Elements for a Public Summary

Transcription

1 VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Parkinson s disease Parkinson s disease (PD) is in the category of movement disorders. It has four main symptoms: tremor and stiffness that affects the limbs, slowness of movement and impaired balance. The onset of symptoms is gradual and worsens with time. PD is recognized as one of the most common disorders affecting the nervous system. The number of PD cases increase with age, and the average age of onset is approximately 60 PhV Page 106/139

2 years. Approximately 1% of individuals older than 60 years have PD. Onset in persons younger than 40 years is relatively uncommon. PD is about 1.5 times more common in men than in women. Environmental risk factors commonly associated with the development of PD include use of pesticides, living in a rural environment, consumption of well water, exposure to herbicides, and proximity to industrial plants or quarries. New cases of PD are diagnosed every year, it has been estimated to be cases per 100,000 people per year, and estimates at any given time from 18 to 328 cases per 100,000 people have PD, with most studies suggesting that approximately 120 cases per 100,000 people have PD. VI.2.2 Summary of treatment benefits To date, PD is only treatable but not curable. The treatment of PD can be divided into two, treating the symptoms and protecting the nervous system to slow down the disease. At this time, there is no proven treatment that protects the nervous system. The cornerstone of treating PD is dopamine replacement therapy. The standard drug of choice is levodopa (L-dopa), a precursor of dopamine, in combination with carbidopa, a peripheral decaboxylase inhibitor (PDI). This combination provides the greatest benefit with the fewest short-term adverse effects. Numerous studies have demonstrated the benefit of entacapone combination with levodopa/carbidopa against parkinson. Levodopa reduces the tremors and some other symptoms of PD during the early stages of the disease, prolonging the time where a persons with PD can live relatively normal lives. Not all of the symptoms of PD respond equally to Levodopa, balance may still be impaired among other non-motor symptoms. Carbidopa reduces the amount of levodopa needed and delays the conversion of levodopa into dopamine until it reaches the brain. By delaying the conversion it can potentially prevent some of the adverse effects or lessen their effect. Entacapone prevents the breakdown of dopamine, therefore prolonging the effects of levodopa. VI.2.3 Unknowns relating to treatment benefits Based on the current information on efficacy for the patients in the main study, there is no evidence to suggest that the results would be any different for patients when taking into account factors such as age, sex race or organ impairment. VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability Impulse control disorders (Pathological gambling, Increased libido, Hypersexuality, Compulsive buying and spending, compulsive and binge eating) The rates of impulse control disorders (ICD) in Parkinson s disease patients are between 3% and 22%. ICDs vary in severity, but may lead to significant reduction in quality of life. ICD covers several different psychiatric disorders and general frequency cannot be obtained. ICD in PD patients must be actively investigated and treated by physicians to improve the lives of patients and caregivers. Reduction of dopamine-dose can Yes, by monitoring for early symptoms PhV Page 107/139

3 Neuroleptic malignant syndrome Disorders affecting the liver and bile Risk What is known Preventability reverse the adverse reaction. Rhabdomyolysis Rhabdomyolysis may occur after (Abnormal muscle cessation of levodopa/carbidopa/entacapone. breakdown which can lead to kidney problems) Controlled cessation reduces the risk of this side effect. Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson's disease. Therefore, any sudden dose reduction or withdrawal of levodopa should be carefully observed, particularly in patients who are also receiving neuroleptics (drugs used to treat mental illness). NMS, including rhabdomyolysis and fever, is characterised by motor symptoms (rigidity, muscle spasms, tremor), mental status changes (e.g. agitation, confusion, coma), autonomic dysfunction (increase in heart rate, labile blood pressure) and high blood levels of creatine phosphokinase enzyme. In individual cases, only some of these symptoms and/or findings may be evident. Sporadic cases of NMS have been reported in association with dose reductions or withdrawal of levodopa carbidopa therapy. Controlled cessation reduces the risk of the adverse reaction. Neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson's disease. Therefore, any abrupt dose reduction or withdrawal of levodopa should be carefully observed, particularly in patients who are also receiving neuroleptics. NMS, including rhabdomyolysis and fever, is characterised by motor symptoms (rigidity, muscle spasms, tremor), mental status changes (e.g. agitation, confusion, coma), autonomic dysfunction (increased heart rate, labile blood pressure) and high blood levels of creatine phosphokinase enzyme. In individual cases, only some of these symptoms and/or findings may be evident. Hepatitis (inflammation of the liver causing yellowing of the skin or Any abrupt dose reduction or withdrawal of levodopa should be carefully observed, particularly in patients who are also receiving neuroleptics (drugs used to treat mental illness) Yes, any abrupt dose reduction or withdrawal of levodopa should be carefully observed, particularly in patients who are also receiving neuroleptics. Levodopa/carbidopa/entacapone should not be used in patients PhV Page 108/139

4 Risk What is known Preventability duct and liver laboratory abnormalities who have a severe liver disease. Heart attack and other heart disease causing inadequate blood flow to the heart Depression (mental state of extreme sadness) with suicidal tendencies Bleeding in the gut Colitis (Inflammation of the colon) Thrombocytopenia (Changes in the eyes) has been reported for levodopa, carbidopa, entacapone. Liver laboratory abnormalities have been described as un uncommon (1 of 100 may be affected) side effect. Entacapone is largely metabolized by the liver, but the relationship between dose, metabolism and liver injury due to entacapone has not been defined. As with levodopa, heart and artery events have been reported in patients treated with levodopa/carbidopa/entacapone combinations. Levodopa is associated with subjective mood changes which sometimes may be quite serious, alternating from depression to extreme sense of well being in a matter of minutes. Higher levodopa doses may induce depression more rapidly. As a characteristic of depression in Parkinson disease (PD), it has been noted that depressed patients have relatively common suicidal thoughts, but reduced frequency of completed suicide. Diagnosing depression in PD patients may often be difficult, as depression shares common features with the disease itself. Serious bleeding events have been identified from studies with levodopa/carbidopa/entacapone. Treatment with levodopa/carbidopa/entacapone may increase the risk of bleeding in the gut in patients with past stomach ulcer. Long-term diarrhoea during treatment may be a sign of colitis. In such cases, diarrhoea is moderate to severe, watery and non-bloody. Other symptoms which may accompany the disease are stomach pain, wind, and bloated feeling. Stopping the treatment results in resolution of diarrhoea in most cases. Changes in the platelet cell count have been uncommonly described Liver values should be monitored. If a liver problem is present, the dose may need to be adjusted. In patients with a history of heart attack, heart function should be monitored with particular care during the period of initial dose adjustments. In the event of previous heart disease, the patient should inform the doctor or pharmacist. Patients treated with levodopa/carbidopa/entacapone should be monitored for the development of mental changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients who have had any form of mental disorder should inform the doctor before taking this medicine. Levodopa/carbidopa/entacapone should be given with caution to patients with past stomach ulcer. Patients who have had stomach ulcer should tell their doctor before start of the therapy. If prolonged and persistent diarrhoea occurs, treatment should be stopped and appropriate therapy started. Patients should talk to their doctor if they experience prolonged diarrhoea, as it could be due to inflammation of the colon. Patients on long-term treatment with levodo- PhV Page 109/139

5 Risk What is known Preventability platelet count which may result in bleeding) Orthostatic hypotension (Low blood pressure when rising from a chair or bed) in levodopa treated patients. This condition may develop into lifethreatening bleeding if appropriate measures are not taken in due time. Similar patterns have been observed in patients with thrombocytopenia following levodopa use, such as: absence of other blood abnormalities, appearance of thrombocytopenia after long term treatment and progressive platelet count recovery beginning shortly after withdrawal of levodopa therapy. A possible mechanism is the formation of drug-induced platelet antibodies that react with the platelets and promote their destruction. Levodopa may cause low blood pressure on its own and may add to the blood pressure lowering effect of other drugs (such as antihypertensives- used to treat high blood pressure). The patient may feel dizzy, experience blurred vision and a feeling of weakness, may fall or lose consciousness over a short period of time. In one study low blood pressure occurred at a higher rate in patients receiving a fixed combination of levodopa/carbidopa/entacapone compared with those receiving carbidopa/levodopa alone. pa/carbidopa/entacapone should periodically have their platelet count monitored. Levodopa/carbidopa/entacapone should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension. Dose reduction of the other blood pressure lowering drug may be needed. Patients should consult their doctor if currently taking other drugs which might cause low blood pressure. PhV Page 110/139

6 Important potential risks Risk What is known (Including reason why it is considered a potential risk) Severe skin and severe allergic reactions as possibly related to levodopa treatment. A recent large study Several cases of skin cancer have been described in the literature found an increased frequency of skin cancer in the group with Parkinson s disease, but this result was recorded before the first hospital contact patients had for their symptoms, and thus before the start of drug treatment for the disease. This seems to dismiss the hypothesis of a causal relationship between treatment of Parkinson disease (including levodopa treatment) and skin cancer. Few severe skin and allergic reactions have in general been reported with the use of levodopa or entacapone. Severe allergic blood vessel inflammation was reported with levodopa, severe widespread blistered breaking out was associated with entacapone and serious allergic reaction causing swelling of the face and neck was reported in studies of entacapone combined with levodopa/dopa decarboxylase (DDC) inhibitor. Prostate cancer Data from a large study suggested that prostate cancer may occur at a higher rate in patients taking a fixed combination of carbidopa/levodopa/entacapone when compared with a carbidopa/levodopa combination. The Food and Drug Administration is conducting a review of this safety issue in order to decide whether this combination truly increases the risk of prostate cancer. Medication error Starting levodopa/carbidopa/entacapone therapy in patients currently treated with levodopa/ddc inhibitor and entacapone preparations or in patients not currently treated with entacapone should follow the current recommendations listed in the Summary of Product Characteristics, so as to achieve an optimal response and maintain a sufficient control of the symptoms. Failing to fulfil the recommendations could lead to toxicity if the initial dose is not adjusted accordingly. The replacement of levodopa/carbidopa/entacapone with other treatment should be done slowly and an increase in levodopa dose might be necessary. Sudden stopping of treatment or sudden dose reduction of levodopa/carbidopa/entacapone may result in worsening of the disease or may trigger unwanted side effects similar to a neuroleptic malignant syndrome. Missing information Risk What is known Pregnancy Very limited information regarding the use of levodopa/carbidopa/entacapone during pregnancy. Considering the indication, the majority of patients will not be of childbearing potential. Some foetal malformation were seen in animal studies. Levodopa/carbidopa/entacapone should not be used during pregnancy. 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 medi- PhV Page 111/139

7 cine, 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. This medicine has no additional risk minimisation measures. VI.2.6 Planned post authorisation development plan No post-authorisation safety or efficacy studies are ongoing or are planned to be conducted for levodopa/carbidopa/entacapone. VI.2.7 Summary of changes to the Risk Management Plan over time Major changes to the Risk Management Plan over time Version Date Safety Concerns Comment 1.0 Submitted Dec-2012 Important Identified Risks Impulse control disorders (pathological gambling, increased libido, hypersexuality) Important Potential Risks None Important Missing information Not approved None Important identified risks Regarding the risk of ICD the following have been added: compulsive buying and spending and compulsive or binge eating as additional ICD symptoms Rhabdomyolysis Neuroleptic malignant syndrome Liver and biliary system disorders and liver laboratory abnormalities Important Potential risks Severe skin and severe allergic reactions, Myocardial infarction and other ischaemic heart disease Important Missing information Pregnancy In accordance with the originator product additional risks are included: New template in according with GVP module V Not approved Severe skin and severe allergic reactions was deleted from the risks, Myocardial infarction and other ischaemic heart disease was changed from Important Potential Risk to Important Identi- RMP was updated in accordance with the AR received by Authority: (Entacapone combi - generic - SE/H/ DCP) PhV Page 112/139

8 Version Date Safety Concerns Comment fied Risk and Pregnancy and breastfeeding was changed from Missing information to Important Potential Risks. The list of risks are now as follows: Not approved Important identified risks ICD (pathological gambling, increased libido, hypersexuality, compulsive buying and spending, compulsive or binge eating) Rhabdomyolysis Neuroleptic malignant syndrome Liver and biliary system disorders and liver laboratory abnormalities Myocardial infarction and other ischaemic heart disease Important Potential risks Pregnancy and breastfeeding Missing information NA The risk Myocardial infarction and other ischaemic heart disease was by mistake listed as an Important potential risk for product number 1. Levocarenta in section VI,1.1, instead of an Important identified risk. This is an administrative update. The following risks have been added: Important identified risks Depression with suicidal tendencies, Gastrointestinal haemorrhage, Colitis, Thrombocytopenia, Orthostatic hypotension Important potential risks Severe skin and severe allergic reactions Prostate cancer Medication error RMP was updated in accordance with the Day 120 RMS Draft AR for (SE/H/ DCP) Not approved The RMP was updated according to the Day 145 comment received from HU (CMS). Additionally, product Levocarenta was removed from the RMP due to withdrawal of procedure DE/H/3809/ PhV Page 113/139

9 Version Date Safety Concerns Comment Pregnancy and breastfeeding was changed to Pregnancy and reclassified as Missing information. PhV Page 114/139