Elements for a Public Summary. VI.2.1 Overview of disease epidemiology

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1 VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Schizophrenia Schizophrenia is a mental disorder often characterized by abnormal social behaviour and failure to recognize what is real. Common symptoms include false beliefs, unclear or confused thinking, auditory hallucinations, reduced social engagement and emotional expression, and inactivity. Schizophrenia occurs throughout the world. The number of cases in a population at any one time point approaches 1 percent internationally. The number of new cases per year is about 1.5 per 10,000 people [1]. Slightly more men are diagnosed with schizophrenia than women [2], and women tend to be diagnosed later in life than men. Some risk factors that are related to the development of schizophrenia include living in a city [3,4], the movement of people into another country or region [5,6] and obstetrical complications [7]. Studies have shown that the risk of schizophrenia is higher with increasing age of the father [8] at conception. Symptoms of schizophrenia typically include hallucinations or delusions, disorganized thinking and speech, poor speech, and difficulties in attention and memory. The primary treatment of schizophrenia is antipsychotic medications.

2 Bipolar I Disorder Bipolar disorder is a brain disorder causing unusual changes in mood, energy, activity levels, and the ability to carry out everyday tasks [9]. Patients with bipolar I disorder have episodes of mania and nearly always experience major depressive episodes. Patients with bipolar II disorder suffer both hypomanic episodes and major depressive episodes. In a study [10], Merikangas et al, 2007 have shown that bipolar disorders are more common than previously thought. The lifetime prevalence for bipolar I and II disorders was 1.0% and 1.1%, respectively. The most common age of onset of bipolar disorder is years. A study conducted by the WHO identified bipolar disorder as the 6th leading cause of disability world-wide in the year age group. The incidence of bipolar disorder is similar in men and women [11] as well as across different cultures and ethnic groups. A study by the WHO found that prevalence and incidence of bipolar disorder are very similar across the world. Late adolescence and early adulthood are peak years for the onset of bipolar disorder [12,13]. VI.2.2 Summary of treatment benefits Schizophrenia Schizophrenia is a severe, complex, chronic and disabling mental illness that affects about 1 in every 100 people around the world. Experts believe that schizophrenia is a cluster of illnesses masquerading as one. Scientists say that schizophrenia is caused by faulty neuronal development in the brain while the fetus is in the uterus, which later on manifests as a full-blown illness. Aripiprazole has been demonstrated to effectively treat a range of schizophrenia symptoms, including: Auditory hallucinations - hearing voices that are not there Unclear thinking Disturbing or uncomfortable thoughts Confusion Being uninterested in things the patient used to enjoy. According to clinical studies, people who take aripiprazole start noticing improvements within a few weeks. It may also be a useful medication for patients who have been stable while on another antipsychotic drug for at least three months and have relapsed for a period of up to 26 weeks. Bipolar I Disorder Bipolar disorder, previously referred to as manic-depression or manic-depressive illness, is characterized by unstable moods, which can sometimes become serious and disabling. A person who lives with bipolar disorder has strange mood changes, as well as shifts in levels of energy, vigor, and the ability to function properly - sometimes a change can cause weeks or even months of despair and anguish. Treatments are available today which can help patients lead full, independent and productive lives. Aripiprazole has been shown in clinical studies to effectively treat acute manic and mixed episodes in adults and older children (aged 10 to 17 years) with bipolar I disorder. In most cases, onset of symptom relief starts within several days, but this may vary from person-to-person.

3 Aripiprazole helps the patient control manic symptoms; it also stabilizes manic or mixed moods, and makes it less likely that a manic relapse may occur. VI.2.3 Unknowns relating to treatment benefits With respect to the irritability associated with autistic disorder, the safety and efficacy of aripiprazole in children and adolescents aged below 18 years have not yet been established. In relation to tics associated with Tourette s disorder, the safety and efficacy of aripiprazole in children and adolescents 6 to 18 years of age have not yet been established. Despite the high comorbidity frequency of Bipolar I Disorder and Attention deficit hyperactivity disorder (ADHD), very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution must be taken when these drugs are co-administered. Also, there are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity. Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole. Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product must not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus. Neonates exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns must be monitored carefully. Finally, aripiprazole is excreted in human breast milk. It may have harmful effects on the infant when ingested. A decision must be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4 VI.2.4 Summary of safety concerns Important identified risks What is known Preventability Extrapyramidal symptoms (EPS), In paediatric clinical trials of including uncontrollable movements of mouth, tongue aripiprazole, akathisia and parkinsonism were observed. and limbs (tardive dyskinesia) Neuroleptic Malignant Syndrome (NMS) Important potential risks In clinical trials of one year or less duration, there were uncommon reports of dyskinesia during treatment with aripiprazole. These symptoms can temporally become worse or can even appear after stopping treatment. NMS is a life-threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Symptoms of NMS are fever, muscle rigidity, altered mental status (agitation, delirium, or coma), and irregular pulse or blood pressure, tachycardia, and cardiac dysrhythmia. Additional signs may include raised creatine phosphokinase, rhabdomyolysis (destruction of muscle tissue), and impaired kidney function. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose must be reduced and close clinical monitoring is advised. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or stopping treatment is advised. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional signs of NMS, all antipsychotic medicinal products, including aripiprazole, must be stopped. Seizures Hyperglycaemia/diabetes What is known (Including reason why it is considered a potential risk) In clinical trials, cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole must be used with caution in patients who have previously experienced seizure disorder or have conditions associated with seizures. Hyperglycaemia has been reported in patients treated with antipsychotic agents, including aripiprazole. Complications are more severe in case of obesity and family history of diabetes. Patients treated with any antipsychotic agents, including aripiprazole, must

5 Suicide-related events Orthostatic hypotension Dyslipidemia Drug interactions What is known (Including reason why it is considered a potential risk) be followed-up for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or at increased risk for diabetes mellitus must be monitored regularly for worsening of glucose control. During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients must be closely monitored throughout this period. Suicidal behaviour appears inherently in psychotic illnesses and mood disorders and in some cases has been reported early after starting or switch of antipsychotic therapy, including treatment with aripiprazole. High-risk patients must be closely supervised during antipsychotic therapy. Aripiprazole must be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose patients to hypotension [dehydration, hypovolemia (a state of decreased blood volume), and treatment with antihypertensive medications]. Undesirable changes in lipids have been observed in patients treated with atypical antipsychotics. (Potential) interactions with the following groups are described: antihypertensive agents alcohol and CNS medicinal products medicinal products known to cause QT prolongation or electrolyte imbalance CYP2D6 and CYP3A4 substrates Missing information Safety in pregnancy and lactation Safety in paediatrics What is known There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Aripiprazole is excreted in human breast milk. Patients must be advised not to breast feed if they are taking aripiprazole. Schizophrenia in adolescents aged 15 years and older: Aripiprazole is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy. Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, aripiprazole is not recommended for use in patients below 13 years of age. Irritability associated with autistic disorder: the safety and efficacy of aripiprazole in children and adolescents aged below 18 years have not yet been established. Tics associated with Tourette s disorder: the safety and efficacy of aripiprazole in children and adolescents 6 to 18 years of age have not

6 What is known yet been established. VI.2.5 Summary of additional risk minimisation measures by safety concern The SmPC for aripiprazole 5 mg, 10 mg, 15 mg and 30 mg tablets provides physicians, pharmacists and other healthcare 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 the SmPC and PL are known as routine risk minimisation measures. Aripiprazole for oral use has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). These additional risk minimisation measures are for the following risks: - The treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older. Safety concern in lay terms (medical term) minimisation measure(s): The treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older. Objective and rationale: For additional education of healthcare professionals and patients/caregivers at the time of the launch of the product for the indication of Bipolar I Disorder in adolescents aged 13 years and older urging vigilance in the ongoing evaluation of extrapyramidal symptoms, weight gain, and AEs related to somnolence/fatigue. The educational materials are provided to physicians and patients/caregivers in order to ensure the safe and effective use of SmPC for Aripiprazole 5 mg, 10 mg, 15 mg and 30 mg tablets within this paediatric indication. Summary description of main additional risk minimisation measures: All healthcare professionals who are expected to prescribe aripiprazole product are provided with an information pack: o Summary of Product Characteristics (SmPC) and Package Leaflet (PL) o Educational material for the healthcare professionals o Educational material for the patients and their caregivers VI.2.6 Planned post authorisation development plan Not applicable VI.2.7 Summary of changes to the risk management plan over time Not applicable