after etanerceptwithdrawal was 190 days. 13 patients were re-treated and the median time to re-treatment fromwithdrawal was estimated as 274 days. Due to the small number of data points, these results should beinterpreted with caution.

The safety profile was consistent with that observed in the parent study.

Studies have not been done in patients with juvenile idiopathic arthritis to assess the effects of continuedetanercept 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 reducing the recommended doseof etanercept following its long-term use in patients with JIA.

Paediatric patients with plaque psoriasis

The efficacy of etanercept was assessed in a randomised, double-blind, placebo-controlled study in211 paediatric patients aged 4 to 17 years with moderate to severe plaque psoriasis (as defined by ansPGA score ≥ 3, involving ≥ 10% of the BSA, and PASI ≥ 12). Eligible patients had a history ofreceiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy.

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 thoserandomised to placebo.

Paediatric plaque psoriasis outcomes at 12 weeks

Etanercept Placebo0.8 mg/kg Once 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: sPGA-static Physician Global Assessment

a. p < 0.0001 compared with placebo

After the 12-week double-blind treatment period, all patients received etanercept 0.8 mg/kg (up to50 mg) once weekly for additional 24 weeks. Responses observed during the open-label period weresimilar to those observed in the double-blind period.

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

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

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

Etanercept is slowly absorbed from the site of subcutaneous injection, reaching maximum concentrationapproximately 48 hours after a single dose. The absolute bioavailability is 76%. With twice-weeklydoses, it is anticipated that steady-state concentrations are approximately twice as high as thoseobserved after single doses. After a single subcutaneous dose of 25 mg etanercept, the averagemaximum serum concentration observed in healthy volunteers was 1.65 ± 0.66 µg/ml, and the areaunder 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 mgetanercept once weekly (n = 21) vs. 25 mg etanercept twice weekly (n = 16), respectively. In anopen-label, single-dose, two-treatment, crossover study in healthy volunteers, etanercept administeredas a single 50 mg/ml injection was found to be bioequivalent to two simultaneous injections of25 mg/ml.

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 mgtwice weekly (N = 148), respectively.

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

Etanercept is cleared slowly from the body. The half-life is long, approximately 70 hours. Clearance isapproximately 0.066 l/hr in patients with rheumatoid arthritis, somewhat lower than the value of0.11 l/hr observed in healthy volunteers. Additionally, the pharmacokinetics of etanercept in rheumatoidarthritis patients, ankylosing spondylitis and plaque psoriasis patients are similar.

There is no apparent pharmacokinetic difference between males and females.

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

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

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

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

Paediatric patients with juvenile idiopathic arthritis

In a polyarticular-course juvenile idiopathic arthritis trial with etanercept, 69 patients (aged 4 to17 years) were administered 0.4 mg etanercept/kg twice weekly for three months. Serum concentrationprofiles were similar to those seen in adult rheumatoid arthritis patients. The youngest children (4 yearsof age) had reduced clearance (increased clearance when normalised by weight) compared with olderchildren (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 haveappreciably lower levels.

Paediatric patients with plaque psoriasis

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

In the toxicological studies with etanercept, no dose-limiting or target organ toxicity was evident.

Etanercept was considered to be non-genotoxic from a battery of in vitro and in vivo studies.

Carcinogenicity studies, and standard assessments of fertility and postnatal toxicity, were not performedwith etanercept due to the development of neutralising antibodies in rodents.

Etanercept did not induce lethality or notable signs of toxicity in mice or rats following a singlesubcutaneous dose of 2,000 mg/kg or a single intravenous dose of 1,000 mg/kg. Etanercept did not elicitdose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneousadministration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AUC-based serumdrug concentrations that were over 27-fold higher than that obtained in humans at the recommendeddose of 25 mg.

Citric acid anhydrous

Sodium citrate dihydrate

Sodium chloride

Sucrose

L-Lysine hydrochloride

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

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 Erelzisolution in the syringe to reach room temperature. Do not warm in any other way. Immediate use is thenrecommended.

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 weeksof removal from refrigeration.

Erelzi solution for injection in pre-filled syringe

Clear type I glass syringe with a stainless steel 29 gauge 12.7 mm needle with a needle guard withfinger flange, a rubber needle cap (thermoplastic elastomer) and a rubber plunger stopper (bromobutylrubber), containing 0.5 ml or 1.0 ml of solution.

Cartons contain 1, 2 or 4 pre-filled syringes.

Multipacks containing 12 (3 packs of 4) 25 mg or 50 mg pre-filled syringes or 8 (2 packs of 4) or24 (6 packs of 4) 25 mg pre-filled syringes of Erelzi.

Not all pack sizes may be marketed.

Erelzi 50 mg solution for injection in pre-filled pen

Erelzi is supplied in a single-use pre-filled syringe assembled into a triangular-shaped pen withtransparent window and label. The syringe inside the pen is made from clear type I glass with a stainlesssteel 29 gauge 12.7 mm needle and an inner rubber needle cap (thermoplastic elastomer) and a rubberplunger stopper (bromobutyl rubber), containing 1.0 ml of solution.

Cartons of 1, 2 or 4 pre-filled pens.

Multipacks containing 12 (3 packs of 4) pre-filled pens.

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-filledsyringe to reach room temperature. The solution should be clear to slightly opalescent, colourless toslightly yellowish and may contain small translucent or white particles of protein.

Comprehensive instructions for administration are given in the package leaflet, section 7, 'Instructionsfor use of the Erelzi pre-filled syringe'.

Instructions for use and handling of the Erelzi pre-filled 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-filledpen to reach room temperature. By looking through the viewing window, the solution should be clear toslightly opalescent, colourless to slightly yellowish and may contain small translucent or white particlesof protein.

Comprehensive instructions for administration are given in the package leaflet, section 7, 'Instructionsfor use of the Erelzi pre-filled pen'.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sandoz GmbH

Biochemiestrasse 106250 Kundl

Austria

Erelzi 25 mg solution for injection in pre-filled syringe

EU/1/17/1195/001

EU/1/17/1195/002

EU/1/17/1195/003

EU/1/17/1195/004

EU/1/17/1195/013

EU/1/17/1195/014

Erelzi 50 mg solution for injection in pre-filled syringe

EU/1/17/1195/005

EU/1/17/1195/006

EU/1/17/1195/007

EU/1/17/1195/008

Erelzi 50 mg solution for injection in pre-filled pen

EU/1/17/1195/009

EU/1/17/1195/010

EU/1/17/1195/011

EU/1/17/1195/012

Date of first authorisation: 23 June 2017

Date of latest renewal: 04 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.