4.1. Therapeutic indications

Tuzulby is indicated as part of a comprehensive treatment programme for attention-deficit / hyperactivity disorder (ADHD) in children and adolescents 6-17 years old when remedial measures alone prove insufficient.

Treatment must be under the supervision of a specialist in childhood behavioural disorders. Diagnosis should be made according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria or the guidelines in International Classification of Diseases, Tenth Revision (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.

4.2. Posology and method of administration

Treatment must be initiated under the supervision of a specialist in childhood and/or adolescent behavioural disorders.

Posology

Tuzulby prolonged-release chewable tablets consists of an immediate release component (30% of the dose, which ensures rapid onset of action) and a prolonged-release component (70% of the dose, which is designed to maintain therapeutic plasma levels over an extended period). This medicinal product is designed to deliver therapeutic plasma levels for a period of approximately 8 hours following administration (see also section 5.2).

Dose titration

Careful dose titration is necessary at the start of treatment with methylphenidate. Dose titration should be started at the lowest possible dose.

Other methylphenidate-containing medicinal products with different strengths may be available.

Switching from immediate-release methylphenidate-containing medicinal products to Tuzulby prolonged-release chewable tablets, administered as a single dose, provides comparable overall exposure of methylphenidate compared to the same total dose of the immediate release formulation administered twice daily.

The recommended dose of Tuzulby should be equal to the total daily dose of the immediate-release methylphenidate-containing formulation not exceeding a total dose of 60 mg. Examples are provided in the table below.

Immediate-release methylphenidate dose

Tuzulby dose

10 mg methylphenidate twice daily

20 mg once daily

15 mg methylphenidate twice daily

30 mg once daily

20 mg methylphenidate twice daily

40 mg once daily

30 mg methylphenidate twice daily

60 mg once daily

Treatment of hyperkinetic disorders/ADHD in children and adolescents (from 6 years to less than 18 years of age)

For patients from 6 years to less than 18 years of age, the recommended starting dose is 20 mg given orally once daily in the morning. The dose may be titrated up or down weekly in increments of 10 mg, 15 mg or 20 mg. The 10 mg and 15 mg doses can each be achieved by breaking in half the functionally scored 20 mg and 30 mg tablets, respectively. The dose should be individualised according to the treatment needs and responses of the patient.

The maximum daily dose of methylphenidate is 60 mg for treatment of children and adolescents (from 6 years to less than 18 years of age) with ADHD.

Long term (more than 12 months) use in children and adolescents (from 6 years to less than 18 years of 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. The physician who elects to use methylphenidate for extended periods (more than 12 months) in children and adolescents (from 6 years to less than 18 years of age) 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 (preferable during school holidays). Improvement may be sustained when the medicinal product is either temporarily or permanently discontinued.

Dose reduction and discontinuation

Treatment must be stopped if the symptoms do not improve after appropriate dose adjustment over a one-month period. If paradoxical aggravation of symptoms or other serious adverse reactions occur, the dosage should be reduced or discontinued.

Special populations

Adults

Methylphenidate is not indicated for use in adults in ADHD. Safety and efficacy have not been established in this age group.

Elderly

Methylphenidate should not be used in the elderly. Safety and efficacy have not been established in this age group.

Hepatic impairment

Methylphenidate has not been studied in patients with hepatic impairment. Caution should be exercised in these patients.

Renal impairment

Methylphenidate has not been studied in patients with renal impairment. Caution should be exercised in these patients.

Paediatric population

Methylphenidate should not be used in children under the age of 6 years. The safety and efficacy of methylphenidate in this age group have not been established.

Method of administration

Tuzulby is for oral use.

Tuzulby should be administered orally once daily in the morning with or without food (see section 5.2).

Tuzulby must be chewed and not swallowed whole or crushed.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Glaucoma

- Phaechromocytoma

- During treatment with monoamine oxidase (MAO) inhibitors, or within a minimum of 14 days of discontinuing those medicinal products, due to risk of hypertensive crisis (see section 4.5)

- Hyperthyroidism 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) (see section 4.4)

- Pre-existing cerebrovascular disorders cerebral aneurysm, vascular abnormalities including vasculitis or stroke or known risk factors for cerebrovascular disorders

4.4. Special warnings and precautions for use

The decision to use the medicinal product must be based on a very thorough assessment of the severity and chronicity of the child's/adolescent's symptoms in relation to the child's/adolescent's age.

Pre-treatment screening

Prior to prescribing, it is necessary to conduct a baseline evaluation of the patient's cardiovascular status, including blood pressure and heart rate. A comprehensive medical history should document concomitant medicinal products, past and present comorbid medical and psychiatric disorders or symptoms, family history of sudden cardiac or unexplained death or malignant arrhythmia, and accurate recording of pre-treatment height and weight on a growth chart (see section 4.3).

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 novo or worsening of pre-existing psychiatric disorders. Psychiatric disorders to be monitored 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/adolescent's condition (preferably during times of school holidays). Improvement may be sustained when the medicinal product is either temporary or permanently discontinued.

Cardiovascular status

Patients who are being considered for treatment with stimulant medicinal products should have a careful history (including assessment for a family history of sudden cardiac or unexplained death or malignant arrhythmia) and physical examination 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 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 centile chart at each adjustment of dose and then at least every 6 months.

Sudden death and pre-existing cardiac structural abnormalities or other serious cardiac disorders

Sudden death has been reported in association with the use of stimulants of the central nervous system (CNS) at usual doses in children and adolescents, 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 medicinal 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 medicinal product.

Misuse and cardiovascular events

Misuse of stimulants of the CNS may be associated with sudden death and other serious cardiovascular adverse reactions.

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.

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 of de novo or worsening of pre-existing 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 (see section 4.8). 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 bearing in mind that upwards or downwards titration may be appropriate.

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.

Bipolar disorder

Particular care should be taken in using methylphenidate to treat ADHD in patients with comorbid 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 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.

Growth

Moderately reduced weight gain and growth retardation have been reported with long-term use of methylphenidate in children (see section 4.8).

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.

Increased intraocular pressure and glaucoma

There have been reports of increased intraocular pressure (IOP) and glaucoma (including open angle glaucoma and angle closure glaucoma) associated with methylphenidate treatment (see section 4.8). Patients should be advised to contact their doctor in case of experiencing symptoms suggestive of increased IOP and glaucoma. An ophthalmologist should be consulted and discontinuation of methylphenidate be considered if IOP increases (see section 4.3). Ophthalmologic monitoring of patients with a history of increased IOP is recommended.

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's age, the presence of risk factors for substance use disorder (such as comorbid 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.

Withdrawal

Careful supervision is required during withdrawal, since this may unmask depression as well as chronic overactivity. Some patients may require long term follow-up.

Careful supervision is required during withdrawal from abusive use since severe depression may occur.

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.

Priapism

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.

Excipients with known effect

Aspartame (E 951)

Tuzulby 20 mg prolonged-release chewable tablets contains 6.1 mg of aspartame (E 951) in each tablet.

Tuzulby 30 mg prolonged-release chewable tablets contains 9.15 mg of aspartame (E 951) in each tablet.

Tuzulby 40 mg prolonged-release chewable tablets contains 12.2 mg of aspartame (E 951) in each tablet.

Aspartame is a source of phenylalanine. It may be harmful if you have phenylketonuria, a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per prolonged-release chewable tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interaction

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 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, primodone), and some antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors). When starting and stopping treatment with methylphenidate, it may be necessary to adjust the dose of these medicinal products already being taken and establish drug plasma concentrations (or for coumarin, coagulation times).

Pharmacodynamic interactions

Anti-hypertensive medicinal products

Methylphenidate may decrease the effectiveness of medicinal products used to treat hypertension.

Use with medicinal products that elevate blood pressure

Caution is advised in patients being treated with methylphenidate with other medicinal products 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 two weeks) with MAO inhibitors (see section 4.3).

Use with alcohol

Alcohol may exacerbate the adverse reactions in CNS with psychoactive medicinal products, 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 and heart rate increase during surgery. If surgery is planned, methylphenidate treatment should not be used on the day of surgery.

Use with centrally acting α2-agonists (e.g., clonidine)

Serious adverse reactions, 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 medicinal products

Caution is recommended when administering methylphenidate with dopaminergic medicinal products, 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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 1 000 women who received methylphenidate during the first trimester of pregnancy, compared with non-exposed pregnancies. Cases of neonatal cardiorespiratory toxicity, specifically foetal tachycardia and respiratory distress have been reported in spontaneous reports.

Animal studies have shown reproductive toxicity at maternally toxic doses (see section 5.3).

Methylphenidate should not be used during pregnancy unless a clinical decision is made that postponing treatment may pose a greater risk to the pregnancy.

Breast-feeding

Methylphenidate has been detected in breast milk of 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 newborn/infants 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.

Fertility

No human data on the effect of methylphenidate on fertility are available.

Methylphenidate did not impair fertility in male or female mice.

No clinically relevant effects on fertility were observed in animal studies.

4.7. Effects on ability to drive and use machines

Methylphenidate has moderate influence on the ability to drive and use machines. It can cause dizziness, drowsiness and visual disturbances, including difficulties with accommodation, diplopia and blurred vision. Patients should be warned of these adverse reactions and advised that if affected, they should avoid potentially hazardous activities such as driving or operating machines.

4.8. Undesirable effects

Summary of the safety profile

In general, the most common adverse reactions associated with methylphenidate treatment have been reported with a very common frequency are decreased appetite, insomnia, nervousness, headache, nausea and dry mouth.

Tabulated list of adverse reactions

Table 1 below shows all adverse reactions reported during clinical trials and post-marketing experience with methylphenidate, as well as those adverse reactions which have been reported with other methylphenidate hydrochloride formulations. If adverse reactions frequencies reported with methylphenidate and other methylphenidate hydrochloride formulations were different, the highest frequency from the safety databases was used.

Adverse reactions are listed by MedDRA system organ class and frequency convention as follows: 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 available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1. Adverse reactions

System organ class

Adverse reactions

Frequency category

Infections and infestations

Nasopharyngitis

Common

Blood and lymphatic system disorders

Leucopenia, thrombocytopenia anaemia, thrombocytopenic purpura

Very rare

Pancytopenia

Not known

Immune system disorders

Hypersensitivity reactions such as angioneurotic oedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticaria, pruritus*, rashes and eruptions*

Uncommon

Metabolism and nutrition disorders*

Decreased appetite**

Very common

Anorexia, moderately reduced weight, height gain decelerated*

Common

Psychiatric disorders*

Insomnia, nervousness

Very common

Abnormal behaviour, aggression*, affect lability, agitation*, anorexia, anxiety*, depression*, irritability, restlessness** sleep disorder**, libido decreased**, panic attack, stress, bruxism

Common

Hypervigilance, auditory, visual, and tactile hallucinations*, mood altered, mood swings, anger, suicidal ideation*, tearfulness, psychotic disorders*, tics*, worsening of pre-existing tics or Tourette's syndrome*, tension, emotional poverty

Uncommon

Mania*, disorientation, libido disorder , obsessive-compulsive disorder (including trichotillomania and dermatillomania)

Rare

Suicidal attempt, suicide*, transient depressed mood*, abnormal thinking, apathy

Very rare

Delusions*, thought disturbances*, confusional state, dependence, logorrhoea*****

Not known

Nervous system disorders

Headache

Very common

Tremour**, somnolence, dizziness, dyskinesia, psychomotor hyperactivity

Common

Sedation, akathisia, decreased apetite

Uncommon

Convulsions, choreo-athetoid movements, reversible ischaemic neurological deficit, neuroleptic malignant syndrome (NMS) ***

Very rare

Cerebrovascular disorders* (including vasculitis, cerebral haemorrhages, cerebrovascular accidents, cerebral arteritis, cerebral occlusion), grand mal convulsions*, migraine, dysphemia

Not known

Eye disorders

Diplopia, blurred vision , dry eye******

Uncommon

Difficulties in visual accommodation, mydriasis, visual disturbance

Rare

Increased intraocular pressure,

Glaucoma

Not known

Cardiac disorders

Tachycardia, palpitations, arrhythmia

Common

Chest pain

Uncommon

Angina pectoris

Rare

Cardiac arrest, myocardial infarction

Very rare

Supraventricular tachycardia, bradycardia, ventricular extrasystoles, extrasystoles

Not known

Vascular disorders

Hypertension, peripheral coldness**

Common

Cerebral arteritis and/or occlusion, Raynaud's phenomenon

Very rare

Gastrointestinal disorders

Nausea**, dry mouth**

Very common

Abdominal pain, diarrhoea, stomach discomfort, vomiting, dyspepsia*, toothache*

Common

Constipation

Uncommon

Hepatobiliary disorders

Hepatic enzyme elevations

Uncommon

Abnormal liver functions, including hepatic coma

Very rare

Skin and subcutaneous tissue disorders

Hyperhidrosis**, alopecia, pruritus, rash, urticaria

Common

Angioneurotic oedema, bullous conditions, exfoliate conditions

Uncommon

Macular rash, erythema

Rare

Erythema multiforme, exfoliate dermatitis, fixed drug eruption

Very rare

Musculoskeletal and connective tissue disorders

Arthralgia

Common

Myalgia, muscle twitching, muscle tightness

Uncommon

Muscle spasms

Very rare

Trismus

Not known

Renal and urinary disorders

Haematuria

Uncommon

Incontinence

Not known

Reproductive system and breast disorders

Gynaecomastia

Rare

Erectile dysfunction, priapism, erection increased and prolonged erection

Not known

General disorders and administration site conditions

Pyrexia, growth retardation during prolonged use in children and adolescents*, feeling jittery, fatigue**, thirst

Common

Chest pain

Uncommon

Sudden cardiac death*

Very rare

Chest discomfort, hyperpyrexia

Not known

Investigations

Changes in blood pressure and heart rate (usually an increase)*, weight decreased*

Common

Cardiac murmur*, hepatic enzyme increased

Uncommon

Blood alkaline phosphatase increased, blood bilirubin increased, platelet count decreased, white blood count abnormal

Very rare

* See section 4.4 “Special warnings and precautions for use”

** Adverse reactions from clinical trials in adult patients that were reported with a higher frequency than in children and adolescents.

*** Reports were poorly documented and in most cases, patients were also receiving other medicinal products, so the role of methylphenidate is unclear

**** These usually occur at the beginning of treatment and may be alleviated by concomitant food intake

***** Cases of abuse and dependence have been described, more often with immediate release formulations.

****** Frequency derived from adult clinical trials and not on data from trials in children and adolescents; may also be relevant for children and adolescents

Description of selected adverse reactions

Very rare cases of sudden death have been also reported in association with the use of stimulants of the CNS at usual doses in children, some of whom had structural cardiac abnormalities or other serious heart problems. Cardiovascular status should be carefully assessed and monitored (see section 4.4.).

Reporting of suspected adverse reactions

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

When treating patients with overdose, allowances must be made for the delayed release of methylphenidate from formulations with extended durations of action.

Signs and symptoms

Acute overdose, mainly due to overstimulation of the central and sympathetic nervous system, may result in vomiting, agitation, tremours, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, dryness of mucous membranes, and rhabdomyolysis.

Treatment

There is no specific antidote to methylphenidate overdose. Treatment consists of appropriate supportive measures.

The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation 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 for gastrointestinal detoxification include administration of activated charcoal and a cathartic. In the presence of severe intoxication, a carefully titrated dose of a 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.