4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Ritalin is indicated as a part of a comprehensive treatment programme for attention-deficit hyperactivity disorder (ADHD) in children aged 6 years of age and over whenre remedial measures alone prove insufficient. Treatment must be under the supervision of a specialist in childhood behavioural disorders. Diagnosis should be made according to DSM-IV criteria or the guidelines in ICD-10 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 symptoms.
Additional information on the safe use of the product: ADHD is also known as attention-deficit disorder (ADD). Other terms used to describe this behavioural syndrome include: hyperkinetic disorder, minimal brain damage, and minimal brain dysfunction in children, minor cerebral dysfunction and psycho-organic syndrome of children.
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 resourses.
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 this syndrome and the decision to use the drug must be based on a very thorough assessment of the severity and the 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. The use of methylphenidate should always be used in the way according to the licencsed indication and according to the prescribing/ diagnostics guidelines.
4.2. Posology and Method of Administration
Treatment must be initiated under the supervision of a specialist in childhood
and/or adolescent behavioural disorders
Pre-treatment screening:
Prior to prescribing, it is necessary to conduct a baseline evaluation of a patient’s cardiovascular status including blood pressure and heart rate. A comprehensive history should document concomitant medications, past and present co-morbid medical and psychiatric disorders or symptoms, family history of sudden cardiac/unexplained death and accurate recording of pre-treatment height and weight on a growth chart (see sections 4.3 and 4.4).
Ongoing monitoring:
Growth, psychiatric and cardiovascular status should be continuously monitored (see section 4.4).
· Blood pressure and pulse should be recorded on a centile chart at each adjustment of dose and then at least every 6 months;
· Height, weight and appetite should be recorded at least 6 monthly with maintenance of a growth chart;
· Development of de novo or worsening of pre-existing psychiatric disorders should be monitored at every adjustment of dose and then at least every 6 months and at every visit.
Patients should be monitored for the risk of diversion, misuse and abuse of methylphenidate.
Dose titration
Careful dose titration is necessary at the start of treatment with methylphenidate. Dose titration should be started at the lowest possible dose.
The maximum daily dose is 60mg.
Other strengths of this medicinal product and other methylphenidate-containing products may be available.
Adults: Not applicable
Elderly:Not applicable
Children: (over 6 years). Begin with 5mg once or twice daily (e.g. at breakfast and lunch), increasing the dose and frequency of administration if necessary by weekly increments of 5-10mg in the daily dose. Doses above 60mg daily are not recommended. The total daily dose should be administered in divided doses. Ritalin is not indicated in children less than 6 years of age.
If the effect of the drug wears off too early in the evening, disturbed behaviour and/or inability to go to sleep may recur. A small evening dose may help to solve this problem.
Long term (more than 12 months) use in children and adolescents
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. 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 drug 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 (preferable during school holidays). Improvement may be sustained when the drug is either temporarily or permanently discontinued.
Dose reduction and discontinuation
Treatment must be stopped if the symptoms do not improve after appropriate dosage adjustment over a one-month period. If paradoxical aggravation of symptoms or other serious adverse events occur, the dosage should be reduced or discontinued.
Adults
Methylphenidate is not licenced for use in adults with ADHD. Safety and efficacy have not yet been established in this age group.
Elderly
Methylphenidate should not be used in the elderly. Safety and efficacy has not been established in this age group.
Children under 6 years of age
Methylphenidate should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.
Note: If improvement of symptoms is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. Ritalin should be discontinued periodically to assess the child's condition. Drug treatment is usually discontinued during or after puberty.
4.3. Contra-indications
The presence of marked anxiety, agitation or tension is a contra-indication to the use of Ritalin as it may aggravate these symptoms.
Ritalin is also contra-indicated in patients with motor tics, tics in siblings, or a family history or diagnosis of Tourette's syndrome.
It is also contra-indicated in patients with hyperthyroidism, severe angina pectoris, cardiac arrhythmias,
· kKnown sensitivity to methylphenidate or to any of the excipients in Ritalin.
- Glaucoma
- Phaechromocytoma
- During treatment with non-selective, irreversible monoamine oxidase (MAO) inhibitors, or within a minimum of 14 days of discontinuing those drugs, due to risk of hypertensive crisis (see section 4.5)
- Hyperthyroidism
Hypertension or thyrotoxicosis
- Diagnosis or history of severe depression, anorexia nervosa/anorexic disorders, suicidal tendencies, psychotic symptoms, severe mood disorders, mania, schizophrenia, psychopathic/borderline personality disorder.
- Diagnosis or history of severe and episodic (Type 1) Bipolar (affective) disorder (that is not well controlled)
- Pre-existing cardiovascular disorders including severe hypertension, heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies (disorders caused by the dysfunction of ion channels)
- Pre-existing cerebrovascular disorders cerebral aneurysm, vascular abnormalities including vasculitis or stroke or known risk factors for cerebrovascular disorders
Ritalin is also contra-indicated in patients with motor tics, tics in siblings, or a family history or diagnosis of Tourette's syndrome.
It is also contra-indicated in patients with hyperthyroidism, severe angina pectoris, cardiac arrhythmias, glaucoma, thyrotoxicosis, or known sensitivity to methylphenidate or to any of the excipients in Ritalin.
4.4. Special Warnings and Precautions for Use
Methylphendate treatment is not indicated in all children with ADHD and the decision to use the drug 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.
Long term use (more than 12 months) in children and adolescents
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 section 4.2 and 4.4 for cardiovascular status, growth, appetite, development of de nevo or worsening of pre-existing psychiatric disoders. Psychiaaitric 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 drug 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 drug is either temporary or permanently discontinued.
Use in adults
Methylphenidate is not licenced for use in adults with ADHD. Safety and efficacy have not yet been established in this age group.
Use in the Elderly
Methylphenidate should not be used in the elderly. Safety and efficacy has not been established in this age group.
Use in children under 6 years of age
Methylphenidate should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.
Cardiovascular status
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 arrthymia) 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 mmHg relative to controls. The short and long term clinical consequences of these cardiovasvular 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 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 Contraindications).
Sudden death and pre-existing cardiac structural abnormalities or other serious cardiac disorders
Pre-existing Structural Cardiac Abnormalities: 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 with structural cardiac abnormalities or other serious heart problems. .
Although some serious heart problems structural cardiac abnormalities alone may carry an increased risk of sudden death, stimulant products are not recommended in children or and adolescents with known structural cardiac structural abnormalities., cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vunerability to the sympathomimetic effects of a stimulant medicine.
Cardiovascular Conditions: Ritalin generally should not be used in patients with severe hypertension. Ritalin increases heart rate and systolic and diastolic blood pressure. Therefore, caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction. Cardiac arrhythmia and severe angina pectoris are contraindicated (see section 4.3 Contraindications).
Blood pressure should be monitored at appropriate intervals in all patients taking Ritalin, especially those with hypertension.
Misuse and Cardiovascular Events: Misuse of stimulants of the central nervous system may be associated with sudden death and other serious cardiovascular adverse events.
Cerebrovascular disorders:
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 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
Psychiatric disorders
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.
Exacerbation of pre-existing psychotic or manic symptoms
In psychotic patients, administration of methylphenidate may exacerbate symptoms of behavioural disturbance and thought disorder.
Emergence of new psychotic or manic symptoms
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.
Aggressive or hostile behaviour
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 least every 6 months and every visit. Physicians should evaluate the need for adjustment of the treatment regimen in patients experiencing behavioural changes.
Suicidal tendency
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.
Tics
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.
Anxiety, agitation or tension
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.
Forms of bipolar disorder
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.
Growth
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.
Seizures
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 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.
Abuse, misuse and diversion
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 in to 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.
Withdrawal
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.
Fatigue
Methylphenidate should not be used for the prevention or treatment of normal fatigue states
Excipients: glactose/sucrose intoleraence
This medicinal product contains lactose: patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-glactose malabsorption should not take this medicine
[b4] Choice of methylphenidate formulation
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.
Drug screening
This product contains methylphenidate which may induce a false positive laboratory test for amphetamines, particularly with immunoassay screen test.
Renal or hepatic insufficiency
There is no experience with the use of methylphenidate in patients with renal or hepatic insufficiency.
Haematological effects
The long-term safety of treatment with methylphenidate is not fully known. In the event of leucopenia, thrombocytopenia, anaemia or other alterations, including those indicative of serious renal or hepatic disorders, discontinuation of treatment should be considered.
Potential for gastrointestinal obstruction
Because Ritalin tablet is nondeformable and does not appreciably change in shape in the gastrointestinal (GI) tract, it should not ordinarily be administered to patients pre-existing severe GI narrowing (pathologic or iatrogenic) or in patients with dsyphagia 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 drugs in nondeformable prolonged-release formulations.
Ritalin should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.
Ritalin should not be used to treat severe exogenous or endogenous depression. ?
Clinical experience suggests that Ritalin may exacerbate symptoms of behavioural disturbance and thought disorder in psychotic children.
Available clinical evidence indicates that treatment during childhood does not increase the likelihood of addiction in later life. ?
Chronic abuse of Ritalin can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes may occur, especially with parenteral abuse.
Females of child-bearing potential (females post-menarche) should not use Ritalin unless clearly necessary (See Section 4.6, Pregnancy and Lactation and Section 5.3, Preclinical Safety Data).
Treatment with Ritalin is not indicated in all cases of Attention-Deficit-Hyperactivity disorders, and should be considered only after detailed history-taking and evaluation. The decision to prescribe Ritalin should depend on an assessment of the severity of symptoms and their appropriateness to the child’s age and not simply on the presence of one or more abnormal behavioural characteristics. Where these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not indicated.
Moderately reduced weight gain and slight growth retardation have been reported with the long-term use of stimulants in children, although a causal relationship has not been confirmed. Careful monitoring of growth is recommended during extended treatment with Ritalin.
Caution is called for in emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because such patients may increase the dosage on their own initiative.
Ritalin should be used with caution in patients with epilepsy as clinical experience has shown that it can cause an increase in seizure frequency in a small number of such patients. If seizure frequency increases, Ritalin should be discontinued.
The long-term safety and efficacy profiles of Ritalin are not fully known. Patients requiring long-term therapy should therefore be carefully monitored and complete and differential blood counts and a platelet count performed periodically.
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.
4.5 Interactions with other Medicaments medicinal products and other forms of Interaction
Pharmacokinetic interaction
It is not known how methylphenidate may effect plasma concentrations of concomitantly administered drugs. Therefore, caution is recommended at combining methylphenidate with other drugs, especially those with 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. Converesely, 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. Phenobarbitol, 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 drugs already being taken and establish drug plasma concentrations (or for coumarin, coagulation times). may have to be reduced. Ritalin should be used cautiously in patients being treated with pressor agents and MAO inhibitors.
Pharmacodynamics interactions
Anti-hypertensive drugs
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension.
Use with drugs that elevate blood pressure
Caution is advised in patients being treated with methylphenidate with other drugs that can also elevate blood pressure (see also sections on cardiovascular and cerebrovascular conditions in section 4.4 Warnings and precautions for use)
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 Contraindications).
Use with alcohol
Alcohol may exacerbate the adverse CNS effects of psychoactive drugs, including methylphenidate. It is therefore advisable for patients to abstain from alcohol during treatment
Use with halogenated anaesthetics
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.
Use with centrally acting alpha-2agonists (e.g. clonidine)
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.
Use with dopaminergic drugs
Caution is recommended when administering methylphenidate with dopaminergic drugs, including antipsychotics. Because a predominant action of methylphenidate is to increase extra cellular 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 antispsychotics.
Ritalin may reduce the antihypertensive effects of guanethidine. ?
Alcohol may exacerbate the adverse CNS effect of psychoactive drugs, including Ritalin. It is therefore advisable for patients to abstain from alcohol during treatment.
4.6 Pregnancy and Lactation
Pregnancy
There is limited amount of data from the use of methylphenidate in pregnant women. are no adequate data from the use of Ritalin in pregnancy.
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, Preclinical Safety Data). The potential risk for humans is unknown.
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. pregnancy unless clearly necessary.
Lactation
Methylphenidate has been found in breast-milk of a women 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.
It is not known whether the active substance of Ritalin and/or its metabolites passes into breast milk, but for safety reasons breast-feeding mothers should not use Ritalin.
4.7 Effects on Ability to Drive or Use Machines
Ritalin may cause dizziness, and 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. It is therefore advisable to exercise caution when driving, operating machinery, or engaging in other potentially hazardous activities.
4.8 Undesirable Effects
The table below shows all adverse drug reactions (ADRs) observed during clinical trials and post market spontaneous reports with methylphenidate and those, which have been reported with other methylphenidate hydrochloride formulations. If ADRs with methylphenidate and the methylphenidate formulation frequencies were different, the highest frequency of both databases was used.
Frequency estimate: very common (³ 1/10%); common (³ 1/100% to < 1/10%;) uncommon (³ 1/1000 to <1/100) 0.1% to < 1%; rare (³ 1/10,000 to <1/1000) 0.01% to < 0.1%; very rare (< 1/10,000) 0.01%.not known (cannot be estimated from available data)
Infections and infestations
Common: Nasopharyngitis
Blood and lymphatic disorders
Very rare: Anaemia, leucopenia, thrombocytopenia, thrombocytopenic purpura
Unknown: Pancytopenia
Immune system disorders
Uncommon: hypersensitivity reactions such as angioneurotic oedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticarias, pruritis, rashes and eruptions
Metabolism and nutritional disorders *
Common: anorexia, decreased appetite, moderately reduced weight and height gain during prolonged use in children
Psychiatric disorders *
Very common: insomnia, nervousness
Common: anorexia, affect lability, aggression*, agitation*, anxiety*, depression*, irritability, abnormal behaviour
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
Rare: mania*, disorientation, libido disorder
Very rare: suicidal attempt (including completed suicide)*, transient depressed mood*, abnormal thinking, apathy, repetitive behaviours, over-focusing,
Not known: delusions*, thought disturbances*, confessional state, dependence.
Cases of abuse and dependence have been described, more often with immediate release formulations (frequency not known)
Nervousness and insomnia are very common adverse reactions occurring at the beginning of treatment, but can usually be controlled by reducing the dosage and/or omitting the afternoon or evening dose.
Decreased appetite is also common but usually transient.
Central and peripheral nNervous system disorders:
Very Ccommon: Headache,
Common: : Drowsiness, Dizziness, dyskinesia, psychomotor hyperactivity, somnolence
Uncommon: Sedation, tremor
Rare: Difficulties in visual accommodation, and blurred vision.
Very rare: Hyperactivity, cConvulsions, muscle cramps, choreo-athetoid movements, reversible ischaemic neurological deficit, neuroleptic malignant syndrome (NMS: Reports were poorly documented and in most cases, patients were also receiving other drugs, 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
tics or exacerbation of existing tics, and Tourette's syndrome, toxic psychosis (sometimes with visual and tactile hallucinations), transient depressed mood, cerebral arteritis and/or occlusion.
Very rare reports of poorly documented neuroleptic malignant syndrome (NMS) have been received. In most of these reports patients were also receiving other medications. It is uncertain what role Ritalin played in these cases.
Eye disorders
Uncommon: Diplopia, blurred vision
Rare: Difficulties in visual accommodation, mydriasis, visual disturbance
Cardiac disorders*
Common: Arrhythmia, tachycardia palpitations
Uncommon: Chest pain
Rare: Angina pectoris
Very rare: Cardiac arrest, myocardial infarction
Not known: Supraventricular tachycardia, bradycardia, ventricular extrasystoles, extrasystoles
Vascular disorders*
Common: Hypertension
Very rare: Cerebral arteritis and/or occlusion, peripheral coldness, Raynaud’s phenomenon
Respiratory, thoracic and mediastinal disorders
Common: Cough, pharyngolaryngeal pain
Uncommon: dyspnoea
Gastro-intestinal disorderstract:
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.
Uncommon: Constipation
Very rare: Abnormal liver function, ranging from transaminase elevation to hepatic coma.
Hepatobiliary disorders
Uncommon: Hepatic enzyme elevations
Very rare: Abnormal liver functions, including hepatic coma
Skin and subcutaneous tissue disorders
Common: Alopecia, pruritis, rash, urticaria
Uncommon: Angioneurotic oedema, bullous conditions, exfoliate conditions
Rare: Hyperhidrosis, macular rash, erythema
Very rare: erythema multiforme, exfoliate dermatitis, fixed drug eruption
Musculoskeletal, connective tissue and bone disorders
Common: Arthralgia
Uncommon:Myalgia, muscle twitching
Very rare: Muscle cramps
Renal and urinary disorders
Uncommon: Haematuria
Reproductive system and breast disorders
Rare: Gynaecomastia
General disorders and administration site conditions
Common: Pyrexia, growth retardation during prolonged use in children*
Uncommon: Chest pain, fatigue
Very rare: Sudden cardiac death*
Not known: Chest discomfort, hyperpyrexia
Investigations
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 “Special warnings and precautions for use”
Cardiovascular system:
Common: Tachycardia, palpitations, arrhythmias, changes in blood pressure and heart rate (usually an increase).
Rare: Angina pectoris.
Skin and appendages:
Common: Rash, pruritus, urticaria, fever, arthralgia, scalp hair loss.
Very rare: Thrombocytopenic purpura, exfoliative dermatitis, and erythema multiforme.
Blood:
Very rare: Leucopenia, thrombocytopenia, anaemia.
Immune system disorders:
Very rare: Hypersensitivity reactions (e.g. skin rash, pruritis, swelling face)
Miscellaneous:
Rare: Moderately reduced weight gain and slight growth retardation during prolonged use in children.
4.9 Overdose
When treating patients with overdose, allowances must be made for the delayed release of methylphenidate from methylphenidate.
Signs and symptoms
Acute overdose, mainly due to overstimulation of the central and sympathetic nervous systems, may result in vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Treatment
There is no specific antidote to methylphenidate overdosage.
Treatment consists of appropriate supportive measures.
,The patient must be protected preventing against self-injury and against protecting the patient from external stimuli that would aggravate over-stimulation already present. If the signs and symptoms are not too severe and the patient is conscious, gastric contents may be evacuated by induction of vomiting or gastric lavage. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. In the presence of severe intoxication, a carefully titrated dose of a short-acting barbiturate benzodiazepine should be given before performing gastric lavage.
Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required to reduce hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal haemodialysis for overdose of methylphenidate has not been established.
5. PHARMACOLOGICAL PROPERTIES[b6]
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: psychostimulants - ATC code: NO6B AO4.
Mode of action: Methylphenidate is a mild CNS stimulant with more prominent effects on mental than on motor activities. Its mode of action in man is not completely understood but its effects are thought to be due to an inhibition of dopamine reuptake in the striatum, without triggering the release of dopamine.
The mechanism by which methylphenidate exerts its mental and behavioural effects in children is not clearly established, nor is there conclusive evidence showing how these effects relate to the condition of the central nervous system.
Methylphenidate is a racemic mixture containing d- and I-enantiomers, where the d-enantiomer is considered as the pharmacologically active enantiomer.
Pregnancy-embryonal/foetal development
Mthlyphenidate is not considered to be teratogenic in rats and rabbits. Foetal toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.
5.3 Preclinical Safety Data
There is evidence that methylphenidate may be a teratogen in two species. Spina bifida and limb malrotations have been reported in rabbits whilst in the rat, equivocal evidence of induction of abnormalities of the vertebrae was found.
Methylphenidate did not affect reproductive performance or fertility at low multiples of the clinical dose.
In life-time rat and mouse carcinogenicity studies, increased numbers of malignant liver tumours were noted in male mice only.The significance of this finding to humans is unknown.
The weight of evidence from geneotoxicity studies reveals no special hazard for humans.
Carcinogenicity
In life-time rat and mouse carcinogenicity studies, increased numbers of malignant liver tumours were noted in male mice only. The significance of this finding to humans is unknown.
Methylphenidate did not affect reproductive performance or fertility at low multiples of the clinical dose.
Pregnancy-embryonal/foetal development
Methylphenidate is not considered to be teratogenic in rats and rabbits. Foetal toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.
