swiss summary of risk management plan (rmp)€¦ · lupus -like reactions evidence for linking the...

Swiss Summary of Risk Management Plan (RMP) for

Benepali® (Etanercept)

Samsung Bioepis CH GmbH

Document version: 2.0

Date of this document: Apr 07, 2020

Based on EU RMP version 6.1 (data lock point: Jan 14, 2019)

The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimise them.

The RMP summary of Benepali® is a concise document and does not claim to be exhaustive.

As the RMP is an international document, the summary might differ from the “Arzneimittelinformation / Information sur le médicament” approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorization.

Please note that the reference document which is valid and relevant for the effective and safe use of Benepali® in Switzerland is the “Arzneimittelinformation / Information sur le médicament” (see www.swissmedic.ch) approved and authorized by Swissmedic. Samsung Bioepis CH GmbH is fully responsible for the accuracy and correctness of the content of the published summary RMP of Benepali®.

Swiss Summary of RMP Benepali® (Etanercept)

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PART VI: SUMMARY OF THE RISK MANAGEMENT PLAN

SUMMARY OF RISK MANAGEMENT PLAN FOR BENEPALI This is a summary of the risk management plan (RMP) for Benepali. The RMP details important risks of Benepali, how these risks can be minimised, and how more information will be obtained about Benepali's risks and uncertainties (missing information).

Benepali's summary of product characteristics (SmPC) and its package leaflet give essential information to healthcare professionals and patients on how Benepali should be used.

This summary of the RMP for Benepali should be read in the context of all this information including the assessment report of the evaluation and its plain-language summary, all which is part of the European Public Assessment Report (EPAR).

Important new concerns or changes to the current ones will be included in updates of Benepali's RMP.

I. The medicine and what it is used for Benepali is authorised for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, non-radiographic axial spondyloarthritis, juvenile idiopathic arthritis (including polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis, adolescent psoriatic arthritis, adolescent enthesitis- related arthritis) and paediatric plaque psoriasis> (see SmPC for the full indication). It contains etanercept as the active substance and it is given by subcutaneous injection in 25mg solution for injection in pre-filled syringe, 50 mg solution for injection in pre-filled syringe or 50 mg solution for injection in pre-filled pen.

Further information about the evaluation of Benepali’s benefits can be found in Benepali’s EPAR, including in its plain-language summary, available on the EMA website, under the medicine’s webpage:

https://www.ema.europa.eu/en/medicines/human/EPAR/benepali

II. Risks associated with the medicine and activities to minimise or further characterise the risks

Important risks of Benepali, together with measures to minimise such risks and the proposed studies for learning more about Benepali's risks, are outlined below.

Measures to minimise the risks identified for medicinal products can be:

• Specific information, such as warnings, precautions, and advice on correct use, in the package leaflet and SmPC addressed to patients and healthcare professionals;

• Important advice on the medicine’s packaging;

• The authorised pack size — the amount of medicine in a pack is chosen so to ensure t


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hat the medicine is used correctly;

• The medicine’s legal status — the way a medicine is supplied to the patient (e.g. with or without prescription) can help to minimise its risks.

Together, these measures constitute routine risk minimisation measures.

In the case of Benepali, these measures are supplemented with additional risk minimisation measures mentioned under relevant important risks, below.

In addition to these measures, information about adverse reactions is collected continuously and regularly analysed , including PSUR assessment, so that immediate action can be taken as necessary. These measures constitute routine pharmacovigilance activities.

II.A List of important risks and missing information Important risks of Benepali are risks that need special risk management activities to further investigate or minimise the risk, so that the medicinal product can be safely administered. Important risks can be regarded as identified or potential. Identified risks are concerns for which there is sufficient proof of a link with the use of Benepali. Potential risks are concerns for which an association with the use of this medicine is possible based on available data, but this association has not been established yet and needs further evaluation. Missing information refers to information on the safety of the medicinal product that is currently missing and needs to be collected (e.g. on the long-term use of the medicine);


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List of important risks and missing information

Important identified risks

Malignancy (including lymphoma and leukaemia)

Serious and opportunistic infections (including TB, Legionella, Listeria, parasitic infection)

Lupus-like reactions

Sarcoidosis and/or granulomas

Allergic reactions

Severe cutaneous adverse reactions (including toxic epidermal necrolysis and Stevens-Johnson Syndrome)

Systemic vasculitis (including ANCA positive vasculitis)

Macrophage activation syndrome

Central demyelinating disorders

Peripheral demyelinating events (CIDP and GBS)

Aplastic anaemia and pancytopenia

Interstitial lung disease (including pulmonary fibrosis and pneumonitis)

Autoimmune hepatitis

Liver events in patients with history of viral hepatitis (including hepatitis B virus reactivation)

Change in morphology and/or severity of psoriasis

CHF in adult subjects

Inflammatory bowel disease in JIA subjects


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List of important risks and missing information

Important potential risks

Autoimmune renal disease

Pemphigus/pemphigoid

Amyotrophic lateral sclerosis

Myasthenia gravis

Encephalitis/leukoencephalomyelitis

Progressive multifocal leukoencephalopathy

Liver failure

Hepatic cirrhosis and fibrosis

Severe hypertensive reactions

Adverse pregnancy outcomes

Potential for medication errors (pre-filled pen)

Potential for male infertility

Weight Gain

Impaired growth and development in juvenile subjects

Acute ischemic CV events in adult subjects

Potential for off label use and medication error in children

Missing information Not applicable

II.B Summary of important risks II.B.1 Important identified risks


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Malignancy (including lymphoma and leukaemia)

Evidence for linking the risk to the medicine

Study SB4-G31-RA; proposed Summary of Product Characteristics (SmPC) for Benepali, section 4.4 ‘Special warnings and precautions for use’; referenced scientific publications.

Risk factors and risk groups

The overall risk of malignancy including cutaneous and non-cutaneous cancers has been reported to be higher in patients with RA compared with healthy subjects.

In addition, the proposed SmPC for Benepali states that there is an increased background risk for lymphoma and leukaemia in RA patients with long-standing, highly active, inflammatory disease.

Studies have shown that patients with RA have an approximately 2-fold increased risk of lymphoma and leukaemia, a 20% to 50% increased risk of respiratory tract cancer, and a 70% increased risk of non-melanoma skin cancers, but a decreased risk for breast and colorectal cancer.4,5 The increase in lymphoma risk is limited to those RA patients who have long-standing and very severe disease.9

Risk minimisation measures

<Routine risk minimisation measures:>

SmPC section 4.4 and 4.8

<Additional risk minimisation measures:>

None

Additional pharmacovigilance activities

<Additional pharmacovigilance activities:>

Registry participation, SB4-G31-RA, SB4-KO41-PMS

See section II.C of this summary for an overview of the post-authorisation development plan.


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Serious and opportunistic infections (including tuberculosis, Legionella, Listeria, parasitic infection)


Study SB4-G31-RA; referenced scientific publications.

Risk factors and risk groups The patients who are on concomitant immunosuppressive therapy, in addition to their underlying disease, can be predisposed to infection.


<Routine risk minimisation measures>

SmPC section 4.3, 4.4, and 4.8

<Additional risk minimisation measures>

Patient alert card


<Additional pharmacovigilance activities>



Lupus-like reactions



Risk factors and risk groups The hypotheses say that patients with lupus or pre-existing autoantibodies may be at risk of development of lupus-like reactions if treated with etanercept or other TNF-α inhibitors.





None






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Sarcoidosis and/or granulomas



Risk factors and risk groups No risk factors for the development or exacerbation of sarcoidosis and/or granulomas in the patients treated with etanercept are known.



SmPC section 4.8


None





Allergic reactions


Study SB4-G31-RA; proposed SmPC for Benepali, Sections 4.3 ‘Contraindications’ and 4.4 ‘Special warnings and precautions for use’; referenced scientific publications.


Hypersensitivity to the active substance, or to any of the excipients, is a risk factor for allergic-type hypersensitivity reactions to etanercept. Use in individuals with known hypersensitivity to the active substance or to any of the excipients is contraindicated (proposed SmPC for Benepali, Section 4.3 ‘Contraindications’).



SmPC section 4.3, 4.4 and 4.8


None






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Severe cutaneous adverse reactions (including toxic epidermal necrolysis and Stevens-Johnson Syndrome)


Study SB4-G31-RA; proposed SmPC for Benepali, Section 4.3 ‘Contraindications’.

Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development of severe cutaneous adverse reactions with etanercept treatment.



SmPC section 4.8


None





Systemic vasculitis (including anti-neutrophilic cytoplasmic antibody positive vasculitis)



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development of systemic vasculitis with etanercept treatment.





None






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Macrophage activation syndrome




Currently, there are no known risk groups or risk factors for the development of macrophage activation syndrome with etanercept treatment.



SmPC section 4.8


None





Central demyelinating disorders


Study SB4-G31-RA; proposed SmPC for Benepali, Section 4.4 ‘Special warnings and precautions for use’; referenced scientific publications.

Risk factors and risk groups Patients with pre-existing or recent-onset central demyelinating disorders.





None






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Peripheral demyelinating events (chronic inflammatory demyelinating polyneuropathy and Guillain-Barré syndrome)



Risk factors and risk groups Patients with pre-existing or recent onset peripheral demyelinating events.





None





Aplastic anaemia and pancytopenia



Risk factors and risk groups Although no high risk group has been identified, caution should be exercised in subjects being treated with etanercept who have a previous history of significant haematological abnormalities.





None






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Interstitial lung disease (including pulmonary fibrosis and pneumonitis)



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development of ILD with etanercept treatment.



SmPC section 4.8


None





Autoimmune hepatitis



Risk factors and risk groups There are no known risk factors for the development of autoimmune hepatitis with etanercept therapy.



SmPC section 4.8


None






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Liver events in patients with history of viral hepatitis (including hepatitis B virus reactivation)


Proposed SmPC for Benepali, Section 4.4 ‘Special warnings and precautions for use’; referenced scientific publications.

Risk factors and risk groups Patients who have a previous diagnosis of HBV and/or HCV or patients who have not been screened for these infectious agents, but are considered as high risk individuals.





None





Change in morphology and/or severity of psoriasis



Risk factors and risk groups Currently, there are no known risk groups or risk factors for a change in morphology and/or severity of psoriasis with etanercept treatment.



SmPC section 4.8


None



Registry participation, SB4-KO41-PMS



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CHF in adult subjects



Risk factors and risk groups Patients with a previous history of CHF.

Patients with diagnosed ischaemic heart disease.





None






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Inflammatory bowel disease in JIA subjects


Referenced scientific publications.

Risk factors and risk groups Subjects with known inflammatory bowel disease and subjects with JIA





None



None



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II.B.2 Important potential risks

Autoimmune renal disease



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development of autoimmune renal disease with etanercept treatment.



None


None





Pemphigus/pemphigoid



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development of pemphigus/pemphigoid with etanercept.



None


None






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Amyotrophic lateral sclerosis



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development or exacerbation of ALS with etanercept.



None


None





Myasthenia gravis



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development or exacerbation of MG with etanercept treatment.



None


None






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Encephalitis/leukoencephalomyelitis


Study SB4-G31-RA.

Risk factors and risk groups Patients with pre-existing or recent onset of encephalitis/leukoencephalomyelitis.



None


None





Progressive multifocal leukoencephalopathy



Risk factors and risk groups C Patients on concomitant immunosuppressive therapy that, along with their underlying disease, could predispose them to PML.



None


None






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Liver failure



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development of liver failure with etanercept.



None


None





Hepatic cirrhosis and fibrosis



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development or worsening of hepatic cirrhosis and/or fibrosis with etanercept.



None


None






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Severe hypertensive reactions


Study SB4-G31-RA.

Risk factors and risk groups Patients with pre-existing hypertensive and cardiovascular disease, or RA.



None


None





Adverse pregnancy outcomes


Study SB4-G31-RA; proposed SmPC for Benepali, Section 4.6 ‘Fertility, pregnancy and lactation’; referenced scientific publications

Risk factors and risk groups Women of child-bearing age who are receiving etanercept treatment.



SmPC section 4.6 <Additional risk minimisation measures>

None






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Potential for medication errors (pre-filled pen)


Not applicable.

Risk factors and risk groups Not applicable.



Clear Package Leaflet Instructions for use of the PFP


Educational programme for healthcare professionals and patients



None

Potential for male infertility



Risk factors and risk groups Male patients of child bearing potential.



None


None






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Weight gain



Risk factors and risk groups Currently, there are no known risk groups or risk factors for weight gain with etanercept.



None


None





Impaired growth and development in juvenile subjects


Referenced scientific publications

Risk factors and risk groups There are currently no known risk groups or risk factors in patients following the administration of etanercept for events in growth and development.



None


None



None


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Acute ischemic CV events in adult subjects



Risk factors and risk groups Currently, there are no known risk groups or risk factors for the development of acute ischemic cardiovascular events with etanercept treatment.



None


None





Potential for off label use and medication error in children


Not applicable.

Risk factors and risk groups Not applicable.



SmPC section 4.2

Package leaflet section Children and adolescents


Patient alert card

Educational programme for healthcare professionals and patients



None

II.B.3 Missing information

Not applicable

II.C Post-authorisation development plan II.C.1 Studies which are conditions of the marketing authorisation


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There are no studies which are conditions of the marketing authorisation or specific obligation of Benepali.

II.C.2 Other studies in post-authorisation development plan

Study

Status Summary of

objectives Safety concerns addressed Milestones Due dates

Category 3 - Required additional pharmacovigilance activities BSRBR-RA - The British Society for Rheumatology Biologics Register-rheumatoid arthritis

An established nationwide register for patients with rheumatological disorders treated with biologic agents. The register is designed as a national prospective study whose primary purpose is to assess long-term toxicity from the use of these agents in routine practice.

Malignancy, serious and opportunistic infections, lupus-like reactions, sarcoidosis and/or granulomas, injection site reactions, allergic reactions, severe cutaneous adverse reactions, systemic vasculitis, macrophage activation syndrome, central demyelinating disorders, peripheral demyelinating events, aplastic anaemia and pancytopenia, interstitial lung disease, autoimmune hepatitis, liver events in patients with history of viral hepatitis, change in morphology and/or severity of psoriasis, CHF in adult subjects, autoimmune renal disease, pemphigus/pemphigoid, amyotrophic lateral sclerosis, myasthenia gravis, encephalitis/leukoencephalomyelitis, progressive multifocal leukoencephalopathy, liver failure, hepatic cirrhosis and fibrosis, severe hypertensive reactions, adverse pregnancy outcomes, potential for male infertility, weight gain, acute ischemic CV events, and use in pregnant women.

Protocol submission

Completeda

Study start April 2016

Study end 2026 (planned)

Final report 2027 (planned) Annual interim reports will be submitted during the study period as individual reports. Summaries of study progress will be presented in PSURs and RMP updates, where applicable.

RABBIT - Rheumatoid Arthritis Observation of Biologic Therapy

A prospective, observational cohort study whose objectives are to evaluate the long-term effectiveness, safety, and costs associated with tumour necrosis factor-inhibitor therapies in the treatment of RA and

Malignancy, serious and opportunistic infections, lupus-like reactions, sarcoidosis and/or granulomas, injection site reactions, allergic reactions, severe cutaneous adverse reactions, systemic vasculitis, macrophage activation syndrome, central demyelinating disorders,

Protocol submission

Completeda

Study start date

April 2016

Study end date

2026 (planned)

Final report 2027 (planned) Annual interim reports will be submitted


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Study

Status Summary of


to compare this to a cohort of RA patients who are treated with non-biologic DMARDs.

peripheral demyelinating events, aplastic anaemia and pancytopenia, interstitial lung disease, autoimmune hepatitis, liver events in patients with history of viral hepatitis, change in morphology and/or severity of psoriasis, CHF in adult subjects, autoimmune renal disease, pemphigus/pemphigoid, amyotrophic lateral sclerosis, myasthenia gravis, encephalitis/leukoencephalomyelitis, progressive multifocal leukoencephalopathy, liver failure, hepatic cirrhosis and fibrosis, severe hypertensive reactions, adverse pregnancy outcomes, potential for male infertility, weight gain, acute ischemic CV events, and use in pregnant women.

during the study period as individual reports. Summaries of study progress will be presented in PSURs and RMP updates, where applicable.

ARTIS - Anti-rheumatic Therapies In Sweden

A national prospective, observational, uncontrolled cohort study whose objectives are to evaluate the risk of selected AEs in RA, juvenile idiopathic arthritis, and other rheumatic disease patients treated with etanercept.

Malignancy, serious and opportunistic infections, lupus-like reactions, sarcoidosis and/or granulomas, injection site reactions, allergic reactions, severe cutaneous adverse reactions, systemic vasculitis, macrophage activation syndrome, central demyelinating disorders, peripheral demyelinating events, aplastic anaemia and pancytopenia, interstitial lung disease, autoimmune hepatitis, liver events in patients with history of viral hepatitis, change in morphology and/or severity of psoriasis, CHF in adult subjects, autoimmune renal disease, pemphigus/pemphigoid, amyotrophic lateral sclerosis, myasthenia gravis, encephalitis/leukoencephalomyelitis, progressive multifocal leukoencephalopathy, liver failure, hepatic cirrhosis and fibrosis, severe hypertensive

Protocol submission

Completeda

Study start date

April 2016

Study end date

2026 (planned)



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Study

Status Summary of


reactions, adverse pregnancy outcomes, potential for male infertility, weight gain, acute ischemic CV events, and use in pregnant women.

BADBIR - British Association of Dermatologists Biologic Interventions Register

A nationwide registry which seeks to assess the long-term safety of biologic treatments for psoriasis. Recommended by NICE that all patients in the UK receiving new therapies for psoriasis be registered in BADBIR.

Malignancy, serious and opportunistic infections, lupus-like reactions, sarcoidosis and/or granulomas, injection site reactions, allergic reactions, severe cutaneous adverse reactions, systemic vasculitis, macrophage activation syndrome, central demyelinating disorders, peripheral demyelinating events, aplastic anaemia and pancytopenia, interstitial lung disease, autoimmune hepatitis, liver events in patients with history of viral hepatitis, change in morphology and/or severity of psoriasis, CHF in adult subjects, autoimmune renal disease, pemphigus/pemphigoid, amyotrophic lateral sclerosis, myasthenia gravis, encephalitis/leukoencephalomyelitis, progressive multifocal leukoencephalopathy, liver failure, hepatic cirrhosis and fibrosis, severe hypertensive reactions, adverse pregnancy outcomes, potential for male infertility, weight gain, acute ischemic CV events, and use in pregnant women.

Protocol submission

Completeda

Study start date

May 2016

Study end date

2026 (planned)


SB4-KO41-PMS - Korean Post-marketing Surveillance of Etoloce

A post-marketing study to assess the real-life safety and possibly efficacy of Etoloce in Korean patients with RA, PsA, AS or psoriasis

Malignancy, serious and opportunistic infections, lupus-like reactions, sarcoidosis and/or granulomas, injection site reactions, allergic reactions, severe cutaneous adverse reactions, systemic vasculitis, macrophage activation syndrome, central demyelinating disorders, peripheral demyelinating events, aplastic anaemia and

Protocol submission

Completed

Study start date

Feb 2016

Study end date

2019 3Q

Final report 2019 4Q (planned)


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Study

Status Summary of


pancytopenia, interstitial lung disease, autoimmune hepatitis, liver events in patients with history of viral hepatitis, change in morphology and/or severity of psoriasis, CHF in adult subjects, autoimmune renal disease, pemphigus/pemphigoid, amyotrophic lateral sclerosis, myasthenia gravis, encephalitis/leukoencephalomyelitis, progressive multifocal leukoencephalopathy, liver failure, hepatic cirrhosis and fibrosis, severe hypertensive reactions, adverse pregnancy outcomes, potential for male infertility, weight gain, acute ischemic CV events, and use in pregnant women.

a The general protocol provided by each registry has already been submitted. Any revisions of the protocol will be submitted with forthcoming RMP updates. The final report plan recommended by EMA PRAC is now proposed in the due date sections. b Etoloce is the trade name of Benepali in Korea

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