Summary of Risk Management Plan (RMP)

Summary of Risk Management Plan (RMP) Neuraceq Florbetaben ( 18 F), solution for injection SWAN Isotopen AG CH-3010 Bern

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 Neuraceq 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 medicament 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 Neuraceq in Switzerland is the Arzneimittelinformation / Information sur le medicament (see www.swissmedic.ch) approved and authorized by Swissmedic. SWAN Isotopen AG is fully responsible for the accuracy and correctness of the content of the published summary RMP of Neuraceq.

3 RMP Public Summary for Florbetaben ( 18 F) Contents 1 Overview of disease epidemiology... 4 2 Summary of benefits/efficacy... 4 2.1 Summary of existing efficacy data... 4 2.2 Uncertainties about efficacy... 4 3 Summary of safety concerns... 5 3.1 Important identified risks... 5 3.2 Important potential risks... 5 3.3 Important missing information... 6 4 Summary of risk minimisation measures by safety concern... 8 5 Planned post-authorisation development plan... 8 6 Summary of changes to the Risk Management Plan over time... 9

4 1 Overview of disease epidemiology Dementia is a frequent and disabling disease in the elderly population. The most common form of dementia is Alzheimer s disease (AD); other forms of dementia are vascular dementia, mixed types, Lewy body dementia, fronto-temporal dementia and others. The cause and progression of Alzheimer's disease are not well understood. Less than 5% of Alzheimer cases are caused by specific genetic changes that indicate that a person will develop the disease. Research indicates that AD is associated with the formation of senile plaques in the brain consisting of deposited protein, called beta-amyloid, causing damage of brain cells and interfering with cell-to-cell communication. The collection of betaamyloid on the outside of brain cells is a prime suspect of brain cell death in AD. Furthermore, brain cells depend on an internal support and transport system to carry nutrients and other essential materials throughout their long extensions. This system requires the normal structure and functioning of a protein called tau. In Alzheimer's disease, threads of tau protein twist into abnormal tangles inside brain cells, leading to failure of the transport system. This failure is also strongly implicated in the decline and death of brain cells. Thus AD is characterized by extensive brain shrinkage over time. The most important risk factors for AD are old age and a positive family history. 2 Summary of benefits/efficacy 2.1 Summary of existing efficacy data Florbetaben ( 18 F) is a radioactive diagnostic imaging agent used to determine if a specific protein deposit called beta-amyloid plaque is present in your brain. Beta-amyloid plaques have been found in subjects with Alzheimer s disease. Knowing if these plaques are in your brain can help your doctor diagnosing dementia. Florbetaben ( 18 F) works by attaching to beta-amyloid plaques, if it is present in your brain. Once bound to plaques it can be detected during positron emission tomography scans (PET). During the clinical development Florbetaben ( 18 F) was studied in 872 subjects. In 87 subjects, the uptake of Florbetaben ( 18 F) in the brain was analysed by PET scanning and the resulting images were compared to the presence of beta-amyloid plaques in the brain during autopsy. The presence or absence of beta-amyloid plaques in the brain was assessed with a high sensitivity and specificity. The results showed that Florbetaben ( 18 F) can detect beta-amyloid plaques in the brain during life time and can act as a visual support in the diagnosis of dementia to trigger further investigations. 2.2 Uncertainties about efficacy The usefulness of Florbetaben ( 18 F) in patients with structural abnormalities in their brain, such as brain trauma or tumours, has not been studied, however, in practice an evaluation for Alzheimer s disease in such patients will not be a priority. Given the fact that beta-

5 amyloid deposition is generally a global event occurring in many regions bilaterally, a structural disruption will in most cases not affect the image assessment. There may be cases in which the grey-white matter boundary or structural landmarks are altered in such a way that the image analysis is not possible. This is felt to be a potential confounder in a small number of cases. 3 Summary of safety concerns 3.1 Important identified risks Reactions around point of injection (local tolerance) Risk due to contact with radiation (carcinogenic and hereditary risk) As with any injected medication, reactions around the point of injection may occur (e.g. Injection site pain or Injection site irritation). These reactions are generally mild and do not require any form of treatment. Older patients are at a higher risk because of their fragile veins. Contact with radiation can cause cancer or the development of hereditary changes. This risk is higher as the quantity of radiation is increased. The radiation doses for Florbetaben ( 18 F) are similar to other examinations involving nuclear medicine and the potential radiation risk associated with the use of Florbetaben ( 18 F) is in the acceptable limits. Care should be taken to avoid any of the medication from being injected outside of the vein. The lowest possible dose of radiation should be used. 3.2 Important potential risks Reactions to the alcohol content of the injection (reactions to ethanol content of formulation) Alcohol is used in many prescription and nonprescription drugs, to help make the drug more soluble. It can also be used as a preservative. The maximum volume of alcohol in an injection of Florbetaben ( 18 F) is the same as 30 ml of beer or 12 ml of wine. Although adverse reactions to this small amount of alcohol are rather unlikely, patients suffering from alcoholism, liver disease or Patients being treated with an alcohol deterrent such as disulfiram should discontinue this medication before receiving Florbetaben ( 18 F). It should be taken into account that the presence of ethanol can also be harmful for high- risk groups such as patients with liver disease or epilepsy.

6 Injection of the drug outside of a vein (extravasation) Hypersensitivity PET scan interpretation errors Off-label use epilepsy are at a higher risk for adverse reactions. If a large proportion of the drug is injected into the tissue around the vein, this could cause a wound because of the radiation, alcohol and another substance (macrogol) that is in the injection. Careful injection of Florbetaben ( 18 F), making sure that the drug is being injected into the vein can reduce the possibility of this from happening. In patients who are allergic to Florbetaben ( 18 F) (or any of the excipients) hypersensitivity reactions may occur after injection of the drug. Such a reaction may even evolve to an anaphylactic reaction, which can be life-threatening. Interpretation errors by the physicians who read the acquired images may lead to subsequent inappropriate treatment strategies for their patients. Florbetaben ( 18 F) is not recommended for the use in patients other than elderly investigated for Alzheimer s disease. The outcome for the use in other populations was not sufficiently conducted in studies. In order to minimise the risk of extravasation, the patency of the vein must be ensured by a test injection of normal saline prior to injection of Florbetaben ( 18 F). Additionally, a slow injection into a large arm vein is recommended, followed by a saline flush of approximately 10 ml. Clarification of existing hypersensitivity towards Florbetaben ( 18 F) or any of the excipients or other drugs prior to administration. Training for PET scan readers/physicians. Neuraceq should be reserved to use only in the labelled indication. The possibility of off-label use will be explored in a forthcoming PASS and risk minimization activities could be proposed as needed. 3.3 Important missing information Safety in patients with impaired renal function The pharmacokinetics of Florbetaben ( 18 F) in patients with reduced kidney function has not Increasing knowledge about the safety profile of Florbetaben ( 18 F) in impaired

7 Safety in patients with impaired hepatic function Drug-drug interaction (disulfiram) Patients with brain structure abnormalities been characterized. The pharmacokinetics of Florbetaben ( 18 F) in patients with hepatic impairment has not been characterized. Consequences of Florbetaben ( 18 F) use in patients with severe hepatic impairment are not known. Therefore Florbetaben ( 18 F) is not recommended in patients with severe hepatic impairment. Drug-drug interactions studies have not been conducted. Due to its alcohol content Florbetaben ( 18 F) may interfere with other drugs such as disulfiram used for the treatment of alcoholics. There are no data indicating that such an interaction exists. The structural abnormalities in this patient population may interfere with the results of a PET imaging scan with Florbetaben ( 18 F) and therefore, affect the efficacy of the drug. renal function: e.g. by collection and evaluation of additional data from patients with impaired renal function in the frame of a postauthorisation safety study (PASS-2) and during evaluation of a terminated phase III trial. Increasing knowledge about the safety profile of Florbetaben ( 18 F) in impaired hepatic function: e.g. by collection and evaluation of additional data from patients with impaired hepatic function in the frame of a post-authorisation safety study (PASS-2) and during evaluation of the terminated phase III trial. Increasing knowledge about potential drug-druginteractions for Florbetaben ( 18 F): Monitoring the effect of potential drug-drug interaction with disulfiram on efficacy and safety in a postauthorisation safety study (PASS-2). Clinical knowledge should ascertain that amyloid deposition is generally a global event occurring in many regions bilaterally and a structural disruption should not affect the image assessment. Training for PET scan readers/physicians is mandatory.

8 4 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 minimising 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. The Summary of Product Characteristics and the Package leaflet for Florbetaben ( 18 F) can be found in CTD Module 1.3.1. Additional risk minimization measures will be conducted by monitoring the effectiveness of the educational material for PET scan readers and the effectiveness of minimising risks by specific warnings in the product information leaflet. For that purpose, a post-authorisation safety study (PASS-1) is planned. In the frame of a post-authorisation safety study, the utilisation of Florbetaben ( 18 F) will be assessed including patients with structural brain abnormalities. 5 Planned post-authorisation development plan Study/activity (including study number) Post-authorisation safety study (PASS-1) Post-authorisation safety study (PASS-2) Objectives To investigate the effectiveness of educational material for PET scan readers and the quality of trained reading Examine precision of PIL reading Extension of Safety Profile Usage of Florbetaben ( 18 F) including off label use Safety concerns /efficacy issue addressed PET scan interpretation errors Labeling (quality of special warnings and precautions for use) Rare adverse drug reactions Risks in specific subgroups of patients Status Planned, protocol adopted by PRAC on June 26, 2014. Study start planned for Q1 2016. Planned; study protocol currently under revision, CHMP adioption expected on 16 July 2015 Study start anticipated in Q1 / 2016. Planned date for submission of (interim and) final results Interim report planned for Q2 / 2017. Final study report planned for Q1 / 2019.. Interim reports planned for Q1 of, 2017, 2018, and 2019 Final study report planned for Q3 / 2020.

9 6 Summary of changes to the Risk Management Plan over time Not applicable