BENEPALI 50mg injectible solution medication leaflet

Benepali 50 mg solution for injection in pre-filled syringe

Benepali 50 mg solution for injection in pre-filled pen

50 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 50 mg of etanercept.

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).

The solution is clear to slightly opalescent, colourless or pale yellow, and is formulated at pH 6.2 ±0.3. The osmolality of the solution is 325 ± 35 mOsm/kg.

Benepali 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.

Benepali can be given as monotherapy in case of intolerance to methotrexate or when continuedtreatment with methotrexate is inappropriate.

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

Benepali, 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 ofthe disease.

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 nonsteroidal 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.

Benepali treatment should be initiated and supervised by specialist physicians experienced in thediagnosis and treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis,ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis or paediatric plaquepsoriasis. Patients treated with Benepali should be given the Patient Card.

Benepali is available in strengths of 25 and 50 mg.

The recommended dose is 50 mg etanercept administered once weekly (see section 5.1).

Psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis

The recommended dose is 50 mg etanercept administered once weekly.

For all of the above indications, available data suggest that a clinical response is usually achievedwithin 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient notresponding within this time period.

Plaque psoriasis

The recommended dose of etanercept is 50 mg administered once weekly. Alternatively, 50 mg giventwice weekly may be used for up to 12 weeks followed, if necessary, by a dose of 50 mg once weekly.

Treatment with Benepali should continue until remission is achieved, for up to 24 weeks. Continuoustherapy beyond 24 weeks may be appropriate for some adult patients (see section 5.1). Treatmentshould be discontinued in patients who show no response after 12 weeks. If re-treatment with Benepaliis indicated, the same guidance on treatment duration should be followed. The dose should be 50 mgonce weekly.

No dose adjustment is required.

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

Benepali is only available as 25 mg pre-filled syringe, 50 mg pre-filled syringe and 50 mg pre-filledpen.

Thus, it is not possible to administer Benepali to paediatric patients that require less than a full 25 mgor 50 mg dose. Paediatric patients who require a dose other than a full 25 mg or 50 mg should notreceive Benepali. If an alternate dose is required, other etanercept products offering such an optionshould be used.

The dosage 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 presentations (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 etanercept 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 patientswho show 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 Benepali 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.

Benepali is for subcutaneous use (see section 6.6).

Comprehensive instructions for administration are given in the package leaflet, section 7, “Instructionsfor use”.

Detailed instructions on unintentional dosing or scheduling variations, including missed doses, areprovided in section 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 Benepali should not be initiated in patients with active infections, including chronic orlocalised infections.

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

Patients should be evaluated for infections before, during, and after treatment with Benepali, takinginto consideration that the mean elimination half-life of etanercept is approximately 70 hours (range7 to 300 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, resultingin delay of appropriate treatment and sometimes death. In evaluating patients for infections, thepatient’s risk for relevant opportunistic infections (e.g., exposure to endemic mycoses) should beconsidered.

Patients who develop a new infection while undergoing treatment with Benepali should be monitoredclosely. Administration of Benepali should be discontinued if a patient develops a serious infection.

The safety and efficacy of etanercept in patients with chronic infections have not been evaluated.

Physicians should exercise caution when considering the use of Benepali in patients with a history ofrecurring or chronic infections or with underlying conditions that may predispose patients toinfections, such as advanced 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 Benepali, all patients must be evaluated for both active and inactive(‘latent’) tuberculosis. This evaluation should include a detailed medical history with personal historyof tuberculosis 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, Benepali therapy must not be initiated. If inactive (‘latent’)tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosistherapy before the initiation of Benepali, and in accordance with local recommendations. In thissituation, the benefit/risk balance of Benepali 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 Benepalitreatment.

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 Benepali. For patients whotest positive for HBV infection, consultation with a physician with expertise in the treatment ofhepatitis B is recommended. Caution should be exercised when administering Benepali in patientspreviously 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. Adequatedata 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, Benepali should bestopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

Worsening of hepatitis C

There have been reports of worsening of hepatitis C in patients receiving etanercept. Benepali shouldbe used with caution in patients with a history of hepatitis C.

Concurrent treatment with anakinra

Concurrent administration of etanercept and anakinra has been associated with an increased risk ofserious infections and neutropenia compared to etanercept alone. This combination has notdemonstrated increased clinical benefit. Thus, the combined use of Benepali 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 clinicalbenefit; 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, Benepali therapy should be discontinued immediately andappropriate therapy initiated.

The possibility exists for TNF-antagonists, including etanercept, to affect host defences againstinfections and malignancies since TNF mediates inflammation and modulates cellular immuneresponses. In a study of 49 adult patients with rheumatoid arthritis treated with etanercept, there wasno evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, orchange in enumeration 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 Benepali therapy and be considered for prophylactic treatmentwith 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 patientsreceiving TNF-antagonist therapy. In the post-marketing setting, cases of leukaemia have beenreported in patients treated with TNF-antagonists. There is an increased background risk forlymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active,inflammatory disease, which complicates risk estimation.

Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or 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 typicallyassociated with immunosuppression. A risk for the development of malignancies in children andadolescents treated with TNF-antagonists cannot be excluded.

Skin cancers

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF-antagonists, including etanercept. Post-marketing cases of Merkel cell carcinoma have been reportedvery infrequently in patients treated with etanercept. Periodic skin examination is recommended for allpatients, 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 Benepali. 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 Benepali 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, havebeen reported in patients treated with etanercept. Caution should be exercised in patients being treatedwith Benepali who have a previous history of blood dyscrasias. All patients and parents/caregiversshould be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias orinfections (e.g., persistent fever, sore throat, bruising, bleeding, and paleness) whilst on Benepali, theyshould seek immediate medical advice. Such patients should be investigated urgently, including fullblood count; if blood dyscrasias are confirmed, Benepali should be discontinued.

Neurological disorders

There have been rare reports of CNS demyelinating disorders in patients treated with etanercept (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 havebeen 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 carefulrisk/benefit evaluation, including a neurologic assessment, is recommended when prescribing Benepalito patients with pre-existing or recent onset of demyelinating disease, or to those who are consideredto have 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-modifyingantirheumatic drugs (DMARD) has not been established.

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

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

Congestive heart failure (Cardiac failure congestive)

Physicians should use caution when using Benepali 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 ofetanercept in the treatment of CHF were terminated early due to lack of efficacy. Although notconclusive, data from one of these trials suggest a possible tendency toward worsening CHF in thosepatients assigned to etanercept 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 mortalityrate in patients treated with etanercept was significantly higher after 6 months. Consequently, Benepalishould not be used in patients for the treatment of alcoholic hepatitis. Physicians should use cautionwhen using Benepali 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 significantlyhigher in patients treated with etanercept than in the control group. Benepali is not recommended forthe treatment of Wegener’s granulomatosis.

Hypoglycaemia in patients treated for diabetes

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

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

Vaccinations, above).

Benepali contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 50 mg, that is to say essentially‘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 (historicaldata).

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 and4.8). 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 clinicalbenefit; 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 significantdecrease in mean white blood cell counts in comparison to groups treated with etanercept orsulfasalazine alone. The clinical significance of this interaction is unknown. Physicians should usecaution when considering combination therapy with sulfasalazine.

Non-interactions

In clinical trials, no interactions have been observed when etanercept was administered withglucocorticoids, salicylates (except sulfasalazine), nonsteroidal 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 Benepali 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 inan observational study comparing pregnancies exposed to etanercept (n=370) during the first trimester,with pregnancies not exposed to etanercept or other TNF-antagonists (n=164) (adjusted odds ratio 2.4,95% CI: 1.0-5.5). The types of major birth defects were consistent with those most commonly reportedin the general population and no particular pattern of abnormalities was identified. No change in therate of spontaneous abortion, stillbirth, or minor malformations was observed. In another observationalmulti-country registry study comparing the risk of adverse pregnancy outcomes in women exposed toetanercept during the first 90 days of pregnancy (n=425) to those exposed to non-biologic medicinalproducts (n=3,497), 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. Benepali 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, infantsmay be at increased risk of infection. Administration of live vaccines to infants for 16 weeks after themother’s last dose of Benepali 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.

Etanercept has no or neglegible 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 defenses 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. Theseinclude rare 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 and on post-marketing experience.

Within the System Organ Class, 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 availabledata)

Infections and Infection Serious infections Tuberculosis, Hepatitis Binfestations (including (including opportunistic reactivation,upper pneumonia, infections listeriarespiratory cellulitis, arthritis (includingtract bacterial, sepsis invasive fungal,infection, and parasitic protozoal,bronchitis, infection)* bacterial,cystitis, skin atypicalinfection)* mycobacterial,viral infectionsand 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’s(incl. cysts and leukaemia sarcomapolyps)

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

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

Skin and neutrophilic ctic reactions dermatomyositisubcutaneous cytoplasmic (including stissue disorders), antibody positive angioedema,autoantibody vasculitis) bronchospasm),formation* sarcoidosis

Nervous system Headache CNSdisorders demyelinatingcases suggestiveof multiplesclerosis orlocaliseddemyelinatingconditions, suchas optic neuritisand transversemyelitis (see

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 availabledata)section 4.4),peripheraldemyelinatingevents, including

Guillain-Barrésyndrome,chronicinflammatorydemyelinatingpolyneuropathy,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

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 availabledata)

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 in 4,114rheumatoid 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 the 2-year active-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 and 43nonmelanoma skin cancers were reported.

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

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

Compared to placebo, patients with rheumatic diseases treated with etanercept had a significantlyhigher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred inthe first month. Mean duration was approximately 3 to 5 days. No treatment was given for themajority of injection site reactions in the etanercept treatment groups, and the majority of patients whowere given treatment received topical preparations, such as corticosteroids, or oral antihistamines.

Additionally, some patients developed recall injection site reactions characterised by a skin reaction atthe most recent site of injection, along with the simultaneous appearance of injection site reactions atprevious injection sites. These reactions were generally transient and did not recur with treatment.

In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated withetanercept developed injection site reactions compared with 3.4% of placebo-treated patients duringthe first 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 the 2-year active-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 withmethotrexate could 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 theirrheumatoid arthritis (see section 4.4). Benepali treatment may increase mortality in patients withestablished 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 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 invasivefungal infections. The most commonly reported invasive fungal infections included Candida,

Pneumocystis, Aspergillus, and Histoplasma. Invasive fungal infections accounted for more than halfof the fatalities amongst patients who developed opportunistic infections. The majority of the reportswith a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungalinfections, and aspergillosis (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-treated patients (5%). The percentage of patients who developed new positive anti-double-stranded

DNA antibodies was also higher by radioimmunoassay (15% of patients treated with etanerceptcompared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treatedwith etanercept compared to none of placebo-treated patients). The proportion of patients treated withetanercept who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with etanercept on the development ofautoimmune 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 arecompatible with 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 hadfatal outcomes (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 etanerceptand methotrexate, the frequency (incidence proportion) of interstitial lung disease was 0.47%(frequency uncommon). There have been post-marketing reports of interstitial lung disease (includingpneumonitis and pulmonary fibrosis), some of which had fatal outcomes.

Concurrent treatment with anakinra

In studies when adult patients received concurrent treatment with etanercept plus anakinra, a higherrate 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 patientdeveloped cellulitis 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, thefrequency (incidence proportion) of adverse events of elevated liver enzymes in patients receivingetanercept without concomitant methotrexate was 0.54% (frequency uncommon). In the double-blindperiods of controlled clinical trials that allowed concomitant treatment with etanercept andmethotrexate, the frequency (incidence proportion) of adverse events of elevated liver enzymes was4.18% (frequency common).

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 etanerceptand methotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0.24%(frequency uncommon).

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 of open-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,and the majority were mild. Several adverse events were reported more commonly in 69 juvenileidiopathic arthritis patients receiving 3 months of etanercept compared to the 349 adult rheumatoidarthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%,1.0 event per patient year), abdominal pain (19%, 0.74 events per patient year), and vomiting (13%,0.74 events per patient year).

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

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 systemlisted in 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

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

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

Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of 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 inpsoriatic lesions compared with levels in uninvolved skin. Etanercept is a competitive inhibitor of

TNF binding to its cell surface receptors, and thereby inhibits the biological activity of TNF. TNF andlymphotoxin are pro-inflammatory cytokines that bind to two distinct cell surface receptors: the 55-kilodalton (p55) and 75-kilodalton (p75) tumour necrosis factor receptors (TNFRs). Both TNFRs existnaturally in membrane-bound and soluble forms. Soluble TNFRs are thought to regulate TNFbiological 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 TNFbinding to cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNFbiologically inactive. Etanercept may also modulate biologic responses controlled by additionaldownstream molecules (e.g., cytokines, adhesion molecules, or proteinases) that are induced orregulated by TNF.

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

Adult patients with rheumatoid arthritis

The efficacy of 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 consecutivemonths. The results of this controlled trial were expressed in percentage improvement in rheumatoidarthritis using American College of Rheumatology (ACR) response criteria.

ACR 20 and 50 responses were higher in patients treated with etanercept at 3 and 6 months than 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 50responses).

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

ACR response 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.

Reintroduction 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 therapybased on results of open-label studies. Continued durable responses have been seen for up to 10 yearsin open-label extension treatment trials when patients received etanercept without interruption.

The efficacy of etanercept was compared to methotrexate in a randomised, active-controlled studywith blinded radiographic evaluations as a primary endpoint in 632 adult patients with activerheumatoid arthritis (< 3 years duration) who had never received treatment with methotrexate. Dosesof 10 mg or 25 mg etanercept were administered subcutaneously (SC) twice a week for up to24 months. Methotrexate doses were escalated from 7.5 mg/week to a maximum of 20 mg/week overthe first 8 weeks of the trial and continued for up to 24 months. Clinical improvement, including onsetof action within 2 weeks with etanercept 25 mg, was similar to that seen in the previous trials and wasmaintained 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 at12 months, with about 44% of patients achieving a normal HAQ score (less than 0.5). This benefit wasmaintained 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. Etanercept25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. Thedifferences in TSS and JSN were not statistically significant between methotrexate and etanercept25 mg. The results are shown in the figure below.

Radiographic progression: comparison of etanercept vs. methotrexate in patients with RA of < 3years duration2.5 12 Months 2.5 24 Months2.22.0 2.01.5 1.3 1.51.2 1.31.0 0.8 0.9 1.0 0.90.6* 0.60.5 0.4* 0.4 0.4 0.50.0 0.0

TSS Erosions JSN TSS Erosions JSN

MTX

Etanercept 25 mg

*p < 0.05

In another active-controlled, double-blind, randomised study, clinical efficacy, safety, andradiographic 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 andmethotrexate initiated concurrently were compared in 682 adult patients with active rheumatoidarthritis of 6 months to 20 years duration (median 5 years) who had a less than satisfactory response toat 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 and52 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 etanerceptmonotherapy and methotrexate monotherapy were also observed after 24 months.

Change from Baseline

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

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

ACR ACR 20 58.8% 65.5% 74.5%†, Φ

Responsesa ACR 50 36.4% 43.0% 63.2%†, Φ

ACR 70 16.7% 22.0% 39.8%†, Φ

DAS (Scoreb) Baseline 5.5 5.7 5.5(Scoreb) Week 52 3.0 3.0 2.3†, Φ

Remissionc 14% 18% 37%†, Φ

HAQ Baseline 1.7 1.7 1.8

Week 52 1.1 1.0 0.8†, 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 atslowing radiographic 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)3.0 2.80 Methotrexate

Etanercept2.5 Etanercept +

Methotrexate2.0 1.681.51.121.00.52*0.5 0.21* 0.320.0

- 0.5 -0.30† -0.23†, Φ

- 0.54†, Φ

- 1.0

TSS Erosions JSN

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 forcomparisons of etanercept + 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 werealso observed after 24 months.

Change from Baseline

In an analysis in which all patients who dropped out of the study for any reason were considered tohave progressed, the percentage of patients without progression (TSS change ≤ 0.5) at 24 months washigher in the etanercept in combination with methotrexate group compared with the etanercept aloneand methotrexate 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 whocompleted a full 24 months of therapy in the study, the non-progression rates were 78%, 70%, and61%, respectively.

The safety and efficacy of 50 mg etanercept (two 25 mg SC injections) administered once weeklywere evaluated in a double-blind, placebo-controlled study of 420 patients with active RA. In thisstudy, 53 patients received placebo, 214 patients received 50 mg etanercept once weekly and153 patients received 25 mg etanercept twice weekly. The safety and efficacy profiles of the twoetanercept 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 single50 mg/ml injection of etanercept was found to be bioequivalent to two simultaneous injections of25 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 nodulesand 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 stabledose of ≤ 25 mg/week methotrexate. Doses of 25 mg of etanercept (based on dose-finding studies inpatients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months. At theend of the double-blind study, patients could enter a long-term open-label extension study for a totalduration of up to 2 years.

Clinical responses were expressed as percentages of patients achieving the ACR 20, 50, and 70response and percentages with improvement in Psoriatic Arthritis Response Criteria (PsARC). Resultsare summarised 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 apparentat the time of the first visit (4 weeks) and were maintained through 6 months of therapy. Etanerceptwas significantly better than placebo in all measures of disease activity (p < 0.001), and responseswere similar with and without concomitant methotrexate therapy. Quality of life in psoriatic arthritispatients was assessed at every timepoint using the disability index of the HAQ. The disability indexscore was significantly improved at all timepoints in psoriatic arthritis patients treated with etanercept,relative to placebo (p < 0.001).

Radiographic changes were assessed in the psoriatic arthritis study. Radiographs of hands and wristswere obtained at baseline and months 6, 12, and 24. The modified TSS at 12 months is presented inthe table 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) annualised change from baseline in total sharp score

Time Placebo Etanercept(n = 104) (n = 101)

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

SE = standard errora 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-blindstudies comparing twice-weekly administration of 25 mg etanercept with placebo. A total of 401patients 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 ankylosingspondylitis defined as visual analog scale (VAS) scores of ≥ 30 for average of duration and intensityof morning stiffness plus VAS scores of ≥ 30 for at least 2 of the following 3 parameters: patientglobal assessment; average of VAS values for nocturnal back pain and total back pain; average of 10questions on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients receiving

DMARDs, NSAIDS, or corticosteroids could continue them on stable doses. Patients with completeankylosis 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 subcutaneouslytwice a week for 6 months in 138 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 and70 responses used the same criteria with a 50% improvement or a 70% improvement, respectively.

Compared to placebo, treatment with etanercept resulted in significant improvements in the ASAS 20,

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

Responses of patients with ankylosing spondylitis in a placebo-controlled trial

Percent of patients

Ankylosing spondylitis response Placebo Etanerceptn = 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 inadequateresponse or intolerance to two or more NSAIDs. In the double-blind period, patients receivedetanercept 50 mg weekly or placebo for 12 weeks. The primary measure of efficacy (ASAS 40) was a40% improvement in at least three of the four ASAS domains and absence of deterioration in theremaining domain. The double-blind period was followed by an open-label period during which allpatients receive etanercept 50 mg weekly for up to an additional 92 weeks. MRIs of the sacroiliac jointand spine were obtained to assess inflammation at baseline and at weeks 12 and 104.

Compared to placebo, treatment with etanercept resulted in statistically significant improvement in the

ASAS 40, ASAS 20 and ASAS 5/6. Significant improvement was also observed for the ASAS partialremission and BASDAI 50. Week 12 results are shown in the table below.

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

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)versus 0.8 for placebo treated (n = 105) patients (p < 0.001). At week 104, the mean change frombaseline 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).

Etanercept showed statistically significantly greater improvement from baseline to week 12 comparedto placebo 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) lessthan 1.3) 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 activesymptoms defined by an ASDAS CRP greater than or equal to 2.1 at the screening visit received openlabel etanercept 50 mg weekly plus stable background NSAID at the optimal tolerated anti-inflammatory dosage for 24 weeks in Period 1. Patients were also required to have an inadequateresponse or intolerance to two or more NSAIDs. At week 24, 119 (57%) patients achieved inactivedisease and entered into the Period 2 40-week withdrawal phase where subjects discontinuedetanercept, yet maintained the background NSAID. The primary measure of efficacy was theoccurrence of flare (defined as an ASDAS erythrocyte sedimentation rate (ESR) greater than or equalto 2.1) within 40 weeks following withdrawal of etanercept. Patients who flared were retreated withetanercept 50 mg weekly 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 etanerceptand additionally compare the time to flare to patients from Study 1 who met the Study 2 withdrawalphase entry 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 overthe equivalent 40-weeks as in Period 2 Study 2. The time to flare was statistically significantly shorterin subjects 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 12weeks, 62% (54/87) reachieved inactive disease, with 50% of them reachieving it within 5 weeks(95% CI: 4 8 weeks).

Adult patients with plaque psoriasis

Etanercept is recommended for use in patients as defined in section 4.1. Patients who “failed torespond to” in the target population is defined by insufficient response (PASI < 50 or PGA less thangood), or worsening of the disease while on treatment, and who were adequately dosed for asufficiently long duration to assess response with at least one of the three major systemic therapies asavailable.

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 comparingetanercept with other systemic therapies. Instead, the safety and efficacy of etanercept were assessedin four randomised, double-blind, placebo-controlled studies. The primary efficacy endpoint in all fourstudies was the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at leasta 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 for 24weeks.

Study 2 evaluated 652 patients with chronic plaque psoriasis using the same inclusion criteria as study1 with the addition of a minimum psoriasis area and severity index (PASI) of 10 at screening.

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

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 thisstudy received a dose of 50 mg etanercept or placebo once weekly for 12 weeks and then all patientsreceived open-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 PASI75 response 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 placebo-treated 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

Placeb 25 mg Placeb 25 m 50 m 50 m 50

Response o BIW 50 mg BIW o g g Placebo g mg(%) BIW BIW QW QWn = n = n = n = n = n = 193 n = n = n = n =166 162 162 164 164 196 196 n = 46 96 90wk 12 wk wk wk wk12 24a 12 24a wk 12 wk wk12 12 wk 12 wk wk12 24a

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 or * *almost 5 34 39 49 55 4 39* 57* 4 39* 64clear

* p ≤ 0.0001 compared with placeboa 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 week24.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 toplacebo were apparent at the time of the first visit (2 weeks) and were maintained through 24 weeks oftherapy.

Study 2 also had a drug withdrawal period during which patients who achieved a PASI improvementof at least 50% at week 24 had treatment stopped. Patients were observed off treatment for theoccurrence of rebound (PASI ≥ 150% of baseline) and for the time to relapse (defined as a loss of atleast half of the improvement achieved between baseline and week 24). During the withdrawal period,symptoms of psoriasis gradually returned, with a median time to disease relapse of 3 months. Norebound flare of disease and no psoriasis-related serious adverse events were observed. There wassome evidence to support a benefit of re-treatment with etanercept in patients initially responding totreatment.

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

PASI 75 response continued to improve between weeks 12 and 36.

In study 4, the 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 75 at 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 generally been non-neutralising and 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 withpolyarticular-course juvenile idiopathic arthritis who had a variety of juvenile idiopathic arthritis onsettypes (polyarthritis, pauciarthritis, systemic onset). Patients aged 4 to 17 years with moderately toseverely active polyarticular-course juvenile idiopathic arthritis refractory to, or intolerant of,methotrexate were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug and/or prednisone (< 0.2 mg/kg/day or 10 mg maximum). In part 1, all patientsreceived 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 placebofor 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/parentglobal assessments, functional assessment, and erythrocyte sedimentation rate (ESR). Disease flarewas defined as a 30% worsening in three of six JRA core set criteria and 30% improvement in notmore 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. Inpart 2, 6 of 25 (24%) patients remaining on etanercept experienced a disease flare compared to 20 of26 (77%) patients receiving placebo (p = 0.007). From the start of part 2, the median time to flare was116 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 thosewho received 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 seriousadverse events 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 aged2 to 18 years with juvenile idiopathic arthritis, 39 of whom were 2 to 3 years of age. Overall,infections were more commonly reported in patients treated with etanercept compared to methotrexatealone (3.8 versus 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 oligoarthrits (EO) (15patients aged 2 to 4, 23 patients aged 5 to 11 and 22 patients aged 12 to 17 years old), 38 patients withenthesitis-related arthritis (12 to 17 years old), and 29 patients with psoriatic arthritis (12 to 17 yearsold) 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 Pedi30 criteria and demonstrated clinical improvement in secondary endpoints such as number of tenderjoints and physician global assessment. The safety profile was consistent with that observed in other

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 inclinical status achieved in the parent study were generally maintained for all efficacy endpoints duringthe entire follow-up period. Patients actively taking etanercept could enter an optional withdrawal-retreatment period once during the extension study based on investigator’s judgement of clinicalresponse. 30 patients entered the withdrawal period. 17 patients were reported to have a flare (definedas ≥ 30% worsening in at least 3 of the 6 ACR Pedi components with ≥ 30% improvement in not morethan 1 of the remaining 6 components and a minimum of 2 active joints); median time to flare afteretanercept withdrawal was 190 days. 13 patients were re-treated and the median time to re-treatmentfrom withdrawal was estimated as 274 days. Due to the small number of data points, these resultsshould be interpreted 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 ofcontinued etanercept therapy in patients who do not respond within 3 months of initiating etanercepttherapy. Additionally, studies have not been conducted to assess the effects of reducing therecommended dose of 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. Atweek 12, more patients randomised to etanercept had positive efficacy responses (e.g., PASI 75) thanthose randomised to placebo.

Paediatric plaque psoriasis outcomes at 12 weeks

Etanercept0.8 mg/kg once Placeboweekly (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 Assessmenta 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 wasassessed in an open-label extension study of 181 paediatric subjects with plaque psoriasis for up to2 years beyond the 48 week study discussed above. Long-term experience with etanercept wasgenerally comparable 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 maximumconcentration approximately 48 hours after a single dose. The absolute bioavailability is 76%. Withtwice-weekly doses, it is anticipated that steady-state concentrations are approximately twice as highas those observed 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 intreated 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 AUCof 297 mg × hr/l vs. 316 mg × hr/l for 50 mg etanercept once weekly (n = 21) vs. 25 mg etanercepttwice weekly (n = 16), respectively. In an open-label, single-dose, two-treatment, crossover study inhealthy volunteers, etanercept administered as a single 50 mg/ml injection was found to bebioequivalent to two simultaneous injections of 25 mg/ml.

In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steadystate AUCs were 466 μg × hr/ml and 474 μg × hr/ml for 50 mg etanercept once weekly (n = 154) and25 mg twice 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 inrheumatoid arthritis 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 etanerceptto patients and volunteers, increased etanercept concentrations were not observed in patients withacute renal 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 etanerceptserum concentrations. 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 years of age) had reduced clearance (increased clearance when normalised by weight) comparedwith older children (12 years of age) and adults. Simulation of dosing suggests that while olderchildren (10-17 years of age) will have serum levels close to those seen in adults, younger childrenwill have appreciably lower levels.

Paediatric patients with plaque psoriasis

Patients with paediatric plaque psoriasis (aged 4 to 17 years) were administered 0.8 mg/kg (up to 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 observedin patients 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 notperformed with 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 notelicit dose-limiting or target organ toxicity in cynomolgus monkeys following twice weeklysubcutaneous administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AUC-based serum concentrations that were over 27-fold higher than that obtained in humans at therecommended dose of 25 mg.

Sucrose

Sodium chloride

Sodium dihydrogen phosphate monohydrate

Disodium hydrogen phosphate heptahydrate

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 or pens in the outer carton in order to protect from light.

After taking a syringe or a pen from the refrigerator, wait approximately 30 minutes to allow the

Benepali solution in the syringe or the pen to reach room temperature. Do not warm in any other way.

Immediate use is then recommended.

Benepali may be stored at temperatures up to a maximum of 30°C for a single period of up to 31 days;after which, it should not be refrigerated again. Benepali should be discarded if not used within 31days of removal from refrigeration.

50 mg solution for injection in pre-filled syringe

Clear glass (type I) pre-filled syringe with stainless steel needle, rubber needle cover and rubberplunger containing 0.98 ml of solution.

Benepali is available in packs containing 4 pre-filled syringes and multipacks containing 12 (3 packsof 4) pre-filled syringes. Not all pack sizes may be marketed.

50 mg solution for injection in pre-filled pen

Pre-filled pen containing a pre-filled syringe of Benepali. The syringe inside the pen is made fromclear type 1 glass with a stainless steel 27 gauge needle, rubber needle cover, and rubber plunger.

Benepali is available in packs containing 4 pre-filled pens and multipacks containing 12 (3 packs of 4)pre-filled pens. Not all pack sizes may be marketed.

50 mg solution for injection in pre-filled syringe

Before injection, Benepali single-use pre-filled syringe should be allowed to reach room temperature(approximately 30 minutes). The needle cover should not be removed while allowing the pre-filledsyringe to reach room temperature. The solution should be clear to slightly opalescent, colourless orpale yellow and may contain small translucent or white particles of protein.

Comprehensive instructions for administration are given in the package leaflet, section 7, ”Instructionsfor use”.

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

50 mg solution for injection in pre-filled pen

Before injection, Benepali single-use pre-filled pens should be allowed to reach room temperature(approximately 30 minutes). The needle cover should not be removed while allowing the pre-filledpen to reach room temperature. By looking though the inspection window, the solution should be clearto slightly opalescent, colourless or pale yellow and may contain small translucent or white particles ofprotein.

Comprehensive instructions for administration are given in the package leaflet, section 7, “Instructionsfor use”.

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

Samsung Bioepis NL B.V.

Olof Palmestraat 102616 LR Delft

The Netherlands

EU/1/15/1074/001

EU/1/15/1074/002

EU/1/15/1074/003

EU/1/15/1074/004

Date of first authorisation: 14 January 2016

Date of latest renewal: 18 November 2020

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

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