Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Medice Arzneimittel Pütter GmbH & Co. KG, Kuhloweg 37, 58638 Iserlohn, Germany
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 (6–18 years).
The safety and efficacy of long term use of methylphenidate has not been systematically evaluated in controlled trials. Methylphenidate treatment should not and need not, be indefinite. Methylphenidate treatment is usually discontinued during or after puberty. Patients on long-term therapy (i.e. over 12 months) must have careful ongoing monitoring according to the guidance in sections 4.2 and 4.4 for cardiovascular status, growth, appetite, development of de novo or worsening of pre-existing psychiatric disorders. Psychiatric disorders to monitor for are described below, and include (but are not limited to) motor or vocal tics, aggressive or hostile behaviour, agitation, anxiety, depression, psychosis, mania, delusions, irritability, lack of spontaneity, withdrawal and excessive perseveration.
The physician who elects to use methylphenidate for extended periods (over 12 months) in children and adolescents with ADHD should periodically re-evaluate the long term usefulness of the medicinal product for the individual patient with trial periods off medication to assess the patient’s functioning without pharmacotherapy. It is recommended that methylphenidate is de-challenged at least once yearly to assess the child’s condition (preferably during times of school holidays). Improvement may be sustained when the medicinal product is either temporarily or permanently discontinued.
Medikinet is not licensed for use in adults with ADHD. Safety and efficacy have not been established in this age group.
Methylphenidate should not be used in the elderly. Safety and efficacy has not been established in this age group.
Methylphenidate should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.
Patients who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden cardiac or unexplained death or malignant arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further specialist cardiac evaluation if initial findings suggest such history or disease. Patients who develop symptoms such as palpitations, exceptional chest pain, unexplained syncope, dyspnoea or other symptoms suggestive of cardiac disease during methylphenidate treatment should undergo a prompt specialist cardiac evaluation.
Analyses of data from clinical trials of methylphenidate in children and adolescents with ADHD showed that patients using methylphenidate may commonly experience changes in diastolic and systolic blood pressure of over 10 mmHg relative to controls. The short- and long-term clinical consequences of these cardiovascular effects in children and adolescents are not known, but the possibility of clinical complications cannot be excluded as a result of the effects observed in the clinical trial data. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate. See section 4.3 for conditions in which methylphenidate treatment is contraindicated.
Cardiovascular status should be carefully monitored. Blood pressure and pulse should be recorded on a centile chart at each adjustment of dose and then at least every 6 months.
The use of methylphenidate is contraindicated in certain pre-existing cardiovascular disorders unless specialist paediatric cardiac advice has been obtained (see section 4.3).
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. Although some serious heart problems alone may carry an increased risk of sudden death, stimulant products are not recommended in children or adolescents 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.
Misuse of stimulants of the central nervous system may be associated with sudden death and other serious cardiovascular adverse events.
See section 4.3 for cerebrovascular conditions in which methylphenidate treatment is contraindicated. Patients with additional risk factors (such as a history of cardiovascular disease, concomitant medications that elevate blood pressure) should be assessed at every visit for neurological signs and symptoms after initiating treatment with methylphenidate.
Cerebral vasculitis appears to be a very rare idiosyncratic reaction to methylphenidate exposure. There is little evidence to suggest that patients at higher risk can be identified and the initial onset of symptoms may be the first indication of an underlying clinical problem. Early diagnosis, based on a high index of suspicion, may allow the prompt withdrawal of methylphenidate and early treatment. The diagnosis should therefore be considered in any patient who develops new neurological symptoms that are consistent with cerebral ischemia during methylphenidate therapy. These symptoms could include severe headache, numbness, weakness, paralysis, and impairment of coordination, vision, speech, language or memory.
Treatment with methylphenidate is not contraindicated in patients with hemiplegic cerebral palsy.
Prolonged and painful erections have been reported in association with methylphenidate products, mainly in association with a change in the methylphenidate treatment regimen. Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. In the case of emergent psychiatric symptoms or exacerbation of pre-existing psychiatric disorders, methylphenidate should not be given unless the benefits outweigh the risks to the patient.
Development or worsening of psychiatric disorders should be monitored at every adjustment of dose, then at least every 6 months, and at every visit; discontinuation of treatment may be appropriate.
In psychotic patients, administration of methylphenidate may exacerbate symptoms of behavioural disturbance and thought disorder.
Treatment-emergent psychotic symptoms (visual/tactile/auditory hallucinations and delusions) or mania in children and adolescents without prior history of psychotic illness or mania can be caused by methylphenidate at usual doses. If manic or psychotic symptoms occur, consideration should be given to a possible causal role for methylphenidate, and discontinuation of treatment may be appropriate.
The emergence or worsening of aggression or hostility can be caused by treatment with stimulants. 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. Physicians should evaluate the need for adjustment of the treatment regimen in patients experiencing behaviour changes, bearing in mind that upwards or downwards titration may be appropriate. Treatment interruption can be considered.
Patients with emergent suicidal ideation or behaviour during treatment for ADHD should be evaluated immediately by their physician. Consideration should be given to the exacerbation of an underlying psychiatric condition and to a possible causal role of methylphenidate treatment. Treatment of an underlying psychiatric condition may be necessary and consideration should be given to a possible discontinuation of methylphenidate.
Methylphenidate is associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported. Family history should be assessed and clinical evaluation for tics or Tourette’s syndrome in children should precede use of methylphenidate. Patients should be regularly monitored for the emergence or worsening of tics during treatment with methylphenidate. Monitoring should be at every adjustment of dose and then at least every 6 months or every visit.
Methylphenidate is associated with the worsening of pre-existing anxiety, agitation or tension. Clinical evaluation for anxiety, agitation or tension should precede use of methylphenidate and patients should be regularly monitored for the emergence or worsening of these symptoms during treatment, at every adjustment of dose and then at least every 6 month or every visit.
Particular care should be taken in using methylphenidate to treat ADHD in patients with comorbid bipolar disorder (including untreated Type I Bipolar Disorder or other forms of bipolar disorder) because of concern for possible precipitation of a mixed/manic episode in such patients. 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; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Close ongoing monitoring is essential in these patients (see above ‘Psychiatric Disorders’ and section 4.2). Patients should be monitored for symptoms at every adjustment of dose, then at least every 6 months and at every visit.
Moderately reduced weight gain and growth retardation have been reported with the long-term use of methylphenidate in children.
The effects of methylphenidate on final height and final weight are currently unknown and being studied.
Growth should be monitored during methylphenidate treatment: height, weight and appetite should be recorded at least 6 monthly with maintenance of a growth chart. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
Methylphenidate should be used with caution in patients with epilepsy. Methylphenidate may lower the convulsive threshold in patient with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and rarely in patients without a history of convulsions and no EEG abnormalities. If seizure frequency increases or new-onset seizures occur, methylphenidate should be discontinued.
Patients should be carefully monitored for the risk of diversion, misuse and abuse of methylphenidate.
Methylphenidate should be used with caution in patients with known drug or alcohol dependency because of a potential for abuse, misuse or diversion.
Chronic abuse of methylphenidate can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes can occur, especially in response to parenteral abuse.
Patient age, the presence of risk factors for substance use disorder (such as co-morbid oppositional-defiant or conduct disorder and bipolar disorder), previous or current substance abuse should all be taken into account when deciding on a course of treatment for ADHD. Caution is called for in emotionally unstable patients, such as those with a history of drug or alcohol dependence, because such patients may increase the dosage on their own initiative.
For some high-risk substance abuse patients, methylphenidate or other stimulants may not be suitable and non-stimulant treatment should be considered.
Careful supervision is required during drug withdrawal, since this may unmask depression as well as chronic over-activity. Some patients may require long-term follow up.
Careful supervision is required during withdrawal from abusive use since severe depression may occur.
Methylphenidate should not be used for the prevention or treatment of normal fatigue states.
The choice of formulation of methylphenidate-containing product will have to be decided by the treating specialist on an individual basis and depends on the intended duration of effect.
This product contains methylphenidate which may induce a false positive laboratory test for amphetamines, particularly with immunoassay screen test.
Athletes must be aware that this medicinal product may cause a positive reaction to ‘anti-doping’ tests.
There is no experience with the use of methylphenidate in patients with renal or hepatic insufficiency.
The long-term safety of treatment with methylphenidate is not fully known. In the event of leukopenia, thrombocytopenia, anaemia or other alterations, including those indicative of serious renal or hepatic disorders, discontinuation of treatment should be considered.
This medicinal product contains lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
It is not known how methylphenidate may affect plasma concentrations of concomitantly administered medicinal products. Therefore, caution is recommended at combining methylphenidate with other medicinal products, especially those with a narrow therapeutic window.
Methylphenidate is not metabolised by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l- enantiomers of methylphenidate do not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.
However, there are reports indicating that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g. phenobarbital, phenytoin, primidone) and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). When starting or stopping treatment with methylphenidate, it may be necessary to adjust the dosage of these medicinal products already being taken and establish drug plasma concentrations (or for coumarin, coagulation times).
Methylphenidate may decrease the effectiveness of active substances used to treat hypertension.
Caution is advised in patients being treated with methylphenidate with any other active substance that can also elevate blood pressure (see also sections on cardiovascular and cerebrovascular conditions in section 4.4).
Because of possible hypertensive crisis, methylphenidate is contraindicated in patients being treated (currently or within the preceding 2 weeks) with non-selective, irreversible MAO-inhibitors (see section 4.3).
Alcohol may exacerbate the adverse CNS effects of psychoactive active substances, including methylphenidate. It is therefore advisable for patients to abstain from alcohol during treatment.
No studies have been performed to study a possible food effect. Therefore it is recommended to take Medikinet tablets in a standardised manner in relation to the timing of meals, i.e. that doses should be given at same times, relative to the time of meals, on each day, preferably with or immediately after meals (see section 4.2).
There is a risk of sudden blood pressure increase during surgery. If surgery is planned, methylphenidate treatment should not be used on the day of surgery.
Serious, adverse events, including sudden death, have been reported in concomitant use with clonidine. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systematically evaluated.
Caution is recommended when administering methylphenidate with dopaminergic active substances, including antipsychotics. Because a predominant action of methylphenidate is to increase extracellular dopamine levels, methylphenidate may be associated with pharmacodynamic interactions when co-administered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) or with dopamine antagonists including antipsychotics.
Data from a cohort study of in total approximately 3,400 pregnancies exposed in the first trimester do not suggest an increased risk of overall birth defects. There was a small increased occurrence of cardiac malformations (pooled adjusted relative risk, 1.3; 95% CI, 1.0-1.6) corresponding to 3 additional infants born with congenital cardiac malformations for every 1000 women who receive methylphenidate during the first trimester of pregnancy, compared with non-exposed pregnancies.
Cases of neonatal cardio-respiratory toxicity, specifically fetal tachycardia and respiratory distress have been reported in spontaneous case reports.
Studies in animals have only shown evidence of reproductive toxicity at maternally toxic doses (see section 5.3).
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.
Methylphenidate has been found in the breast-milk of a woman treated with methylphenidate.
There is one case report of an infant who experienced an unspecified decrease in weight during the period of exposure but recovered and gained weight after the mother discontinued treatment with methylphenidate. A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from methylphenidate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Methylphenidate can cause dizziness, drowsiness and visual disturbances including difficulties with accommodation, diplopia and blurred vision.
Medikinet may have a moderate influence on the ability to drive and use machines. Patients should be warned of these possible effects and advised that if affected, they should avoid potentially hazardous activities such as driving or operating machinery.
The list below shows all adverse drug reactions (ADRs) observed during clinical trials and post-market spontaneous reports with Medikinet and those, which have been reported with other methylphenidate hydrochloride formulations. If the ADRs with Medikinet and the methylphenidate formulation frequencies were different, the highest frequency of both databases was used.
Frequency estimate: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Common: nasopharyngitis
Uncommon: gastroenteritis
Very rare: anaemia, leukopenia, thrombocytopenia, thrombocytopenic purpura
Not known: pancytopenia
Uncommon: hypersensitivity reactions such as angioneurotic oedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticarias, pruritus, rashes and eruptions
Common: anorexia, decreased appetite, moderately reduced weight and height gain during prolonged use in children*
Very common: insomnia, nervousness
Common: anorexia, affect lability, aggression*, agitation*, anxiety*, depression*, irritability, abnormal behaviour, panic attack**, stress**, bruxism∞
Uncommon: psychotic disorders*, auditory, visual and tactile hallucinations*, anger, suicidal ideation*, mood altered, mood swings, restlessness, tearfulness, tics*, worsening of pre-existing tics or Tourette’s syndrome*, hypervigilance, sleep disorder, tension**
Rare: mania*, disorientation, libido disorder
Very rare:suicidal attempt* (including completed suicide), transient depressed mood*, abnormal thinking, apathy, repetitive behaviours, over-focussing
Not known: delusions*, thought disturbances*, confusional state, dependence, logorrhea
Cases of abuse and dependence have been described, more often with immediate-release formulations (frequency not known).
Very common: headache
Common: dizziness, dyskinesia, psychomotor hyperactivity, somnolence
Uncommon: sedation, tremor, akathisia**
Very rare: convulsions, choreo-athetoid movements, reversible ischaemic neurological deficit
Neuroleptic malignant syndrome (NMS; Reports were poorly documented and in most of cases, patients were also receiving other active substances, so the role of methylphenidate is unclear.)
Not known: cerebrovascular disorders* (including vasculitis, cerebral haemorrhages, cerebrovascular accidents, cerebral arteritis, cerebral occlusion), grand mal convulsions*, migraine, dysphemia
Uncommon: diplopia, blurred vision
Rare: difficulties in visual accommodation, mydriasis, visual disturbance
Common: arrhythmia, tachycardia, palpitations
Uncommon: chest pain
Rare: angina pectoris
Very rare:cardiac arrest, myocardial infarction
Not known: supraventricular tachycardia, bradycardia, ventricular extrasystoles, extrasystoles
Common: hypertension
Very rare: cerebral arteritis and/or occlusion, peripheral coldness, Raynaud’s phenomenon
Common: cough, pharyngolaryngeal pain
Uncommon: dyspnoea
Common: abdominal pain, diarrhoea, nausea, stomach discomfort and vomiting: - These usually occur at the beginning of treatment and may be alleviated by concomitant food intake. Dry mouth, dyspepsia**, toothache**
Uncommon: constipation
Uncommon: hepatic enzyme elevations
Very rare: abnormal liver function, including hepatic coma
Common: alopecia, pruritus, rash, urticaria
Uncommon: angioneurotic oedema, bullous conditions, exfoliative conditions
Rare: hyperhidrosis, macular rash, erythema
Very rare: erythema multiforme, exfoliative dermatitis, fixed drug eruption
Not known: dry skin
Common: arthralgia
Uncommon: myalgia, muscle twitching, muscle tightness**
Very rare: muscle cramps
Not known: trismus∞
Uncommon: haematuria
Not known: incontinence
Rare: gynaecomastia
Not known: erectile dysfunction, priapism, erection increased and prolonged erection
Common: pyrexia, growth retardation during prolonged use in children*
Uncommon: chest pain, fatigue, thirst**
Very rare: sudden cardiac death*
Not known: chest discomfort, hyperpyrexia
Common: changes in blood pressure and heart rate* (usually an increase), weight decreased*
Uncommon: cardiac murmur*, hepatic enzyme increased
Very rare: blood alkaline phosphatase increased, blood bilirubin increased, platelet count decreased, white blood count abnormal
* see section 4.4
** ADRs from clinical trials in adult patients that were not reported in children and adolescents
∞ Based on the frequency calculated in adult ADHD studies (no cases were reported in the paediatric studies)
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.
Not applicable.
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