Latuda (lurasidone) Summary of the Risk Management Plan (RMP) for the Public An introduction to Risk Management Plans When a medicine is approved, the patient leaflet gives information about the side effects that we know might happen. These are the side effects found in clinical studies. However, the clinical studies may not tell us what happens in the real world. This means there may be other risks and side effects that might only be found after a medicine is approved. That is why we have a Risk Management Plan. This summary is for patients and the public. It is a shortened version of the full Risk Management Plan. The purpose of this public summary is to show how possible future risks will be managed for Latuda when used to treat schizophrenia. What is in this summary? This summary starts with general information about Latuda and schizophrenia: 1. What is schizophrenia? 2. How many people have the illness? 3. What have completed studies shown about the benefits of Latuda? 4. Groups of people where we have less information about lurasidone It then talks about possible future safety risks and how they will be managed: 5. Summary of safety concerns 6. Summary of actions to minimise the risk to patients 7. Studies happening now and in the future - to find answers to the most important questions 8. Summary of changes to the risk management plan over time What else should I read? Patient leaflet: Read the patient leaflet that came with the medicine if you are taking Latuda, or are caring for someone who does. It will tell you more about Latuda, and how to take it safely and effectively. If you are just interested in Latuda, you may also find reading the patient leaflet useful, before you read this summary. You can find the patient leaflet here. EPAR summary: The European Public Assessment Report (EPAR) summary tells you how the benefits and risks were weighed up before a decision was made to make Latuda available to patients in Europe. You can find the EPAR summary here. Page 1 of 11
1. What is schizophrenia? Schizophrenia is a severe mental illness, where: you have mixed up thoughts and speech you hear or see things that are not there (hallucinations) you are suspicious and believe things that are not true (delusions). It usually starts as a teenager or when people are in their 20s. 2. How many people have the illness? The number of men and women who are affected is the same. However the illness starts at a slightly earlier age in men. About 1 in every 100 people (1%) have the illness at any one time. Each year in Europe, about 15 new people are found to have schizophrenia in every 100,000. 3. What have completed studies shown about the benefits of Latuda? Latuda is type of medicine used for schizophrenia in adults. This type of medicine is called an anti-psychotic. The first medicines used for schizophrenia were called first generation anti-psychotics Latuda is called a second generation anti-psychotic - these are newer medicines for schizophrenia Latuda is the name given by the company to the medicine - the brand name. The name of the active medicine in Latuda is lurasidone. From now on we will use the name lurasidone. You can find out more about the medicine in the patient leaflet. Short term studies There have been 3 clinical studies to see if lurasidone works in the short term. The total number of patients was 1,466. The dose of lurasidone was 37 to 148 mg each day. In all 3 studies, the medicine was compared with a dummy treatment (a placebo ) for 6 weeks. In 2 studies, lurasidone was also compared with two other schizophrenia medicines called olanzapine and quetiapine XR One of the studies kept going for 12 months in 292 patients. This was to see if the effect of lurasidone lasted. This was compared with patients taking quetiapine. What did the studies show? Overall, patients showed an improvement in symptoms in the short term (6 weeks) studies. In the 12 month study, lurasidone was as effective as quetiapine XR (200-800 mg per day) in stopping the schizophrenia from coming back. Page 2 of 11
Long term studies Two studies looked at the long-term effects of lurasidone. It was compared with another schizophrenia medicine, risperidone, or placebo. The total number of patients was 914. What did the studies show? The studies showed lurasidone has benefits over the long term. However, it was not shown to be as effective as risperidone. One of the long term studies showed that patients treated with lurasidone had a longer time until symptoms came back than patients on placebo. 4. Groups of people where we have less information about lurasidone The people taking part in the studies described above were over 18 years old and mostly under 65 years. This means there is limited information on how well lurasidone works in: elderly patients children under 18 years - studies have started, but results are not yet available. There are other areas where we have limited information - see the last part of the next section ( Areas where we have little or no information ). 5. Summary of safety concerns The safety of lurasidone is generally the same as other second generation anti-psychotics. This section describes: a) Risks we know about - and how to lower the risk b) Possible other risks which are important - and what we know about them c) Areas where we have little or no information Page 3 of 11
a) Risks we know about Risk What we know How to lower the risk Movement problems: shaking (tremor) muscle stiffness (parkinsonism) being unable to stay still (akathisia) reduced movement muscle spasms (dystonia) Problems with other medicines The way lurasidone works can be affected by other medicines. These types of medicine are called: Strong CYP3A4 inhibitors Strong CYP3A4 inducers In the studies, about a quarter (25 out of 100) of people taking lurasidone had some movement problems. This compares with 9% of people who received placebo. These types of side effects were seen in both the long- and short-term studies. These medicines affect the way the body breaks down lurasidone. CYP3A4 inhibitors increase the amount of lurasidone in the body. This could increase the risk of side effects. CYP3A4 inducers lower the amount of lurasidone in the body. This could make the medicine work less well. Patients must tell the doctor if they get any signs of movement problems - such as stiffness, shaking or problems moving. The doctor will then be able to keep an eye on this - and lower the dose of lurasidone if needed. Patients must tell the doctor about any other medicines they are taking. The doctor will check if any of the other medicines are strong CYP3A4 inhibitors or strong CYP3A4 inducers. The doctor will then discuss with the patient whether the lurasidone or the other medicine is more important. Less strong (moderate) CYP3A4 inhibitors or inducers may be able to be taken. However, the doctor may need to change the dose of lurasidone. Page 4 of 11
b) Possible other risks which are important Risk What we know Swelling under the skin This swelling happens quickly. It is called angioedema. One person in the studies of lurasidone had severe swelling. 18 other people had swelling in the United States and Canada - where the medicine has been approved for longer. In 4 of these people the swelling was serious. Swelling could be a sign of a serious allergic reaction (called hyper-sensitivity ). This means it could be a risk from lurasidone. However, in all of these people, we do not know if lurasidone caused the swelling. This means that patients taking lurasidone must tell the doctor about any allergic reactions in the past to: lurasidone any other ingredients listed in the patient leaflet. Signs of a severe allergic reaction include fever, swollen mouth, face, lip or tongue, shortness of breath, itching, skin rash and sometimes a drop in blood pressure (may make the patient dizzy or light-headed), fast or uneven heart-beat. Neuroleptic malignant syndrome (NMS) This illness can be life-threatening. Signs include high fever, sweating, unstable blood pressure, stupor, and muscle stiffness (muscular rigidity). Repeated twitching or shaking of the arms, legs and lower face This can happen months or years after starting an anti-psychotic medicine. It is called: tardive dyskinesia. Signs include pulling a face, tongue sticking out, lip smacking, puckering and pursing of the lips, and fast eye blinking. Effects on metabolism (metabolic profile) These include: high levels of sugar in the blood (called hyper-glycaemia ) weight gain having too much fat in the blood (called dys-lipidemia ) Two people in the studies of lurasidone had NMS. 5 other people may have had NMS in the United States and Canada - where the medicine has been approved for longer. The number of people getting NMS is about the same as in those taking other anti-psychotic medicines. However, there may have been other reasons for each of the cases seen with lurasidone. NMS is therefore a possible risk for lurasidone, as it is for all anti-psychotic medicines. Eleven people in the studies of lurasidone had repeated twitching or shaking of the arms, legs and lower face. 48 people have had this side effect in the United States and Canada - where the medicine has been approved for longer. This side effect has also been reported with other anti-psychotic medicines. These are side effects with other anti-psychotic medicines and may affect patients health. However, in studies of lurasidone there was very little effect on weight gain, or increase of blood sugar or blood fats. Page 5 of 11
Risk What we know Rhabdomyolysis Signs include muscle pain, being sick, being confused, abnormal heart rate or heart-beat, and dark urine. Suicide or thoughts of suicide Low white blood cells ( agranulocytosis ) Signs include fever, chills, infections that keep coming back, aches and pains. Two people in the studies of lurasidone had this side effect. 2 people have had this side effect in the United States and Canada - where this medicine has been approved for longer. People with schizophrenia may try to kill themselves or have thoughts of suicide. There is no evidence that people taking lurasidone are more likely to try to kill themselves or have thoughts of suicide. However, it is important that reports about this are monitored. There were no cases of low white blood cells in any of the studies with lurasidone. 1 person has had this side effect in the United States and Canada - where the medicine has been approved for longer. This means there is no reason to suggest that lurasidone causes this problem. Fits (seizures) Increased levels in the blood of creatinine (increased serum creatinine) Patients with moderate or severe kidney problems (kidney impairment) Five people in the studies of lurasidone had fits. 16 people have had this side effect in the United States and Canada - where this medicine has been approved for longer. This side effect has also been reported with other anti-psychotic medicines. Creatinine is a waste substance that is removed from the body by the kidneys. Increased creatinine in the blood could mean that the kidneys are not working properly. In some studies there were slight increases in creatinine - but the patients kidneys were working properly. Lurasidone is removed from the body by the kidneys. In patients with all kinds of kidney damage, the amount of lurasidone in the blood is increased. This could result in more side effects. This means that in patients with moderate or severe kidney damage: the recommended starting dose of lurasidone is 18.5 mg. the dose should not be more than 74 mg a day. Page 6 of 11
Risk What we know Patients with moderate or severe liver problems (liver impairment) Lurasidone is broken down in the body by the liver. In patients with all kinds of liver damage, the amount of lurasidone in the blood is increased. This could result in more side effects. In patients with moderate or severe liver damage: the recommended starting dose of lurasidone is 18.5 mg. the dose should not be more than 74 mg a day for moderate damage or 37 mg a day for severe damage. Patients with bipolar disorder (off-label use in bipolar disorder) Elderly patients with dementia (off-label use in the elderly with dementia) Use at doses higher than 148 mg a day (off-label use at doses higher than 148 mg a day) Pregnancy - use in last 3 months of pregnancy and risk to new-born babies The use of lurasidone in bipolar disorder is not approved in the European Union. It is therefore not recommended to be prescribed to people with this illness. Lurasidone has not been studied in elderly patients with dementia. Elderly patients with dementia treated with anti-psychotic medicines may be at higher risk of stroke or death. Therefore, lurasidone should not be taken by these patients. Lurasidone is approved for use up to 148 mg a day. Doses higher than 148 mg a day are not approved for treatment of schizophrenia and should not be prescribed. Lurasidone has not been studied in pregnant women. Anti-psychotic medicines like lurasidone may affect unborn babies if taken by a woman in the last 3 months of pregnancy. The unborn baby may be at risk of movement problem side effects. These are the same movement problems that the person taking the medicine may get. When they are born, these babies may get withdrawal symptoms. Therefore, lurasidone should not be taken by pregnant women. Page 7 of 11
c) Areas where we have little or no information Use in elderly patients (65 years or above) Use in patients with heart problems (cardiac impairment) Use in pregnant or breast-feeding women Use in children and teenagers Safety of use over long periods Possible effect on medicines which break down and remove medicines from the body (called drug metabolising enzymes and transporters ) Only 72 out of the 3,202 people in the clinical studies were aged 65 years or over. However, there is no evidence that lurasidone has an increased risk in these patients. However, as elderly patients may have liver or kidney problems, the doses used need to be carefully chosen. See sections above on use in patients with kidney or liver problems. Lurasidone has not been studied in patients with heart problems or recent heart attacks. A study has shown that lurasidone does not affect the electrical activity of the heart. However, use lurasidone with care in these patients. Also take care in patients at risk of stroke or low blood pressure. Lurasidone has not been studied in women who are pregnant or breast-feeding. Anti-psychotic medicines like lurasidone may affect unborn babies if taken by a woman in the last 3 months of pregnancy. The unborn baby may be at risk of movement problem side effects. These are the same movement problems that the person taking the medicine may get. When they are born, these babies may get withdrawal symptoms. We do not know how safe or effective lurasidone is in children under 18 years. A total of 3,202 patients have been treated with lurasidone (18.5 to 148 mg lurasidone each day). This was in 52 clinical studies each lasting between 3 weeks and 22 months. More long-term clinical studies are being carried out. The safety monitoring of lurasidone in the real world will continue now it is approved. We do not know how lurasidone affects some other medicines. At the moment we do not think that it affects other medicines. We will check for this in studies in the future. Page 8 of 11
6. Summary of actions to minimise the risk to patients There are two types of actions taken to minimise risks of medicines, once they have been approved: Routine risk minimisation measures The well understood risks about a medicine are included in the information about a medicine for health professionals (called the SmPC ) and patients (the patient leaflet). There is also information there about how to minimise those risks. Additional risk minimisation measures For some medicines there are extra actions to reduce the risk to patients. In the case of Latuda, there are no extra actions at the moment. 7. Studies happening now and in the future The following studies are happening now or planned for the future. They are part of what is called the Planned post-authorisation development plan. Studies with patients Name of the study PASS Study Characterizing the safety profile of lurasidone in clinical practice Planned in the future We do not yet know when this will be finished. Study D1001057 Long-term safety and effectiveness of lurasidone in patients with schizophrenia Study happening now Planned to finish in February 2016. Study D1001056 Short-term effectiveness and safety of lurasidone in patients with schizophrenia Study happening now Planned to finish August 2015. What the study is looking at This study will look further into the overall safety of lurasidone when use in practice. This is to find out more about safety issues we know about. It will: Collect information on safety in schizophrenia for lurasidone and other anti-psychotic medicines in the real world. Look at the way lurasidone is used that might affect its safety. It will include use in children. It also includes other patients who may be at risk. This study will look at the effectiveness and long-term safety of lurasidone in schizophrenia. It will: Collect information on long-term safety. This study will look at the effectiveness and short-term safety of lurasidone. It will: Collect information on the effectiveness and safety of lurasidone taken for 6 weeks in patients with schizophrenia. Page 9 of 11
Name of the study Study D1050298 Long-term effectiveness and safety of lurasidone in patients with schizophrenia Study happening now Planned to finish August 2016. Study D1050238 Maintenance activity of lurasidone in patients with schizophrenia All data collected, final study report being written Planned to finish April to June 2014. Study D1050307 Long-term effectiveness and safety of lurasidone in clinically stable outpatients with schizophrenia All data collected, final study report being written Planned to finish April 2014. Study D1050300 PK, safety and tolerability study in subjects from 6 to 17 years of age with schizophrenia, bipolar, autistic spectrum disorder or any other psychiatric disorders All data collected, final study report being written Planned to finish April to June 2014. What the study is looking at This study will look at the long-term effectiveness and safety of lurasidone. It will: Collect information on the long-term safety, tolerability and effectiveness of lurasidone in patients who have already received lurasidone. This study will look at the long-term effectiveness of lurasidone. It will: Collect information on the effectiveness of lurasidone as a maintenance treatment for patients with schizophrenia. To collect information on the long-term effectiveness and safety of lurasidone in patients with stable schizophrenia. This study will look at use of lurasidone in children and young people. PK is short for pharmacokinetics. This is about how a medicine moves around the body. This study will collect this information for lurasidone in children and young people. It will look at the use of lurasidone in children aged 6 to 17 years old with schizophrenia, bipolar disorder, autistic spectrum disorder, or other mental health problems. It will look to see how safe and tolerable doses are (as single doses or repeat doses). The doses looked at will be 18.5, 37, or 74 mg each day by mouth. Page 10 of 11
Studies in the laboratory (called in vitro studies) Name of the study Possible effects of lurasidone on other medicines: medicines called liver uptake transporters (OATP1B1 and OATP1B3). planned in the future planned to finish end of 2014. Possible effects of lurasidone on other medicines: medicines called CYP2C8 and CYP2B6 inhibitors planned in the future planned to finish end of 2014. Possible effects of lurasidone on other medicines: medicines called drug metabolizing enzymes and transporters planned in the future planned to finish end of 2014. What the study is looking at Whether lurasidone affects how these other medicines work. Whether lurasidone affects how these other medicines work. Whether lurasidone affects how these other medicines work. For some medicines, approval is given only if certain studies are going to be carried out. This is not the case for Latuda. 8. Summary of changes to the risk management plan over time As we get more information about the risks of lurasidone from these studies, the risk management plan will be updated. At the moment there are no updates to this plan. This summary was last updated in XX-XXXX. Page 11 of 11