Elements for a Public Summary. Overview of disease epidemiology

Transcription

1 VI.2 VI.2.1 Elements for a Public Summary Overview of disease epidemiology Schizophrenia is a chronic and disabling brain disorder that affects 1 of 10,000 adults (12 to 60 years of age) each year. The incidence rates appear stable across countries and cultures and over time, at least for the last 50 years. Schizophrenic patients are not born into ecological and social disadvantage. The uneven distribution of prevalence rates is a result of social selection: an early onset leads to social stagnation; a late onset to descent from a higher social status (Häfner H, 1997). The main age range of risk for schizophrenia is 20 to 35 years. It is still unclear whether schizophrenia-like late-onset psychoses (for example, late paraphrenia) after age 60 should be classified as schizophrenia either psychopathologically or etiologically. (Häfner H, 1997) Laboratorios Normon, S.A. 196

2 Two independent systematic reviews showed differences in the incidence of schizophrenia between genders, with higher incidence rate in males (male/women proportion: 1.42/1.00) (Guiasalud, 2009) VI.2.2 Summary of treatment benefits Olanzapine is an atypical antipsychotic used to treat the symptoms of schizophrenia in adults. It is also used to treat bipolar disorder. Poor treatment response is an important factor contributing to lack of treatment adherence. In a post-hoc analysis of pooled data from 5 clinical trials it was concluded that olanzapine-treated patients experienced a significantly greater improvement in positive symptoms and in hostility. This could explain why olanzapine-treated patients continue treatment more often (Liu-Seifert H, Osuntokun O, Feldman P, 2012). VI.2.3 Unknowns relating to treatment benefits Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (SmPC Olanzapina Normon comprimidos bucodispersables). VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability Bradycardia (slow heart rate) Drug interactions with inhibitors and inducers of CYP1A2 (drugs like carbamazepine (antiepileptic), fluvoxamine (an antidepressant), ciprofloxacin (an antibiotic)) Dyslipidemia (changes in the levels of circulating fats) Dysregulation of glucose (alteration of glucose levels and or initial symptoms of Olanzapine has been associated with cardiac disorders. Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine Alterations in lipid values may occur in patients receiving olanzapine, for that reason, periodic controls are considered necessary. Patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored Educational material and routine minimisation activities including the SmPC, the PL and monitoring ADRs Educational material and routine minimisation activities including the SmPC, the PL Laboratorios Normon, S.A. 197

3 Risk What is known Preventability worsening of diabetes) Eosinophilia (increase in a type of white blood cell (eosinophils)) Hepatic related events (liver disease appearing as yellowing of the skin and white parts of the eyes) Hyperprolactinemia (increses in levels of prolactin in the blood) Leukopenia(decrease of white blood cells), neutropenia (decrease in some white blood cells (neutrophils) and thrombocytopenia (decrease of platelets) regularly for measuring blood glucose levels. Olanzapine has been associated with eosinophilia (increase in a type of white blood cell (eosinophils)). A lower starting dose (5 mg) should be considered for such patients with hepatic impairment. Caution should be exercised and follow-up organised in patients with elevated ALT and /or AST, in patients with sighs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic medicines. In cases where hepatitis has been diagnosed, olanzapine treatment should be discontinued. In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin value. Caution should be exercised in patients with low leucocyte and/or neutrophil counts for any reason, in patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in aptients and monitoring ADRs the PL, monitoring ADRs Laboratorios Normon, S.A. 198

4 Risk What is known Preventability with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia (decrease in some white blood cells (neutrophils) has been reported commonly when olanzapine and valproate are used concomitantly. Narrow-angle glaucoma (increased pressure in the eye) Photosensitivity reaction (sensitivity to sunlight) QTc prolongation (abnormality of electrocardiogram) Sedation (sommolence) Seizures (epilepsy), neuroleptic malignant syndrome (a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness), dystonia and tardive dyskinesia (unusual movements mainly of the Olanzapine is contraindicated in patients with known risk of narrow-angle glaucoma (increased pressure in the eye). Olanzapine has been associated with photosensitivity reactions (sensitivity to sunlight) Caution should be exercised when olanzapine is prescribed with medicines known to increase QTc interval (abnormality of electrocardiogram), especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia. Given the primary central nervous system effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol Rare cases reported as neuroleptic malignan syndrome (a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness) have also been received in association with olanzapine. Olanzapine should be used the PL, monitoring ADRs the PL, monitoring ADRs reported (signal detection) the PL, monitoring ADRs reported (signal detection) Laboratorios Normon, S.A. 199

5 Risk What is known Preventability face or tongue; muscle stiffness or spasms (including eye movements) Ventricular tachycardia /fibrillation (heart/abnormal rhythms of the heart), sudden death (sudden unexplained death) Weight gain Withdrawal symptoms (symptoms that appear when the treatment is stopped) Withdrawal symptoms in neonatal (symptoms that appear when the treatment is cautiously in patients who have a history of seizures (epilepsy) or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur rarely in patients when treated with olanzapine. The risk of tardive dyskinesia (unusual movements mainly of the face or tongue; muscle stiffness or spasms (including eye movements) increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. Ventricular tachycardia /fibrillation (heart/abnormal rhythms of the heart), sudden death (sudden unexplained death) has been reported in patients with olanzapine. Olanzapine has been associated with cardiac disorders Weight gain was reported in patients on olanzapine treatment. Wheigh should be monitored during treatment. Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly. It should be considered to reduce the dose gradually before stopping treatment. Neonates exposed to antipsychotics (including olanzapine) during the third the PL, monitoring ADRs reported (signal detection) Educational material and routine minimisation activities including the SmPC, the PL and monitoring ADRs Laboratorios Normon, S.A. 200

6 Risk What is known Preventability stopped in neonates) trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms. Consequently, newborns should be monitored carefully Important potential risks Risk Increased risk of mortality primarily associated with concomitant bezodiazepine use Use in children and adolescents below the age 18 Thromboebolism (blood clots in the veins especially in the legs) What is known Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. Risk factors that may predispose this patient population to increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterations has been reported in short term studies of adolescent patients than in studies of adult patients Temporal association of olanzapine treatment and venous thromboembolism (blood clots in the veins especially in the legs) has been reported uncommonly ( 0.1% and <1%). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism all possible factors of VTE e.g. immobilization of patients should be identified and preventive measures undertaken. Missing information Risk Potential long-terms effects of hyperprolactinemia (abnormal production of breast milk) on growth What is known In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the central nervous system depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland. Laboratorios Normon, S.A. 201

7 Risk What is known There is no information in humans. Use during pregnancy Use during lactation There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, become human experience is limited; olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed an infant if they are taking olanzapine. 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 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 Olanzapine Normon can be found on the web pages of the national competent authorities in the EU. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures) according to the reference product. How they are implemented in each country however will depend upon agreement between the manufacturer and the national authorities. These additional risk minimisation measures are for the following risks: Table 2 Weight gain, dysregulation of glucose and lipid alterations. Risk minimisation measure(s) DHCP and the Checklist Objective and rationale The objective is to minimise the risk of weight gain, glucose disregulation and lipid alterations during treatment with olanzapine. Summary description of main additional risk minimisation measures - to inform about the risk of weight gain during treatment and the controls recommended - to inform about the risk of dysregulation of glucose levels in diabetic patients or patients with risk factors for diabetes mellitus and controls recommended - to inform about the risk of alteration of lipidic levels in patients treated with olanzapine and controls recommended Laboratorios Normon, S.A. 202

8 VI.2.6 Planned post authorisation development plan Neither planned studies nor studies imposed by the Committee for Medicinal Products for Human Use (CHMP)/National Competent Authorities (NCA) are foreseen for the aforementioned product. Therefore, there is no need to perform with post-authorisation efficacy studies (PAES) or post-authorisation safety studies (PASS). List of studies in post authorisation development plan Not applicable. Studies which are a condition of the marketing authorisation Not applicable. VI.2.7 Summary of changes to the over time Version Date Safety Concerns Comment 1.0 Not approved additional information required Important identified risks: - Allergic reaction - Bradycardia - Dementia-related psychosis and/or behavioural disturbances - Development of exacerbation of diabetes - Discontinuation - Drug withdrawal syndrome - Effects on ability to drive and use machines - Eosinophilia - Hepatitis - Lactose - Leukopenia, neutropenia and thrombocytopenia - Narrow-angle glaucoma; - Pancreatitis - Pregnancy and breastfeeding - QTc prolongation; - Sedation - Seizures, neuroleptic malignant syndrome, dystonia and tardive dyskinesia; - Thromboembolism; - Rhabdomyolisis - Ventricular tachycardia/fibrillation, sudden death Important potential risks NA Laboratorios Normon, S.A. 203

9 - NA Missing information: - Paediatric population 1.1 Proposal Information added as important identified risks: - Drug interactions with inhibitors and inducers of CYP1A2 - Dyslipidemia - Hepatic related events - Hyperprolactinemia - Photosensitivity reactions - Sedation - Weight gain Update performed according to list of question received during RMP assessment in DCP procedure: DK/H/1810/01-04/DC Information deleted as important identified risks: - Allergic reaction - Dementia-related psychosis and/or behavioural disturbances - Effects on ability to drive and use machines - Lactose - Pancreatitis - Rhabdomyolisis Rephrased risks which remains as identified risks: - Discontinuation withdrawal symptoms - Drug withdrawal syndrome neonatal withdrawal symptoms in neonatal Information added as important potential risks: - Increased risk of mortality primarily associated with concomitant benzodiazepine use - Use in children and adolescent below the age 18 - Thromboembolism Information added as missing information - Potential long-term effects of Laboratorios Normon, S.A. 204

10 hyperprolactinemia on growth - Use during pregnancy - Use during lactation Information deleted as missing information: - Paediatric population 1.1. Proposal Educational material for the following identified risks: - Weigh gain - Dysregulation of glucose - Dyslipidemia 1.2. Proposal Changes in section VI.2.4 Summary of safety concerns Update performed according to list of question received during RMP assessment in DCP procedure: DK/H/1810/01-04/DC Update performed according to list of questions received during RMP assessment in DCP procedure: DK/H/1810/01-04/DC Laboratorios Normon, S.A. 205