Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Sandoz SA (Pty) Ltd<sup>1</sup>, Waterfall 5-lr, Magwa Crescent West, Waterfall City, Jukskei View, 2090 1 Company Reg. No.: 1990/001979/07
Methylphenidate treatment is not indicated in all children with ADHD and the decision to use the medicine 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.
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 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 medical practitioner 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 medicine for the individual patient with trial periods off medicine 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 medicine is either temporary or permanently discontinued.
Safety and efficacy have not been established for the initiation of treatment in adults or the routine continuation of treatment beyond 18 years of age. If treatment withdrawal has not been successful when an adolescent has reached 18 years of age, continued treatment into adulthood may be necessary. The need for further treatment of these adults should be reviewed regularly and undertaken annually.
Methylphenidate should not be used in the elderly. Safety and efficacy have not been established in this age group.
MEFEDINEL should not be used in patients under 6 years old. Sufficient data on the safety of long-term use of MEFEDINEL is not yet available.
Patients who are being considered for treatment with stimulant medicines should have a careful history (including assessment for a family history of sudden cardiac or unexplained death or malignant dysrhythmia) 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, exertional 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 mm Hg 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 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 structural cardiac abnormalities or other serious heart problems.
Although some serious heart problems alone may carry an increased risk of sudden death, stimulant medicines 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 medicines 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.
Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant medicines. 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. Medical practitioners should evaluate the need for adjustment of the treatment regimen in patients experiencing behavioural 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 medical practitioner. 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 months or every visit.
Particular care should be taken in using methylphenidate to treat ADHD in patients with co-morbid bipolar disorder (including untreated type 1 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 co-morbid 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 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 patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and in patients without a history of convulsions and no EEG abnormalities. If seizure frequency increases or new onset seizures occur, methylphenidate should be discontinued.
Prolonged and painful erections have been reported in association with methylphenidate medicines, 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.
Serotonin syndrome has been reported following co-administration of methylphenidate with serotonergic medicinal products. If concomitant use of methylphenidate with a serotonergic medicinal product is warranted, prompt recognition of the symptoms of serotonin syndrome is important. These symptoms may include mental-status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Methylphenidate must be discontinued as soon as possible if serotonin syndrome is suspected.
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 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 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.
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.
Because MEFEDINEL prolonged release tablet is non-deformable and does not appreciably change in shape in the gastrointestinal (GI) tract, it should not ordinarily be administered to patients with pre-existing severe GI narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of medicines in non-deformable prolonged release formulations.
Due to the prolonged-release design of the tablet, MEFEDINEL prolonged release tablets should only be used in patients who are able to swallow the tablet whole. Patients should be informed that MEFEDINEL must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a non-absorbable shell designed to release the medicines at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
MEFEDINEL contains lactose.
Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption should not take MEFEDINEL.
It is not known how methylphenidate may affect plasma concentrations of concomitantly administered medicines.
Therefore, caution is recommended at combining methylphenidate with other medicines, 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 I- 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. phenobarbitone, phenytoin, primodone), and some antidepressants (tricyclic and selective serotonin reuptake inhibitors). When starting and stopping treatment with methylphenidate, it may be necessary to adjust the dosage of these medicines already being taken and establish drug plasma concentrations (or for coumarin, coagulation times).
Methylphenidate may decrease the effectiveness of medicines used to treat hypertension.
Caution is advised in patients being treated with methylphenidate with other medicines 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 medicines, including methylphenidate. It is therefore advisable for patients to abstain from alcohol during treatment.
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.
The long-term 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 medicines, 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.
There have been reports of serotonin syndrome following co-administration of methylphenidate with serotonergic medicines. If concomitant use of MEFEDINEL with a serotonergic medicine is warranted, prompt recognition of the symptoms of serotonin syndrome is important. MEFEDINEL must be discontinued as soon as possible if serotonin syndrome is suspected.
MEFEDINEL may induce false positive laboratory tests for amphetamines, particularly with immunoassays screen test.
MEFEDINEL is contraindicated in pregnancy, as safety has not been demonstrated. Cases of neonatal cardiorespiratory toxicity, specifically foetal tachycardia and respiratory distress have been reported in spontaneous reports.
Studies in animals have only shown evidence of reproductive toxicity at maternally toxic doses. (See section 5.3.)
Methylphenidate has been found in breast-milk of women treated with methylphenidate. Mothers on MEFEDINEL should not breastfeed their infants.
There were no relevant effects observed in the non-clinical studies.
MEFEDINEL may cause dizziness, drowsiness and visual disturbances including difficulties with accommodation, diplopia and blurred vision. It 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 table below shows all adverse reactions observed during clinical trials and post-market spontaneous reports with methylphenidate prolonged-release tablets and those which have been reported with other methylphenidate hydrochloride formulations. If the adverse reactions with methylphenidate prolonged-release tablet and the methylphenidate formulation frequencies were different, the highest frequency of both databases was used.
| System Organ Class | Adverse reaction | ||
|---|---|---|---|
| Frequency | |||
| Frequent | Less frequent | Frequency unknown | |
| Infections and infestations | Nasopharyngitis, upper respiratory tract infection#, sinusitis# | ||
| Blood and lymphatic system disorders | Anaemia†, leukopenia†, thrombocytopenia, thrombocytopenic purpura | Pancytopenia | |
| Immune system disorders | Hypersensitivity reactions such as angioedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticaria, pruritus, rashes, and eruptions | ||
| Metabolism and nutrition disorders* | Anorexia, decreased appetite†, moderately reduced weight and height gain during prolonged use in children* | ||
| Psychiatric disorders* | Insomnia, nervousness, affect lability, aggression*, agitation*, anxiety*†, depression*#, irritability, abnormal behaviour, mood swings, tics*, initial insomnia#, depressed mood#, libido decreased#, tension#, bruxism#, panic attack# | Psychotic disorders*, auditory, visual and tactile hallucination*, anger, suicidal ideation*, mood altered, restlessness†, tearfulness, worsening of pre- existing tics of Tourette’s syndrome*, logorrhoea, hypervigilance, sleep disorder, mania*†, disorientation, libido disorder, confusional state†, suicidal attempt* (including completed suicide)†, transient depressed mood*, abnormal thinking, apathy†, repetitive behaviours, over-focusing | Delusions*†, thought disturbances*, dependence; cases of abuse and dependence have been described more often with immediate release formulations |
| Nervous system disorders | Headache, dizziness, dyskinesia, psychomotor hyperactivity, somnolence, paraesthesia#, tension headache# | Sedation, tremor†, lethargy#, convulsion, choreoathetoid movements, reversible ischaemic neurological deficit, neuroleptic malignant syndrome (NMS; reports were poorly documented and in most cases patients were also receiving other medicines, so the role of methylphenidate is unclear). | Cerebrovascular disorders*† (including vasculitis, cerebral haemorrhages, cerebrovascular accidents, cerebral arteritis, cerebral occlusion), grand mal convulsion*, migraine†, dysphemia |
| Eye disorders | Accommodation disorder# | Blurred vision†, dry eye#, difficulties in visual accommodation, visual impairment, diplopia | Mydriasis |
| Ear and labyrinth disorders | Vertigo# | ||
| Cardiac disorders | Dysrhythmia, tachycardia, palpitations | Chest pain, angina pectoris, cardiac arrest; myocardial infarction | Supraventricular tachycardia, bradycardia, ventricular extrasystoles†, extrasystoles† |
| Vascular disorders | Hypertension | Hot flush#, cerebral arteritis and/or occlusion, peripheral coldness†, Raynaud’s phenomenon | |
| Respiratory, Thoracic and mediastinal disorders | Cough, oropharyngeal pain | Dyspnoea† | |
| Gastrointestinal disorders | Upper abdominal pain, diarrhoea, nausea†, abdominal discomfort, vomiting, dry mouth†, dyspepsia# | Constipation† | |
| Hepatobiliary disorders | Alanine aminotransferase increased# | Hepatic enzyme increased, abnormal liver function, including acute hepatic failure and hepatic coma, blood alkaline phosphatase increased, blood bilirubin increased† | |
| Skin and subcutaneous tissue disorders | Alopecia, pruritus, rash, urticaria | Angioedema, bullous conditions, exfoliative conditions, hyperhidrosis†, macular rash, erythema, erythema multiforme, exfoliative dermatitis, fixed drug eruption | |
| Musculoskeletal and connective tissue disorders | Arthralgia, muscle tightness#, muscle spasms# | Myalgia†, muscle twitching, muscle cramps | Trismus^ |
| Renal and urinary disorders | Haematuria, pollakiuria | Incontinence | |
| Reproductive system and breast disorders | Erectile dysfunction# | Gynaecomastia | Priapism*, erection increased* and prolonged erection* |
| General disorders and administration site conditions | Pyrexia, growth retardation during prolonged use in children*, fatigue†, irritability#, feeling jittery#, asthenia#, thirst# | Chest pain, sudden cardiac death* | Chest discomfort†, hyperpyrexia |
| Investigations | Changes in blood pressure and heart rate* (usually an increase), weight decreased* | Cardiac murmur*, platelet count decreased, abnormal white blood cell count | |
* See section 4.4
# Frequency derived from adult clinical trials and not on data from trials in children and adolescents; may also be relevant for children and adolescents.
† Frequency derived from clinical trials in children and adolescents and reported at a higher frequency in clinical trials in adult patients.
^ 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 providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8. Suspected adverse reactions can also be reported directly to the HCR via Patientsafety.sacg@novartis.com.
Not applicable.
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