Summary of the risk management plan (RMP) for Benepali (etanercept)

Transcription

1 EMA/783235/2015 Summary of the risk management plan (RMP) for Benepali (etanercept) This is a summary of the risk management plan (RMP) for Benepali, which details the measures to be taken in order to ensure that Benepali is used as safely as possible. For more information on RMP summaries, see here. This RMP summary should be read in conjunction with the EPAR summary and the product information for Benepali, which can be found on Benepali s EPAR page. Overview of disease epidemiology Benepali is a medicine used to treat rheumatic conditions such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondylitis as well as skin diseases such as psoriasis. These are autoimmune conditions in which the body s defence system attacks healthy tissue. Rheumatoid arthritis (RA) is a chronic (long-term) inflammatory disorder causing pain, stiffness, swelling, and limitation of movement, usually starting in small joints such as in the hand and fingers. If untreated, severe cases can lead to progressive joint destruction and disability. The condition can also affect other organs such as the heart. RA usually occurs in middle-aged women about 3 times as many women as men are affected. In Europe and the United States, RA affects approximately 0.5 to 1.0% of the population. The exact cause of RA is unknown; however, both lifestyle factors (such as smoking) and genetic factors may play a role. Ankylosing spondylitis (AS) is a form of chronic arthritis that involves the spine. Severe cases of AS can lead to stiffness of the spine and greatly hinder movement. Unlike RA, AS is 3 times more common in men than in women and most commonly starts between the ages of 20 and 30 years. In Europe, it is found in 0.1 to 1.4% of the general population. AS has a strong genetic risk factor called HLA-B27, which is found in 80-90% of patients with AS. AS is usually diagnosed by X-ray examination but a form called non-radiographic axial spondylitis has similar symptoms to AS but is not readily visible using X-ray. Psoriasis and psoriatic arthritis (PsA) are related diseases. Psoriasis is a chronic skin disease that results in raised patches on the skin. These patches are known as plaques and are flaky and can be itchy. Psoriatic arthritis is an inflammatory arthritis which can occur in patients with psoriasis. Both psoriasis and PsA occur equally often in males and females. In Europe, psoriasis affects between 0.2 and 4.8% of the general population whereas PsA is much less common, affecting 0.06 to 0.2% of the general population. Summary of treatment benefits Benepali contains the active substance etanercept and is approved as a biosimilar medicine. This means that Benepali is similar to a biological medicine (also known as the reference medicine ) that is already authorised in the European Union (EU). The reference medicine for Benepali is Enbrel. Page 1/13

2 Etanercept is a protein that has been designed to block the activity of a chemical messenger in the body called tumour necrosis factor (TNF). By doing so it reduces inflammation associated with rheumatic conditions and psoriasis. The studies with Benepali were designed to show that Benepali has an acceptable level of similarity to Enbrel. Benepali was also compared with Enbrel in one main study involving 596 patients with moderate to severe rheumatoid arthritis despite treatment with the medicine methotrexate. The main measure of effectiveness was the proportion of patients who achieved at least a 20% reduction in ACR scores (a measure of painful, swollen joints and other symptoms) after 24 weeks of treatment. Results of this study showed that Benepali was as effective as Enbrel at reducing symptoms of rheumatoid arthritis: 78% of patients given Benepali (193 out of 247) achieved at least a 20% reduction in ACR scores after 24 weeks of treatment, compared with 80% of patients given Enbrel (188 out of 234). Unknowns relating to treatment benefits Results about the effects of Benepali were obtained from a study in patients with rheumatoid arthritis, which suggested that the treatment benefit of Benepali is comparable to Enbrel. There are no data to suggest that the benefits of Benepali would be different from those of Enbrel for other diseases (such as ankylosing spondylitis, non-radiographic axial spondyloarthritis, psoriatic arthritis, or psoriasis) that Enbrel is used for. Summary of safety concerns Important identified risks Risk What is known Preventability Cancers (including blood cancers such as leukaemia and lymphoma) Serious infections (including opportunistic infections, tuberculosis, Legionella, Listeria Etanercept can affect the immune system, and so may decrease the body s defence against cancer. Various cancers have been reported with the use of etanercept, including cancers of the breast, lung, skin, lymph glands (lymphoma) and of blood and bone marrow (leukaemia). Etanercept can affect the immune system and may reduce the body s defences against infections. Etanercept may increase the risk of an infection or make an existing Because etanercept can affect the immune system, caution should be exercised when considering Benepali treatment for patients with a history of cancer or when continuing treatment in patients who develop a cancer. Cancers may affect any part of the body (including the skin and blood), and possible signs and symptoms depend on where the cancer occurs and what kind of cancer it is. These signs may include weight loss, fever, swelling (with or without pain), persistent cough, and lumps or growths on the skin. Patients who develop any of these signs or symptoms should see their doctor. All patients must be screened for both active and inactive ( latent ) tuberculosis before starting Benepali. Patients with active tuberculosis must not start Benepali. Page 2/13

3 Risk What is known Preventability and parasitic infections) Overactivation of the immune system, resulting in damage of normal, healthy organs or tissues as in the disease lupus (lupus-like syndrome) Immune disorder that can affect the lungs, skin and lymph nodes (sarcoidosis and granulomas) Pain, swelling, itching, redness, bruising or bleeding at the injection site (injection-site reactions) Allergic reactions infection worse. Serious infections occur uncommonly (in less than 1 in 100 patients) in patients treated with etanercept, and include tuberculosis and infections caused by viruses, fungi, or bacteria. In severe cases, infections can spread throughout the body and may be lifethreatening or fatal. While the usual effect of etanercept is to dampen the immune system (as seen above in the case of serious infection), it can rarely (in less than 1 in 1000 patients) cause the immune system to attack the patient s body tissue. This is called drug-induced lupus (or lupus-like syndrome). Sarcoidosis is an immune-related disease that results in skin rash, lung problems, and enlargement of lymph nodes. Sarcoidosis has been reported rarely (in less than 1 in 1000 patients) with etanercept use. Injection-site reactions are the most commonly (in less than 1 in 10 patients) reported side effect of etanercept. Injection-site reactions usually occur during the first month of etanercept use. Allergic reactions, such as rash (urticarial) or swelling of eyes or lips (angioedema), have been reported commonly (in less than 1 in 10 patients) with etanercept use. Serious allergic reactions (called Patients should also be evaluated thoroughly before, and throughout Benepali treatment, for signs and symptoms of infections such as fever, chills, cough, or swelling/warmth on the skin or on joints. Benepali should be stopped if a patient develops a serious infection. The package leaflet gives information about this. Patients should carry the patient alert card and tell any doctor they see for an infection that they are being treated with etanercept. Patients should be aware of the symptoms of lupus-like syndrome and should mention them to their doctor if any occur. These symptoms include weight changes, persistent rash, fever, joint or muscle pain, or fatigue. There are no measures to prevent sarcoidosis or granulomas. There are no measures to prevent such injection-site reactions when using Benepali or any method to determine whether a patient may be more or less likely to develop such reactions. While usually tolerable with (or without) treatment, if injection-site reactions get severe, patients should discuss it with their doctor. There are no measures to prevent allergic reactions when using Benepali or any tests to determine who would be more likely to develop an allergic reaction. Benepali should not be used in patients Page 3/13

4 Risk What is known Preventability Life-threatening skin condition with a widespread blistering rash and shedding of the top layer of skin (severe cutaneous adverse reactions, including toxic epidermal necrolysis [TEN] and Stevens- Johnson Syndrome [SJS]) Inflammation of the blood vessels affecting multiple organs (systemic vasculitis, including antineutrophil cytoplasmic antibodies [ANCA] positive vasculitis) Excessive activation of white blood cells associated with inflammation (macrophage activation syndrome) Nerve disorders caused by a breakdown of the myelin sheath that covers the nerves in the brain and anaphylaxis), which include severe localised swelling of the skin, wheezing, difficulty in swallowing or breathing, or collapse, are rare. These severe skin reactions, which may be fatal, have been reported rarely (in less than 1 in 1000 patients) in patients being treated with etanercept. Inflammation of the blood vessels (vasculitis) can involve organs such as kidneys or lungs and cause damage. Systemic vasculitis has been reported uncommonly (in less than 1 in 100 patients) in patients being treated with etanercept. Macrophage activation syndrome has been reported mainly in patients with juvenile idiopathic arthritis (JIA) (a type arthritis for which Benepali is not meant to be used). The frequency of this adverse reaction is not well known. Central demyelinating disorders such as multiple sclerosis while using etanercept have occurred rarely (in less than 1 in 1000 patients). who are allergic to etanercept or any of the other ingredients of the medicine. The package leaflet gives information about this. If severe allergic reactions occur, Benepali should be stopped immediately and patients should urgently seek medical attention. There are no particular measures to prevent such skin reactions while using Benepali or any useful tests to predict which patients would be more likely to develop severe skin reactions. While rare, if such severe skin reactions occur, Benepali must be stopped and emergency medical care must be sought immediately. There are no particular measures to prevent vasculitis while using Benepali. If signs of inflammation of blood vessels such as pain, fever, redness or warmth of the skin, or itching occur, the patient should consult the doctor. There are no particular measures to prevent macrophage activation syndrome while using Benepali. If the patient has or has had multiple sclerosis, optic neuritis (inflammation of the nerves of the eyes), or transverse myelitis (inflammation of the spinal cord), the patient should mention this to the doctor before using Benepali. Page 4/13

5 Risk What is known Preventability spinal cord (central demyelinating disorders) Nerve disorders caused by a breakdown of myelin in the peripheral nervous system (i.e., nerves outside the brain and spinal cord, peripheral demyelinating events such as chronic inflammatory demyelinating polyneuropathy [CIDP] and Guillain-Barré syndrome [GBS]) Abnormal reduction of all types of blood cells (pancytopenia) Failure of the body to make blood cells (aplastic anaemia) Lung diseases affecting the tissue and space around the air sacs of the lungs (interstitial lung disease, including pulmonary fibrosis and pneumonitis) There have been very rare reports (in less than 1 in 10,000 patients) of peripheral demyelinating events (including GBS, CIDP, demyelinating polyneuropathy, and multifocal motor neuropathy) in patients treated with etanercept. Rare (in less than 1 in 1000 patients) cases of pancytopenia (reductions of red blood cells, white blood cells and platelets) and very rare cases of aplastic anaemia, some with fatal outcomes, have been reported in patients treated with etanercept. There have been uncommon (in up to 1 in 100 patients) post-marketing reports of interstitial lung disease (including pulmonary fibrosis and pneumonitis) in patients treated with etanercept, some of which had fatal outcomes. If there are signs of nerve disorders such as numbness, tingling, changes in vision, eye pain, or onset of weakness in an arm or leg, the patient should consult the doctor. If the patient has or has had CIDP or GBS, the patient should consult the doctor before using Benepali. If there are signs of nerve disorders (see above), the patient should consult the doctor. If the patient has or has had a bloodrelated disease (dyscrasia), the patient should tell the doctor before using Benepali. If the patient develops any of the following symptoms: persistent fever, sore throat, bruising, bleeding, or paleness, the patient should seek immediate medical attention as these can sometimes be symptoms of a reduction in blood cells. If blood dycrasias are confirmed, Benepali must be stopped. If symptoms such as shortness of breath occur, the patient should see the doctor as this could indicate lung problems. Page 5/13

6 Risk What is known Preventability Inflammation of the liver caused by the body s own immune system (autoimmune hepatitis) Liver events in patients with history of viral hepatitis, including hepatitis B virus (HBV) reactivation Change in features and/or severity of psoriasis Worsening heart failure (worsening of congestive heart failure [CHF] in adult subjects) There have been rare (up to 1 in a 1,000) reports of autoimmune hepatitis in patients treated with etanercept. Autoimmune hepatitis can manifest as abnormal liver function blood tests, or as symptoms such as jaundice (yellow skin). If a person has had hepatitis virus infection, treatments such as etanercept, which suppress the immune system, may allow reactivation of the virus. This has occurred in patients being treated with tumour necrosis factor antagonists, which are medicines of the same class as etanercept. While etanercept is actually used to treat psoriasis, there have been uncommon reports (in up to 1 in a 100 patients) of new psoriasis or worsening of existing psoriasis, or of changes in the pattern of psoriasis symptoms, including the development of psoriasis affecting the palms of the hands and soles of the feet. There have been reports of rare cases of worsening heart failure, both with and without other identifiable causes for worsening heart failure, in patients taking etanercept. This can be detected by blood tests to monitor how well the liver is working. If there are any symptoms of liver damage such as yellow skin and/or eyes or bleeding, then patients should see their doctor immediately. Patients should be tested for hepatitis B virus (HBV) infection before initiating treatment with Benepali. Patients who are positive for HBV infection should be seen by a specialist in liver diseases before etanercept treatment is started. If the patient has been infected with HBV, the patient should consult the doctor before using Benepali. If the patient contracts HBV after using Benepali, treatment with Benepali should be stopped and medical attention sought. If the patient has psoriasis and is taking Benepali, and symptoms seem to worsen, the patient should consult the doctor. If the patient already has heart failure, the patient should tell the doctor before using Benepali. If the patient has symptoms of heart failure (such as fatigue, shortness of breath with activity, swelling in the ankles, a feeling of fullness in the neck or abdomen, night-time shortness of breath or coughing, or bluish colour of the nails or lips) while taking Benepali, the patient must see a doctor immediately. Page 6/13

7 Important potential risks Risk Autoimmune renal disease Rare blistering autoimmune skin disorders (pemphigus/ pemphigoid) Progressive degeneration of nerve cells in the brain and spinal cord, leading to damage and loss of the ability to initiate and control voluntary muscle movement (amyotrophic lateral sclerosis [ALS]) Defect in the transmission of nerve impulses to the muscles, preventing contraction and causing muscle weakness (myasthenia gravis) Inflammation of the brain and spinal cord (encephalitis/leukoen cephalomyelitis) Progressive damage or inflammation of the brain white matter due to a virus (progressive multifocal leukoencephalopathy [PML]). This causes severe disability and can lead to death. What is known Autoimmune renal disease occurs when a person s immune system attacks the kidneys. As etanercept is associated with other autoimmune diseases such as lupus-like syndrome, there could be a possibility that etanercept use could be associated with autoimmune renal disease. Pemphigus or pemphigoid is a skin disease that results in blisters in the skin. There is a possibility that etanercept could cause autoimmune skin diseases. ALS is a rare disease that results in gradual weakness of the body. In theory, TNF-α may be beneficial to the nervous system in certain cases. Therefore, there is a possibility that blocking TNF which is the mechanism of action of etanercept could be associated with ALS. However, there is no clear evidence proving this for etanercept. Myasthenia gravis is an autoimmune disease which results in muscle weakness such as difficulty in moving around. There is a possibility that etanercept might induce autoimmunity that causes or worsens myasthenia gravis. However, there are no clear data and, in some cases, etanercept is thought to be beneficial in myasthenia gravis. Brain inflammation can be caused by immunological effect. There is a possibility that etanercept may alter the immune system and lead to encephalitis. JC virus infects a large number of people whose immune system is healthy and usually does not cause any harm most people are unaware they have been infected. In people infected with JC virus, etanercept may suppress the immune system and allow the virus to become active and cause progressive inflammation and damage leading to PML. Page 7/13

8 Risk Inability of the liver to perform its normal function due to liver injury (liver failure) Conditions of abnormal liver structure and function (hepatic cirrhosis and fibrosis) Severe increase in blood pressure (severe hypertensive reactions) Adverse pregnancy outcomes Potential for medication errors (pre-filled pen) Potential for male infertility Weight gain Events caused by restriction in blood flow and oxygen supply of the heart (acute ischaemic cardiovascular [CV] events in adult subjects) Potential use in children, for whom this medicine is not authorised (paediatric off-label use) What is known Liver failure is a rapid shutdown of liver functions that may be life-threatening. There are reports of liver failure in etanercept users but the association between liver failure and etanercept is unclear. Hepatic cirrhosis is a disease that results in scarring of the liver and gradual decrease of liver function. Whether etanercept can cause this is unclear since methotrexate, a drug that is commonly used with Benepali in rheumatoid arthritis, is also associated with this condition. There are cases of severe increase in blood pressure after use of etanercept; however, the exact reason for this and whether it is cause by etanercept is unknown. The use of etanercept during pregnancy might potentially be related to adverse pregnancy outcomes such as stillbirth or fetal malformations. Currently, the use of etanercept in pregnant patients is not recommended and women planning to be pregnant should not use etanercept. To reduce the potential for medication errors, clear instructions on the use of the pre-filled pen are provided in the package leaflet and educational materials have been developed for patients and healthcare professionals regarding the correct use of the pre-filled pen. There have been cases of infertility after etanercept use in men; however, the true relationship is not clear. There is research indicating that TNF inhibition can be either beneficial or detrimental to sperm quality. There have been reports of weight gain after etanercept use. Since rheumatic diseases are associated with muscle wasting or weight loss, improvement of such conditions could possibly lead to recovery of muscle wasting, resulting in weight gain. Cardiovascular events such as heart attacks or strokes might possibly occur during etanercept use. The exact mechanism or true association with etanercept is not clear. Benepali is not authorised for use in children under the age of 18 years. Currently the approved formulations of Benepali are meant for adults and use in children may result in dangerous overdoses. Page 8/13

9 Missing information Risk Use in hepatic (liver) and renal (kidney) impaired patients Use in different ethnic groups Use in pregnant women What is known Information on the use of etanercept in patients with hepatic and renal impairment is limited because these patients were not included in the clinical studies. There is no evidence to suggest that the etanercept is absorbed, altered (metabolised) or eliminated from the body any differently by people of different races. Information on the use of etanercept in pregnant women is limited because pregnant women were excluded from the clinical studies. Etanercept is not recommended during pregnancy and women of childbearing potential are advised to avoid pregnancy during etanercept treatment. Summary of risk minimisation measures by safety concern All medicines have a summary of product characteristics (SmPC) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet. The measures listed in these documents are known as routine risk minimisation measures. The SmPC and the package leaflet are part of the medicine s product information. The product information for Benepali can be found on Benepali s EPAR page. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). Full details on these conditions and the key elements of any educational material can be found in Annex II of the product information which is published on Benepali s EPAR page; how they are implemented in each country however will depend upon agreement between the marketing authorisation holder and the national authorities. These additional risk minimisation measures are for the following risks: Serious infections (including opportunistic infections, TB, Legionella, Listeria, parasitic infection) Risk minimisation measure: Patient alert card Objective and rationale: To provide information to patients to make them aware that during treatment with Benepali there is an increased risk of acquiring serious infections, or that existing infections may get worse. Description: Patient alert card will be provided to Benepali prescribing physicians for distribution to patients receiving Benepali. This card provides important safety information for patients, including information relating to infections. Page 9/13

10 Worsening heart failure (worsening of CHF in adult subjects) Risk minimisation measure: Patient alert card Objective and rationale: To provide adequate information to patients to make them aware of the increased risk of worsening of heart failure during treatment with Benepali. Description: The patient alert card will be provided to prescribing physicians for distribution to patients receiving Benepali. This card provides important safety information for patients, including information relating to heart failure. Potential for medication errors (pre-filled pen) Risk minimisation measure: Educational material for healthcare professionals and patients Objective and rationale: To alert patients and healthcare professional to the risk of medication errors in patients using a prefilled pen. Description: A mock pre-filled pen device for practice will be provided to HCPs. An educational programme will be provided to HCPs and patients. Potential for paediatric off-label use Risk minimisation measure: Educational material/patient alert card Objective and rationale: To remind patients and healthcare professionals that Benepali is not indicated for children under the age of 18 years. Description: Warnings will be inserted in the patient alert card. An educational programme will be provided to HCPs and patients. Page 10/13

11 Planned post-authorisation development plan List of studies in post-authorisation development plan Study/activit y (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results SB4-G31-RA A Randomised, Double-blind, Parallel Group, Multicentre Clinical Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Immunogenicity of SB4 (Benepali) Compared to Enbrel in Subjects with Moderate to Severe Rheumatoid Arthritis despite methotrexate Therapy. This is an open-label extension of the clinical trial in subjects with rheumatoid arthritis; it will monitor all the safety concerns described above, including serious and/or opportunistic infections, cancers, heart failure, and injection-site reactions. The first 52 weeks of the study have been completed. The openlabel part of the study is currently ongoing. Final study report planned around March 2016 The first 52 weeks is a double blind, randomised equivalence study comparing SB4 (Benepali) and Enbrel in methotrexateresistant RA patients, and the next 48 weeks is an openlabel study switching the Enbrel arm to SB4 (Benepali). The British Society for Rheumatology Biologics Registerrheumatoid arthritis (BSRBR-RA) An established nationwide register for patients with rheumatological disorders treated with biological agents. The register is designed as a national prospective study whose primary purpose is to assess long-term toxicity This study will monitor for all of the safety concerns described above, including serious and/or opportunistic infections, cancers, heart failure, and injection-site reactions. Planned for Q Final report planned for 2027 Annual interim reports with PSUR/RMP updates where applicable Page 11/13

12 Study/activit y (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results from the use of these agents in routine practice. Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) A prospective, observational cohort study whose objectives are to evaluate the longterm effectiveness, safety, and costs associated with tumour necrosis factor inhibitor therapies in the treatment of rheumatoid arthritis (RA) and to compare this to a cohort of RA patients who are treated with nonbiological diseasemodifying antirheumatic medicines. This study will monitor for all the safety concerns described above, including serious and/or opportunistic infections, cancers, heart failure, and injection-site reactions. Planned for Q Final report planned for 2027 Annual interim reports with PSUR/RMP updates where applicable Anti-rheumatic Therapies In Sweden (ARTIS) A national prospective, observational, uncontrolled cohort study whose objectives are to evaluate the risk of selected adverse events in RA, JIA, and other rheumatic disease patients treated with etanercept. This study monitors all the safety concerns described above, including serious and/or opportunistic infections, cancers, heart failure, and injection-site reactions. Planned for Q Final report planned for 2027 Annual interim reports with PSUR/RMP updates where applicable British Association of Dermatologists Biologic Interventions Register (BADBIR) A nationwide registry in the UK to assess the long-term safety of biological treatments for psoriasis. Long-term safety of biologic treatments for psoriasis. Planned for Q Final report planned for 2027 Annual interim reports with PSUR/RMP updates where Page 12/13

13 Study/activit y (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results applicable Studies which are a condition of the marketing authorisation None of the above studies are conditions of the marketing authorisation. Summary of changes to the risk management plan over time Major changes to the Risk Management Plan over time Not applicable. This summary was last updated in Page 13/13