RISPERDAL CONSTA belongs to a group of medicines called atypical antipsychotics.

Transcription

1 VI.2. Elements for a Public Summary RISPERDAL CONSTA belongs to a group of medicines called atypical antipsychotics. RISPERDAL CONSTA is used in adults to maintain the treatment of schizophrenia, where you may see, hear, or feel things that are not there; believe things that are not true; or feel unusually suspicious or confused. RISPERDAL CONSTA is intended for patients who are currently treated with oral (e.g., tablets, capsules) antipsychotics. RISPERDAL CONSTA is given as an intramuscular injection either in the arm or buttock every two weeks, administered by a health care professional. VI.2.1. Overview of Disease Epidemiology Schizophrenia is a disorder with symptoms such as hearing voices, seeing or sensing things that are not there, mistaken beliefs, unusual suspiciousness, becoming withdrawn, incoherent speech, and behaviour and emotional flatness. People with this disorder often may also feel depressed, anxious, guilty, or tense. The World Health Organization estimates that there are 24 million people with schizophrenia worldwide or approximately 1% of the general population. Schizophrenia usually appears in men between 20 and 24 years of age and appears in women between 29 and 32 years of age. Schizophrenia is more common in men than in women. Schizophrenia is a chronic disease and is one of the leading causes of disability worldwide. People with schizophrenia are at increased risk of having other health problems, including substance abuse, alcohol abuse and smoking. VI.2.2. Summary of Treatment Benefits The main treatment for schizophrenia is antipsychotic medicine. Newer, atypical antipsychotic medicines are usually preferred over older, typical antipsychotic medicines because atypical medicines have fewer side effects on the nervous system. Psychosocial treatments such as therapy, work training, and life skills training are also important in the long-term management of schizophrenia. Several atypical antipsychotics are available as long-acting injections, which can be beneficial in patients who are not willing or able to stay on treatment with oral medicines. RISPERDAL CONSTA was approved in the EU based on the results of 3 main clinical trials in patients with schizophrenia. In a short-term trial, RISPERDAL CONSTA was compared with placebo (a dummy treatment) in adults with schizophrenia. After 12 weeks of treatment, RISPERDAL CONSTA was useful in managing schizophrenia/schizoaffective disorder. Page 1 of 20

2 In a second short-term trial, RISPERDAL CONSTA was compared with RISPERDAL (tablet taken by mouth) in stable patients with schizophrenia. After 12 weeks of treatment, RISPERDAL CONSTA was as effective as RISPERDAL. In a long-term trial in stable patients with schizophrenia or schizoaffective disorder, the effectiveness of RISPERDAL CONSTA was maintained for 50 weeks. The key measure showing benefit was the amount of change in symptoms on a standard scale for schizophrenia. VI.2.3. Unknowns Relating to Treatment Benefits Most patients in the clinical trials of RISPERDAL CONSTA had paranoid schizophrenia; therefore, little information is available about the benefits in less common (nonparanoid) types of schizophrenia, including catatonic and hebephrenic types. Benefits have not been established in elderly patients (aged >65 years) or paediatric patients (aged <18 years). Page 2 of 20

3 VI.2.4. Summary of Safety Concerns Important Identified Risks RISPERDAL CONSTA What is known Preventability High levels of a hormone called "prolactin" found in a blood test (Hyperprolactinaemia and potentially prolactinrelated adverse events) RISPERDAL CONSTA, as with other antipsychotic medicines that affect dopamine levels in the brain, can raise levels of a hormone called prolactin found in a blood test. A high level of prolactin in the blood may or may not cause symptoms. RISPERDAL CONSTA raises levels of prolactin commonly, but symptoms of high prolactin occur uncommonly. In men, symptoms may include breast swelling, difficulty in getting or maintaining erections, decreased sexual desire, or other problems with sexual performance. In women, symptoms may include breast discomfort, leakage of milk from the breasts, missed menstrual periods, other problems with the menstrual cycle, or changes in the ability to produce children. If such side effects occur, evaluation of the prolactin level in the blood is recommended. CONSTA is needed in patients who already have an abnormally high level of the hormone prolactin in the blood before treatment or if they have a possible prolactin-dependent tumour (for example, a tumour in the pituitary gland in the brain). A doctor may order a blood test of prolactin for a patient who is experiencing symptoms that might be related to high levels of prolactin. As with all medications, a patient's doctor may decide to stop treatment with RISPERDAL CONSTA if the risks are considered to outweigh the benefits in an individual patient. A patient should not stop taking RISPERDAL CONSTA without discussing this with the doctor who prescribed it. Page 3 of 20

4 RISPERDAL CONSTA What is known Preventability An increase in time of contraction and relaxation of the heart ventricles found on an electrical tracing of heart activity (QT prolongation) Low blood pressure upon standing (Orthostatic hypotension) QT prolongation was reported uncommonly, in 0.1% to 1% of patients taking RISPERDAL CONSTA. There is a very small chance that this may lead to more serious heart problems, such as abnormal heart rhythms ('arrhythmias'), particularly in patients with underlying heart problems that could increase their risk of death from such conditions. Orthostatic hypotension is a side effect of some atypical antipsychotic medicines, including RISPERDAL CONSTA. Some people taking RISPERDAL CONSTA may feel faint, dizzy, or may pass out when they stand up or sit up suddenly. Elderly patients are at a higher risk for orthostatic hypotension. CONSTA is needed in patients with certain heart problems or other conditions that may increase the risk for QT prolongation, such as a family history of QT prolongation. Special care is needed when using RISPERDAL CONSTA along with medicines that: may change the electrical activity of the heart, such as medicines for malaria, heart rhythm problems, allergies (antihistamines), some antidepressants, or other medicines for mental problems; cause a slow heart beat; or cause low blood potassium (such as certain diuretics). CONSTA is needed in patients with certain heart problems. Examples include patients with an irregular heart rhythm, patients prone to low blood pressure, or patients using medicines to treat raised blood pressure. RISPERDAL CONSTA may cause low blood pressure. The dose may need to be adjusted. Page 4 of 20

5 RISPERDAL CONSTA What is known Preventability Slow or impaired movement or uncontrollable muscle movements (Extrapyramidal symptoms/tardive dyskinesia) Extrapyramidal symptoms/tardive dyskinesia are side effects of atypical antipsychotic medicines, including RISPERDAL CONSTA. Extrapyramidal symptoms may include a sensation of stiffness or tightness of the muscles, a slow shuffling walk, a loss of expression on the face, restlessness, abnormal movements of the eyes, mouth, tongue, or jaw, and repetitive, spastic, or writhing movements. Some extrapyramidal symptoms were reported in 1% to 10% of patients taking RISPERDAL CONSTA, while other extrapyramidal symptoms were reported in more than 10% of patients taking RISPERDAL CONSTA. There is also a small risk (between 0.1% and 1% of patients taking RISPERDAL CONSTA) of a more serious movement disorder called tardive dyskinesia, which involves uncontrollable twitching or jerking movements in the face, tongue, or other parts of the body. RISPERDAL CONSTA should be used carefully in patients who have experienced movement problems in the past, including Parkinson's disease or dementia with Lewy bodies. CONSTA is needed in patients who have ever experienced involuntary movements of the tongue, mouth, and face. A patient needs to tell his/her doctor immediately if he/she experiences involuntary rhythmic movements of the tongue, mouth, and face. Withdrawal of RISPERDAL CONSTA may be needed. In patients who require long-term treatment, the aim is to control symptoms with the smallest dose and the shortest duration of treatment. Page 5 of 20

6 RISPERDAL CONSTA What is known Preventability A condition with symptoms that include high temperature, muscle stiffness, sweating, or a lowered level of consciousness (Neuroleptic malignant syndrome) Diabetes or problems due to a high blood sugar level (Diabetes mellitus and hyperglycaemia-related adverse events) Neuroleptic malignant syndrome is a rare but serious side effect that could be fatal and has been reported with RISPERDAL CONSTA and similar medicines. Neuroleptic malignant syndrome occurs rarely (in 0.01% to 0.1% of patients taking RISPERDAL CONSTA). Diabetes mellitus or worsening of pre-existing diabetes mellitus have been seen with patients taking RISPERDAL CONSTA. With RISPERDAL CONSTA, high blood sugar was observed in 1% to 10% of patients and diabetes in 0.1% to 1% of patients. Risk factors for diabetes include being overweight or having a family history of diabetes. CONSTA is needed in patients who have ever had neuroleptic malignant syndrome. Patients need to tell their doctor immediately if they experience fever, muscle stiffness, shaking, sweating more than usual, increased heart rate or blood pressure, or muscle pain or weakness, confusion, or a lowered level of consciousness. Immediate medical treatment may be needed. All antipsychotics should be discontinued if a patient develops signs or symptoms of neuroleptic malignant syndrome. Patients treated with RISPERDAL CONSTA should be checked by their doctor for signs of high blood sugar. CONSTA is needed in patients with diabetes and blood glucose should be monitored regularly in these patients. In patients at increased risk of cardiovascular disease, blood glucose should be monitored regularly. Page 6 of 20

7 RISPERDAL CONSTA What is known Preventability An increase in body weight (Weight gain) Convulsion (fits) (Seizures) Significant weight gain may adversely affect health. Patients with schizophrenia may be at higher risk for weight gain due to poor dietary choices and decreased levels of physical activity. Weight gain was reported in 1% to 10% of patients taking RISPERDAL CONSTA. Convulsions were reported uncommonly, in 0.1% to 1% of patients taking RISPERDAL CONSTA. Before RISPERDAL CONSTA treatment is started, body weight should be measured and it should be regularly monitored during treatment, especially in patients at increased risk of cardiovascular disease or diabetes mellitus. Lifestyle measures (such as change in diet and increase in exercise) should be considered early if patients experience significant weight gain. CONSTA is needed in patients with epilepsy, in patients who have ever had seizures, or in patients with an increased risk for seizures. Page 7 of 20

8 RISPERDAL CONSTA What is known Preventability Feeling sleepy or less alert (Somnolence) A prolonged or painful erection (Priapism) Feeling sleepy or less alert was reported in 1% to 10% of patients taking RISPERDAL CONSTA. This may affect the ability to drive a car, operate machines, or do other things that require alertness. These problems are more likely to happen if RISPERDAL CONSTA is taken in combination with other medicines (or alcohol) that work in the brain. Priapism was reported rarely, in 0.01% to 0.1% of patients taking RISPERDAL CONSTA. Special care is needed when using RISPERDAL CONSTA along with medicines that work on the brain to help patients calm down (such as benzodiazepines) or some medicines for pain (opiates), medicines for allergy (some antihistamines), as RISPERDAL CONSTA may increase the sedative effect of all of these. Special care is needed when using RISPERDAL CONSTA along with alcohol, as RISPERDAL CONSTA may increase its sedative effect. Since tiredness may occur during treatment with RISPERDAL CONSTA, patients should not drive or use any tools or machines without talking to their doctor first. CONSTA is needed in men who have ever had a prolonged or painful erection. Men treated with RISPERDAL CONSTA need to tell their doctor immediately if they experience a prolonged or painful erection. Immediate medical treatment may be needed. Page 8 of 20

9 RISPERDAL CONSTA What is known Preventability Stroke or "mini" stroke (Cerebrovascular accident) Blood clots in the veins, typically in the legs ("DVT"). In some cases (i.e., a venous thromboembolism), these clots may travel to the lungs (Venous thromboembolism) It is not known how often strokes occur in patients with schizophrenia who do not receive treatment. Sudden loss of blood supply to the brain (stroke or "mini" stroke) was reported uncommonly, in 0.1% to 1% of patients taking RISPERDAL CONSTA. Blood vessel problems in the brain were reported rarely, in 0.01% to 0.1% of patients taking RISPERDAL CONSTA. With RISPERDAL CONSTA, blood clots in veins and lungs have been reported rarely, in 0.01% to 0.1% of patients. CONSTA is needed in patients with any factors which would favour having a stroke, such as high blood pressure, cardiovascular disorder, or circulation disorders of the brain. RISPERDAL CONSTA is not for use in elderly patients with dementia. Medical treatment should be sought straight away if a patient or caregiver notices a sudden change in mental state or sudden weakness or numbness of the face, arms or legs, especially on one side, or slurred speech, or speech or vision problems, even for a short period of time. These may be signs of a stroke. CONSTA is needed if a patient or someone else in their family has a history of blood clots. Patients should seek medical advice immediately if they experience blood clots in the veins, especially in the legs (symptoms include swelling, pain, and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty breathing. Page 9 of 20

10 RISPERDAL CONSTA What is known Preventability White blood cell count decreased (Leukopenia) A dangerously low number of a certain type of white blood cell needed to fight infection (Agranulocytosis) Low numbers of a certain type of white blood cell needed to protect the body against infection have been reported with RISPERDAL CONSTA. With RISPERDAL CONSTA, agranulocytosis has been reported rarely, in 0.01% to 0.1% of patients. CONSTA is needed in patients who have had low levels of white blood cells in the past (which may or may not have been caused by other medicines). White blood counts should be monitored. A patient's doctor may decide to stop RISPERDAL CONSTA treatment if there is a serious decrease in white blood cells without a known cause. CONSTA is needed in patients who have had low levels of white blood cells in the past (which may or may not have been caused by other medicines). White blood counts should be monitored. Patients should be carefully monitored for fever or other symptoms of infection and treated promptly. For serious cases, a patient's doctor should stop RISPERDAL CONSTA treatment and monitor white blood cell counts until the patient recovers. Page 10 of 20

11 RISPERDAL CONSTA What is known Preventability A decrease in platelets, the type of blood cell that helps stop bleeding (Thrombocytopenia) Breakdown of muscle fibres and pain in muscles (Rhabdomyolysis) Increased risk of death in elderly patients with dementia (Overall increased mortality in elderly patients with dementia) Stroke or "mini" stroke in elderly patients with dementia (Cerebrovascular adverse events in elderly patients with dementia) A decrease in platelets was reported in 0.1% to 1% of patients taking RISPERDAL CONSTA. Often, decreased platelet levels do not cause problems, but can increase the risk of bruising, nosebleeds and/or bleeding gums. Patients with low platelets may also feel more weak and tired than usual. This condition was reported rarely (in 0.01% to 0.1% of patients taking RISPERDAL CONSTA). Increased risk of death in elderly patients with dementia is a safety concern with some atypical antipsychotic medicines. Stroke or "mini" stroke in elderly patients with dementia is a safety concern with some atypical antipsychotic medicines. Platelet counts and symptoms can be monitored during treatment with RISPERDAL CONSTA. In most cases when this condition is caused by a medicine, stopping the medicine leads to recovery. If rhabdomyolysis occurs, a patient's doctor should stop all antipsychotic medications, including RISPERDAL CONSTA. By monitoring for early symptoms. If a patient develops signs or symptoms indicative of neuroleptic malignant syndrome, including rhabdomyolysis, all antipsychotics should be discontinued. RISPERDAL CONSTA is not for use in elderly patients with dementia. RISPERDAL CONSTA is not for use in elderly patients with dementia. Page 11 of 20

12 RISPERDAL CONSTA What is known Preventability Allergic reactions to RISPERDAL CONSTA in patients who previously tolerated oral risperidone (Hypersensitivity reactions to RISPERDAL CONSTA in patients who previously tolerated oral risperidone) Important Potential Risks Even if a patient previously had no allergic reaction with oral risperidone, serious allergic reactions may occur rarely after receiving injections of RISPERDAL CONSTA. Allergic reactions were reported in 0.1% to 1% of patients treated with RISPERDAL CONSTA. Severe allergic reactions were reported in 0.01% to 0.1% of patients treated with RISPERDAL CONSTA. RISPERDAL CONSTA should not be used by patients who are allergic to risperidone or any of the other ingredients of RISPERDAL CONSTA. Patients who have never taken any form of risperidone should begin with oral risperidone before starting treatment with RISPERDAL CONSTA. Doctors should monitor patients for symptoms, and patients should seek medical attention right away if they experience a rash, swelling of the throat, itching, or problems breathing, since these may be signs of a serious allergic reaction. RISPERDAL CONSTA Cancer of the pituitary gland, pancreas, or breast (Carcinogenicity [pituitary adenomas, endocrine pancreas tumours, breast cancer]) What is known (Including reason why it is considered a potential risk) Information gathered with RISPERDAL CONSTA and similar medicines has not shown that people who take them are at any increased risk of developing cancer compared with people who do not. Animals that were given risperidone (the active substance in RISPERDAL CONSTA) showed an increase in certain types of cancer (including tumours in the pituitary gland in the brain, tumours in the pancreas, or breast cancer). While this increased risk in animals has not been seen in humans receiving RISPERDAL CONSTA, the risk cannot be totally ruled out. Page 12 of 20

13 RISPERDAL CONSTA Problems controlling body temperature (Body temperature dysregulation) What is known (Including reason why it is considered a potential risk) Antipsychotic medicines may interfere with the body's ability to reduce its inner temperature. CONSTA is needed in patients who have problems controlling their body temperature or overheating. This could cause problems for patients who exercise hard, who are exposed to high heat, who are taking certain medicines, or who may become dehydrated. These patients may have trouble cooling off or be more likely to become dehydrated. It is unclear if antipsychotic drugs like RISPERDAL CONSTA do have an effect on body temperature. Some studies suggest that problems with body temperature may be related to having schizophrenia, rather than taking medicine. Suicide, suicide attempt, or thoughts of committing suicide (Suicidality) Feelings of depression in patients with bipolar disorder (Depression in patients with affective disorders) Suicide or thoughts of suicide are common in patients with schizophrenia. High-risk patients (such as those with previous attempts or a history of substance abuse) should be closely supervised. Patients taking RISPERDAL for manic episodes associated with bipolar disorder may be at risk of their symptoms switching from mania (where they may feel very excited, elated, agitated, enthusiastic, or hyperactive) to depression. RISPERDAL CONSTA is not approved for use in patients with bipolar disorder. Page 13 of 20

14 RISPERDAL CONSTA Increased sensitivity to antipsychotics in patients who have Parkinson's disease or a certain type of dementia (Increased sensitivity to antipsychotics in patients with Parkinson's disease or dementia with Lewy bodies) What is known (Including reason why it is considered a potential risk) Increased sensitivity to antipsychotics in patients with Parkinson's disease or dementia with Lewy bodies is a side effect of atypical antipsychotic medicines, including RISPERDAL CONSTA. RISPERDAL CONSTA is not for use in elderly patients with dementia. CONSTA is needed in patients with Parkinson's disease. Parkinson's disease may get worse with RISPERDAL CONSTA treatment. Patients with Parkinson's disease or dementia with Lewy bodies may be more likely to develop side effects of antipsychotic treatments like RISPERDAL CONSTA, such as confusion, movement problems, and unsteadiness when standing, which may lead to falls. These patients may also be at an increased risk of neuroleptic malignant syndrome (see Additional information above). Special care is needed when using RISPERDAL CONSTA along with medicines for Parkinson's disease (such as levodopa). RISPERDAL CONSTA has not been studied in patients with Parkinson's disease or dementia with Lewy bodies. Decrease in bone strength/fragile bones (Decreased bone mineral density/osteoporosis) Osteoporosis may be a side effect of some atypical antipsychotic medicines, including RISPERDAL CONSTA. It is thought that the high level of prolactin in the blood that is a side effect of some atypical antipsychotic medicines, including RISPERDAL CONSTA, may cause the bones to become weaker over a long period of time. This needs to be studied more before any conclusions can be made. Page 14 of 20

15 RISPERDAL CONSTA Effects on bone growth in adolescents (Effects on skeletal growth) What is known (Including reason why it is considered a potential risk) Effects on bone growth, including delayed growth, were seen in animal studies with risperidone. In contrast, heights in long-term open-label extension human trials of oral RISPERDAL were within expected values. However, the effect of long-term risperidone treatment on height has not been adequately studied. One small postmarketing observational study showed that children and adolescents exposed to oral risperidone were on average approximately 3.0 to 4.8 cm taller than those who received other atypical antipsychotics, but this study was not adequate to determine whether exposure to oral risperidone had any impact on final adult height, or whether the result was due to a direct effect of oral risperidone on bone growth, or the effect of the underlying disease itself on bone growth, or the result of better control of the underlying disease with resulting increase in linear growth. Since animal studies, human trials, and postmarketing studies have conflicting evidence, no trend can be concluded and this risk is considered "potential" and not "identified". RISPERDAL CONSTA is not for use in children and adolescents. Effects on sexual development in adolescents (Effects on puberty) Effects on sexual development were seen in an animal study with risperidone, so this is considered a potential risk. High levels of prolactin in the blood over time may affect growth and sexual development in adolescents. High prolactin is a side effect of some atypical antipsychotic medicines, including RISPERDAL CONSTA. RISPERDAL CONSTA is not for use in children and adolescents. Page 15 of 20

16 Missing Information Missing Information with RISPERDAL CONSTA Use by patients with kidney problems, including those who need kidney dialysis (a treatment for people whose kidneys no longer work) (Use in patients with renal impairment, including those who require haemodialysis) What is known Although some limited studies have been performed with oral RISPERDAL in patients with kidney problems, RISPERDAL CONSTA has not been studied in patients with kidney problems, including those who need kidney dialysis. RISPERDAL CONSTA should be administered with caution in this patient group. Before taking RISPERDAL CONSTA, patients should tell their doctors if they have kidney problems. For patients with kidney problems, doctors may give lower than usual doses of oral RISPERDAL to test whether starting RISPERDAL CONSTA treatment is expected to be tolerable. Use by patients with liver problems (Use in hepatic impairment) Although some limited studies have been performed with oral RISPERDAL in patients with liver problems, RISPERDAL CONSTA has not been studied in patients with liver problems. RISPERDAL CONSTA should be administered with caution in this patient group. Before taking RISPERDAL CONSTA, patients should tell their doctors if they have liver problems. For patients with liver problems, doctors may give lower than usual doses of oral RISPERDAL to test whether starting RISPERDAL CONSTA treatment is expected to be tolerable. Page 16 of 20

17 Missing Information with RISPERDAL CONSTA Use by pregnant women (Exposure during pregnancy) What is known RISPERDAL CONSTA has not been studied in pregnant women. Women should talk to their doctor before using RISPERDAL CONSTA if they are pregnant or trying to become pregnant. The doctor will decide if RISPERDAL CONSTA can be taken. Newborn babies of mothers who have used RISPERDAL CONSTA in the last trimester (last three months of their pregnancy) need to be watched carefully for side effects or withdrawal symptoms. Use by breastfeeding women (Exposure via breastfeeding) RISPERDAL CONSTA has not been studied in breastfeeding women. RISPERDAL CONSTA can pass into breast milk. Women should talk to their doctor before using RISPERDAL CONSTA if they are breastfeeding. The doctor will decide if RISPERDAL CONSTA can be taken. Use in children and adolescents who are younger than 18 years old RISPERDAL CONSTA is not for use in children and adolescents aged under 18 years. (Off-label use in paediatric patients [<18 years of age]) VI.2.5. Summary of Additional 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 safety 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 SmPC and PL for RISPERDAL CONSTA are available nationally from the company that markets RISPERDAL CONSTA. Page 17 of 20

18 The company considers that the safety risks associated with this medicine can be managed with the information in the SmPC and PL, and therefore no special conditions or restrictions for its safe and effective use (additional risk minimisation measures) have been proposed. VI.2.6. Planned Postauthorisation Development Plan List of Studies in Postauthorisation Development Plan Study/activity type, title and category (1-3) a Objectives (primary objectives, for studies with both primary and secondary objectives) Safety concerns addressed Status (planned, started) Submission of interim or final reports (planned or actual) "Risperidone Exposure and the Risk of Breast Cancer" Epidemiological study Category 3 "To compare the exposure of risperidone and other atypical antipsychotics in association with breast cancer incidence." "To estimate and compare the incidence of breast cancer in users of risperidone, users of other atypical antipsychotics, and users of conventional antipsychotics." Important Potential Risk: "Carcinogenicit y (pituitary adenomas, endocrine pancreas tumours, breast cancer)" Started Estimated: Dec "Risperidone Exposure and the Risk of Osteoporosisrelated Fractures" Epidemiological study "To compare the exposure of risperidone and other atypical antipsychotics in association with hip/femur fracture." "To compare the incidence of hip/femur fracture in users of risperidone, users of other atypical antipsychotics, and users of conventional antipsychotics." Important Potential Risk: "Decreased bone mineral density/ osteoporosis" Started Estimated: Apr 2016 (interim report, with data from Taiwan only). Aug 2016 (final report, including data from Sweden). Category 3 Page 18 of 20

19 Study/activity type, title and category (1-3) a Objectives (primary objectives, for studies with both primary and secondary objectives) Safety concerns addressed Status (planned, started) Submission of interim or final reports (planned or actual) a This table shows only the Categories 1, 2, or 3 studies, per the applicable guidances for European Union Risk Management Plans. Note: This table does not show studies that include oral RISPERDAL but exclude RISPERDAL CONSTA. Studies Which Are a Condition of the Marketing Authorisation The above studies are not a condition of the marketing authorisation. VI.2.7. Summary of Changes to the Risk Management Plan Over Time Version Date Safety Concerns and Other Substantive Changes, for RISPERDAL CONSTA Comment Dec 2013 Original version of the Risk Management Plan. None Jun 2014 Expanded the "use in haemodialysis patients" Missing Information safety concern to be "use in patients with renal impairment, including those receiving haemodialysis." Added "use in hepatic impairment" as a Missing Information safety concern. Harmonised the Important Potential Risk of "effects on skeletal growth" and the Important Identified Risk of "hyperprolactinaemia and potentially prolactin-related adverse events" with more recent SmPCs. Annex 2 (SmPCs and PLs) and Annex 12.2 (references) were updated; all other Annexes were the same as in the previous version. Page 19 of 20

20 Version Date Safety Concerns and Other Substantive Changes, for RISPERDAL CONSTA Comment 3.0 current Added "off-label use in paediatric patients (<18 years of age)" as Missing Information. Updated for contemporaneity (more recent data lock date). Added "hypersensitivity reactions to RISPERDAL CONSTA in patients who previously tolerated oral risperidone" as an Important Identified Risk. See Also this line of the oral RISPERDAL public summary, for changes that were specific to that product. Updated information about device improvements for RISPERDAL CONSTA. Clarified that the Important Potential Risk of "risperidone to methylphenidate 'switch' reactions in the paediatric population" is applicable to oral RISPERDAL but not to RISPERDAL CONSTA, since the prolonged-release nature of RISPERDAL CONSTA does not result in abrupt cessation (in the way oral RISPERDAL could) to precipitate a "switch" reaction. Clarified Missing Information terminology: previously "use during pregnancy" now "exposure during pregnancy," and previously "use in nursing mothers" now "exposure via breastfeeding." Key: PL = Package Leaflet; SmPC = Summary of Product Characteristics. Page 20 of 20