Part VI: Summary of the risk management plan Summary of risk management plan for Methylphenidate modifiedrelease hard capsules (methylphenidate) This is a summary of the risk management plan (RMP) for Methylphenidate modified-release hard capsules. The RMP details important risks of Methylphenidate modified-release hard capsules, how these risks can be minimised, and how more information will be obtained about Methylphenidate modified- release hard capsules' risks and uncertainties (missing information). Methylphenidate modified-release hard capsules' summary of product characteristics (SmPC) and its package leaflet (PL) give essential information to healthcare professionals and patients on how Methylphenidate modified-release hard capsules should be used. Important new concerns or changes to the current ones will be included in updates of Methylphenidate modified-release hard capsules' RMP. I. The medicine and what it is used for Methylphenidate modified-release hard capsules is authorised: - Attention-Deficit/Hyperactivity Disorder (ADHD) Methylphenidate is indicated as part of a comprehensive treatment programme for attentiondeficit/hyperactivity disorder (ADHD) in children aged 6 years of age and over and adults when remedial measures alone prove insufficient. Treatment must be initiated and supervised by a physician specialised in the treatment of ADHD such as an expert paediatrician, a child and adolescent psychiatrist or a psychiatrist. Special diagnostic considerations for ADHD in children Diagnosis should be made according to DSM criteria or the guidelines in ICD and should be based on a complete history and evaluation of the patient. Diagnosis cannot be made solely on the presence of one or more symptom. The specific aetiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and specialised psychological, educational, and social resources. A comprehensive treatment programme typically includes psychological, educational and social measures as well as pharmacotherapy and is aimed at stabilising children with a behavioural syndrome characterised by symptoms which may include chronic history of short attention span, distractibility, emotional lability, impulsivity, moderate to severe hyperactivity, minor neurological signs and abnormal EEG. Learning may or may not be impaired. Methylphenidate treatment is not indicated in all children with ADHD and the decision to use the medicinal product must be based on a very thorough assessment of the severity and chronicity of the child s symptoms in relation to the child s age. Appropriate educational placement is essential, and psychosocial intervention is generally necessary. Where remedial measures alone prove insufficient, the decision to prescribe a stimulant must be based on rigorous assessment of the severity of the child's symptoms. Methylphenidate should always be used in this way according to the licensed indication and according to prescribing/diagnostic guidelines. - Special diagnostic considerations for ADHD in adults Diagnosis should be made according to DSM criteria or the guidelines in ICD and should be based on a complete history and evaluation of the patient. The specific aetiology of this syndrome is unknown, and there is no single diagnostic test. Adults with ADHD have symptom patterns characterised by, restlessness, impatience, and inattentiveness. Symptoms such as hyperactivity tend to diminish with increasing age possibly due to adaptation, neurodevelopment and self-medication. Inattentive symptoms are more prominent and have a greater impact on adults with ADHD. Diagnosis in adults should include a structured patient interview to determine current symptoms. The pre-existence of childhood ADHD is required
and has to be determined retrospectively (by patients records or if not available by appropriate and structured instruments/interviews). Third-party corroboration is desirable and <invented name> should not be initiated when the verification of childhood ADHD symptoms is uncertain. Diagnosis should not be made solely on the presence of one or more symptoms. The decision to use a stimulant in adults must be based on a very thorough assessment and diagnosis should include moderate or severe functional impairment in at least 2 settings (for example, social, academic, and/or occupational functioning), affecting several aspects of an individual s life. It contains methylphenidate as the active substance and it is given orally. II. Risks associated with the medicine and activities to minimise or further characterise the risks Important risks of Methylphenidate modified-release hard capsules, together with measures to minimise such risks and the proposed studies for learning more about Methylphenidate modified-release hard capsules risks, are outlined below. Measures to minimise the risks identified for medicinal products can be: Specific information, such as warnings, precautions, and advice on correct use, in the package leaflet and SmPC addressed to patients and healthcare professionals; Important advice on the medicine s packaging; The authorised pack size the amount of medicine in a pack is chosen so to ensure that the medicine is used correctly; The medicine s legal status the way a medicine is supplied to the patient (e.g. with or without prescription) can help to minimise its risks. Together, these measures constitute routine risk minimisation measures. In the case of Methylphenidate modified-release hard capsules, these measures are supplemented with additional risk minimisation measures mentioned under relevant important risks, below. In addition to these measures, information about adverse reactions is collected continuously and regularly analysed so that immediate action can be taken as necessary. These measures constitute routine pharmacovigilance activities. II.A List of important risks and missing information Important risks of Methylphenidate modified-release hard capsules are risks that need special risk management activities to further investigate or minimise the risk, so that the medicinal product can be safely taken. Important risks can be regarded as identified or potential. Identified risks are concerns for which there is sufficient proof of a link with the use of Methylphenidate modified-release hard capsules. Potential risks are concerns for which an association with the use of this medicine is possible based on available data, but this association has not been established yet and needs further evaluation. Missing information refers to information on the safety of the medicinal product that is currently missing and needs to be collected (e.g. on the long-term use of the medicine); List of important risks and missing information Important identified risks Hypertension Tachycardia Raynaud s phenomenon Hallucinations (auditory, skin, sensation, visual disturbance) Psychosis/Mania Anorexia Decreased rate of growth Aggression Depression
Important potential risks Migraine Repetitive behaviours QT prolongation Cyanosis Arrhythmias Sudden death Ischaemic cardiac events Cerebrovascular disorders Hostility Suicidality Tics/Tourette s syndrome/dystonias Effect on final height Sexual maturation (delayed) Carcinogenicity Off-label use Diversion Withdrawal syndrome Drug abuse and Drug dependence Lymphocytic leukaemia Neonatal cardio-respiratory toxicity neonatal Neonatal effects on growth Cardiomyopathy List of important risks and missing information Missing information None II.B Summary of important risks Important identified risk: Hypertension A contraindication in patients with pre-existing severe hypertension is stated in section 4.3. The concomitant or recent use of MAOIs and methylphenidate is also contraindicated as stated in sections 4.3 and 4.5. Recommendations of recording blood pressure and pulse are included in section 4.4 of the SmPC. According to Section 2 of the PL, product must not be used in case of treatment with non-selective, irreversible MAO inhibitors or in case of very high blood pressure; in this section there is also a warning stating that patient should inform the doctor or pharmacist in case of high blood pressure.
Important identified risk: Tachycardia A contraindication in patients with pre-existing cardiovascular disorders is stated in section 4.3. Recommendation of performing a physical exam to assess for the presence of cardiac disease is included in section 4.4 of the SmPC. According to Section 2 of the PL, product must not be used in case of heart problems such as uneven heartbeat. Important identified risk: Tachycardia Important identified risk: Hallucinations (auditory, skin, sensation, visual disturbance) A contraindication in patients diagnosed with schizophrenia, is stated in section 4.3. Recommendation of performing a psychiatric exam to assess the presence of pre-existing psychiatric disorders is included in section 4.4 of the SmPC. According to Section 2 of the PL, product must not be use in patients with mental health problems such as abnormal thoughts, hallucinations or schizophrenia. There is also a warning in this section of the PL stating that patient should inform the doctor or pharmacist in case of having a mental health problem of hallucinations or delusions.
Important identified risk: Psychosis/Mania A contraindication in patients diagnosed with psychotic symptoms, severe mood disorders, mania, schizophrenia, psychopathic/borderline disorder is stated in section 4.3. In section 4.4 of the SmPC there is a warning stating that the use of product may cause or exacerbate psychotic or manic symptoms. According to Section 2 of the PL, product must not be used in case of mental health problems such as psychopathic, borderline personality, schizophrenia or mania. Important identified risk: Anorexia A contraindication in patients with anorexia nervosa or anorexic disorders is stated in section 4.3. According to Section 2 of the PL, product must not be used in case of anorexia nervosa. Important identified risk: Decreased rate of growth Recommendation of recording height in children is included in section 4.4 of the SmPC.
Important identified risk: Aggression According to section 4.4 of the SmPC, patients treated with methylphenidate should be closely monitored for the emergence or worsening of aggressive behaviour or hostility at treatment initiation, at every dose adjustment and then at least every 6 months and every visit. According to Section 2 of the PL, there is a warning stating that patient should inform the doctor or pharmacist in case of starting or increasing to be aggressive or hostile. Important identified risk: Depression A contraindication in patients with pre-existing severe depression is stated in section 4.3. According to section 4.4 of the SmPC, prior to initiating treatment with methylphenidate, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder. According to Section 2 of the PL, product must not be used in case of severe depression; in this Section there is also a warning stating that patient should inform the doctor or pharmacist in case of mood swings.
Important potential risk: Migraine PL section 4. Important potential risk: Repetitive behaviours PL section 4. Important potential risk: QT prolongation None. Important potential risk: Arrhythmias A contraindication in patients with pre-existing potentially lifethreatening arrhythmias is stated in section 4.3.
Important potential risk: Arrhythmias According to section 4.4 of the SmPC, cardiovascular status should be carefully monitored in patients using product. According to Section 2 of the PL, there is a warning stating that patient should inform the doctor or pharmacist in case of heart problems. Important potential risk: Sudden death As stated in section 4.4 of the SmPC, sudden death has been reported in association with the use of stimulants of the central nervous system at usual doses in children, some of whom had cardiac structural abnormalities or other serious heart problems; therefore, product is not recommended in patients with known cardiac structural abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems. In addition, misuse of stimulants of the central nervous system may be associated with sudden death and other serious cardiovascular adverse events. Section 2 of the PL stated that doctor should check whether there is any family history of sudden unexplained death. Important potential risk: Ischaemic cardiac events
Important potential risk: Ischaemic cardiac events A contraindication in patients with pre-existing cardiovascular disorders including heart failure, angina pectoris, and myocardial infarction is stated in section 4.3. Recommendations of monitoring cardiovascular status is included in section 4.4 of the SmPC. In addition, in this section is stated that misuse of stimulants of the central nervous system may be associated with serious cardiovascular adverse events. According to Section 2 of the PL, product must not be used in case of pre-existing heart problems such as a heart attack or heart failure. Important potential risk: Cerebrovascular disorders PL section 4. A contraindication in patients with pre-existing cerebrovascular disorders cerebral aneurysm, vascular abnormalities including vasculitis or stroke is stated in section 4.3. Recommendations of considering the diagnosis of cerebral vasculitis in any patient who develops new neurological symptoms that are consistent with cerebral ischaemia during methylphenidate therapy is included in section 4.4 of the SmPC. These symptoms could include severe headache, numbness, weakness, paralysis, and impairment of coordination, vision, speech, language or memory. According to Section 2 of the PL, product must not be used in case of pre-existing problems with the brain blood vessels such as a stroke, swelling and weakening of part of a blood vessel (aneurysm), narrow or blocked blood vessels, or inflammation of the blood vessels (vasculitis).
Important potential risk: Hostility A contraindication in patients with pre-existing severe mood disorders is stated in section 4.3. In section 4.4 of the SmPC is recommended that patients treated with methylphenidate should be closely monitored for the emergence or worsening of aggressive behaviour or hostility at treatment initiation, at every dose adjustment and then at least every 6 months and every visit. According to Section 2 of the PL, there is a warning stating that the patient should inform the doctor or pharmacist in case of starting to be aggressive or hostile. Important potential risk: Suicidality A contraindication in patients with pre-existing suicidal tendencies is stated in section 4.3. In section 4.4 of the SmPC is recommended that patients with emergent suicidal ideation during treatment for ADHD should be evaluated immediately by their physician.
Important potential risk: Tics/Tourette s syndrome/dystonias In section 4.4 of the SmPC is recommended that patients should be regularly monitored for the emergence or worsening of tics during treatment with methylphenidate. Monitoring is recommended at every adjustment of dose and then at least every 6 months or every visit. According to Section 2 of the PL, there is a warning stating that patients should inform the doctor or pharmacist if they or any other member of their family have hard-to-control repeated twitching of any parts of the body or repeat sounds and words (tics). Important potential risk: Effect on final height Recommendations of recording of height according to the child s age at least 6 monthly with maintenance of a growth chart is included in section 4.4 of the SmPC. Important potential risk: Off-label use According to section 4.2, product must not be used in children less of 6 years and in elderly as safety and efficacy has not been established in these groups of age.
Important potential risk: Off-label use In addition, as stated in section 4.4 of the SmPC, product should not be used for prevention or treatment of normal fatigue states. According to section 1 of the PL, it is not known if product is safe or its benefits in children under 6 years of age. Important potential risk: Diversion Recommendations of monitoring the risk of diversion is included in section 4.4 of the SmPC. Important potential risk: Drug abuse and Drug dependence Recommendations of monitoring the risk of abuse is included in section 4.4 of the SmPC. Important potential risk: Lymphocytic leukaemia None.
Important potential risk: Neonatal cardio-respiratory toxicity neonatal In section 4.6 of the SmPC is stated that cases of neonatal cardiorespiratory toxicity, specifically foetal tachycardia and respiratory distress have been reported in spontaneous case reports. In addition, methylphenidate is not recommended for use during pregnancy unless a clinical decision is made that postponing treatment may pose a greater risk to the pregnancy. According to Section 2 of the PL, there is a warning stating that patients should inform the doctor or pharmacist in case of pregnancy. Important potential risk: Neonatal effects on growth In section 4.6 of the SmPC is stated that methylphenidate has been found in the breast-milk of women treated with it. In addition, it is stated to make a decision whether to discontinue breastfeeding or to discontinue/abstain from methylphenidate therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. According to Section 2 of the PL, there is a warning stating that patients should inform the doctor or pharmacist if they are breastfeeding or are planning to breast-feed. Important potential risk: Neonatal effects on growth
Important potential risk: Cardiomyopathy II.C Post-authorisation development plan As stated in Section 4.3 of the SmPC, product is contraindicated in case of pre-existing cardiovascular disorders, including cardiomyopathies. In addition, there is a warning in Section 4.4 stating that stimulant products are not recommended in patients with known cardiac structural abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant medicine. According to Section 2 of the PL, product must not be used in patients that have ever had heart problems. II.C.1 Studies which are conditions of the marketing authorisation There are no studies which are conditions of the marketing authorisation or specific obligation of Methylphenidate modified-release hard capsules. II.C.2 Other studies in post-authorisation development plan There are no studies required for Methylphenidate modified-release capsules.