Prophylaxis of acute transplant rejection in patients receiving allogeneic renal transplants:

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1 VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology Prophylaxis of acute transplant rejection in patients receiving allogeneic renal transplants: Over 1 million people worldwide have undergone successful organ transplantation till date. The annual kidney transplantation rate in Europe is 15, 000. Numbers and rates per million population varies widely within the European Union, from just few to 50 for kidney transplantations. The proportion of transplant procedures performed in children and adolescents is about 5% of the overall annual transplantation rate in Europe. One year patient survival exceeds 95% in kidney transplantation. Five years survival rates for most organ transplant programmes exceed the ranges from 50 to a 70%. The percentage of patients and graft survival are roughly similar in children and adolescents, depending on the age of the organ recipient and the type of transplant procedure. VI.2.2 Summary of treatment benefits Prophylaxis of acute transplant rejection in patients receiving allogeneic renal transplants: Mycophenolate sodium Accord contains a substance called mycophenolic acid. This belongs to a group of medicines called immunosuppressants. Mycophenolate sodium is used to stop the body s immune system from rejecting a kidney transplant. It is used together with other medicines containing ciclosporin and corticosteroids.mycophenolate capsules and tablets have been studied in three studies involving a total of 1,493 adults following kidney transplantation. Mycophenolate was compared with azathioprine (another anti-rejection medicine) in all studies except for one of the kidney transplant studies, in which it was compared with placebo (a dummy treatment). In all of the studies, all of the patients also received ciclosporin and corticosteroids, and the main measure of effectiveness was the proportion of patients whose new organ had been rejected after six months. Mycophenolate was as effective as azathioprine and more effective than placebo in preventing the rejection of transplanted kidneys after six months. Accord has not conducted any studies for mycophenolate sodium on expected benefit considering the similarities of active ingredient and the route of administration to the currently marketed product.

2 VI.2.3 Unknowns relating to treatment benefits The efficacy and safety of Mycophenolate sodium has not been established in Children VI.2.4 Summary of safety concerns Important identified risks Congenital malformations (Birth defects) and spontaneous abortions (related to exposure during pregnancy) Mycophenolic acid may harm the foetus and increase the risk of pregnancy loss, mycophenolic acid should not be used during pregnancy unless clearly necessary. Yes. Mycophenolate sodium should not be used during pregnancy unless clearly necessary. The doctor should advise about using contraception before taking Mycophenolate sodium, whilst taking Mycophenolate sodium, and for 6 weeks after having stopped taking Mycophenolate sodium. Tell your doctor straight away if you become pregnant during treatment with Mycophenolate sodium. Ask the doctor or pharmacist for advice before taking any medicine. If you are a sexually active man it is recommended to use condoms during treatment, and for a total of 13 weeks after your last dose of Mycophenolate

3 sodium. In addition, your female partners are recommended to use highly effective contraception during your treatment and for a total of 13 weeks after the last dose of Mycophenolate sodium. Serious infections (bacterial, fungal, viral and protozoal) and sepsis If you are taking Mycophenolate sodium, you may therefore catch more infections than usual such as infections of the brain, skin, mouth, stomach and intestines, lungs and urinary tract. Some effects could be serious: Signs of infection including fever, chills, sweating, feeling tired, drowsy, or lack of energy. If you are taking Mycophenolate sodium you may be more likely to get an infection than usual. Such infections could affect various parts of your body, but the parts most commonly Yes Doctor will perform regular blood tests to monitor any changes in the number of blood cells Like all medicines, this medicine can cause side effects, although not everybody gets them If you experience any of the above after taking Mycophenolate sodium, talk to your doctor straight away

4 affected are the kidneys, bladder, upper and/or lower airways. Common (may affect up to 1 in 10 people) respiratory infections Uncommon (may affect up to 1 in 100 people) Infection of the bones, blood and the skin Other side effects reported with medicines similar to Mycophenolate sodium serious infections such as inflammation of the heart and its valves and of the membrane that covers the brain and spinal cord, and other less common bacterial infections usually resulting in a serious lung disorder (tuberculosis and atypical mycobacterial infection) GI ulcerative and haemorrhage (Distinct breach in the mucosal lining of the stomach and Like all medicines, this medicine can cause side effects, although not Yes If you experience any of the above after taking

5 bleeding) Malignancies (lymphomas and other malignancies, particularly of the skin) (Cancer) everybody gets them Some effects could be serious: Stomach or intestinal ulcer Other side effects reported with medicines similar to Mycophenolate sodium inflammation of the colon (large intestine), inflammation of the stomach lining caused by cytomegalovirus, development of a hole in the intestinal wall, resulting in severe abdominal pain with possible bleeding, stomach or duodenal ulcers You should also be aware that Mycophenolate sodium lowers the skin s level of protection from the sun. This increases the risk of skin cancer. Like all medicines, this medicine can cause side effects, although not everybody gets them Mycophenolate sodium, talk to your doctor straight away Yes Patient should limit exposure to sunlight and ultraviolet (UV) light by covering exposed skin areas as much as possible and regularly applying sunscreen with a high protective factor. Ask doctor for advice on protection from the sun

6 Some effects could be serious: Swelling of glands, development of a new skin growth or enlargement of an existing skin growth, or changes in an existing mole. As can happen in patients taking immunosuppressants, a very small number of Mycophenolate sodium patients have developed cancer of the skin or lymph nodes. Blood and lymphatic system disorders including pure red cell aplasia (PRCA) Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (which include mycophenolate mofetil and mycophenolate sodium) in combination with other immunosuppressants. Commonly (may affect up to 1 in 10 people) patiens may experience low level of red blood cells which can result in Yes Pure red cell aplasia may resolve with dose reduction or cessation of therapy. Changes to Mycophenolate sodium therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection Doctor will perform regular blood tests to monitor any changes in the number of

7 tiredness, breathlessness and looking pale (anaemia), unexpected bleeding and bruising (possible signs of a low level of blood platelets) blood cells Important potential risks Risk BK virus associated nephropathy (BK virus associated kidney disorder) JC virus associated progressive multifocal leukoencephalopathy (PML) (JC virus associated extensive brain damage) Serious adverse reactions in breast-fed babies (related to exposure during breastfeeding) What is known Cases of BK virus associated nephropathy have been reported in patients treated with immunosuppressants, including Mycophenolate sodium. Cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Mycophenolate sodium. Because of the potential for serious adverse reactions to MPA in breast-fed infants, Mycophenolate sodium is not advised (contra-indicated) in women who are breast-feeding. It is not known whether Mycophenolate sodium passes into breast milk. Do not breast-feed during treatment with Mycophenolate sodium or for 6 weeks after you have stopped taking Mycophenolate sodium. Missing information Risk Use in paediatric population What is known The use of Mycophenolate sodium in children and adolescents is not recommended due to lack of data.

8 Interaction with other immunosuppressants (e.g. tacrolimus and azathioprine) It is recommended that Mycophenolate sodium not be administered concomitantly with other immunosuppressant medicines such as azathioprine because concomitant administration of these drugs has not been evaluated.the efficacy and safety of the use of Mycophenolate sodium with other immunosuppressive agents (for example, tacrolimus) have not been studied. VI.2.5 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimizing them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. This medicine has no additional risk minimization measures. VI.2.6 Planned post authorisation development plan No studies planned. VI.2.7 Summary of changes to the risk management plan over time

9 Version Date Safety Concerns Comment JUL 2014 Following safetyconcerns are added: Important identified risk: merged the identified risks of As per the comments received from AEMPS Part VI.2.1 miscarriage and congenital Overview of disease malformation as Congenital epidemiology and malformations and spontaneous VI.2.2 Summary of abortions (related to exposure treatment benefits during pregnancy have been updated Serious infections (bacterial, and the relevant fungal, viral and protozoal) and sections of the RMP sepsis updated as per the GI ulcerative and haemorrhage final agreed safety Malignancies (lymphomas and concerns. other malignancies, particularly of the skin) Blood and lymphatic system disorders including pure red cell aplasia (PRCA) Important potential risk: BK virus associated nephropathy JC virus associated progressive multifocal leukoencephalopathy (PML) Serious adverse reactions in breast-fed babies (related to exposure during breastfeeding) Missing information: Interaction with other immunosuppressants (e.g.