4.1. Therapeutic indications

Attention Deficit Hyperactivity Disorder (ADHD)

Xenidate XL is indicated as part of a comprehensive treatment programme for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over and adults when remedial measures alone prove insufficient.

Treatment must be initiated and supervised by a physician specialised in the treatment of ADHD such as an expert paediatrician, a child and adolescent psychiatrist or an adult psychiatrist.

Special Diagnostic Considerations for ADHD in children

Diagnosis should be made according to the current DSM criteria or ICD guidelines and should be based on a complete history and evaluation of the patient. Third-party corroboration is desirable and diagnosis cannot be made solely on the presence of one or more symptoms.

The specific aetiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and specialised psychological, educational, and social resources.

A comprehensive treatment programme typically includes psychological, educational and social measures as well as pharmacotherapy and is aimed at stabilising children with a behavioural syndrome characterised by symptoms which may include chronic history of short attention span, distractibility, emotional lability, impulsivity, moderate to severe hyperactivity, minor neurological signs and abnormal EEG. Learning may or may not be impaired.

Methylphenidate treatment is not indicated in all children with ADHD and the decision to use the medicinal product must be based on a very thorough assessment of the severity and chronicity of the child's symptoms in relation to the child's age.

Appropriate educational placement is essential, and psychosocial intervention is generally necessary. Where remedial measures alone prove insufficient, the decision to prescribe a stimulant must be based on rigorous assessment of the severity of the child's symptoms. Methylphenidate should always be used according to the licensed indication and according to prescribing / diagnostic guidelines.

Special Diagnostic Considerations for ADHD in adults

Diagnosis should be made according to the current DSM criteria or ICD guidelines and should be based on a complete history and evaluation of the patient.

The specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adults with ADHD have symptom patterns characterised by restlessness, impatience, and inattentiveness.

Symptoms such as hyperactivity tend to diminish with increasing age, possibly due to adaptation, neurodevelopment and self-medication. Inattentive symptoms are more prominent and have a greater impact on adults with ADHD. Diagnosis in adults should include a structured patient interview to determine current symptoms. The pre-existence of childhood ADHD is required and has to be determined retrospectively (by patient's records or, if not available, by appropriate and structured instruments/interviews). Third-party corroboration is desirable and treatment should not be initiated when the verification of childhood ADHD symptoms is uncertain. Diagnosis should not be made solely on the presence of one or more symptoms. The decision to use a stimulant in adults must be based on a very thorough assessment and diagnosis should include moderate or severe functional impairment in at least 2 settings (for example, social, academic, and/or occupational functioning), affecting several aspects of an individual's life.

4.2. Posology and method of administration

Treatment must be initiated and supervised by a physician specialised in the treatment of ADHD such as an expert paediatrician, a child and adolescent psychiatrist or an adult psychiatrist.

Pre-treatment screening

In adults new to methylphenidate, and if required by national practice, cardiologist advice is needed prior to treatment initiation in order to check the absence of cardiovascular contraindications.

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 in children should be recorded at least every 6 months with maintenance of a growth chart;

- Weight should be recorded for adults regularly.

- 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.

For doses not realisable/practicable with this medicinal product, other strengths and medicinal products are available.

The dosage may be adjusted in 18 mg increments. In general, dosage adjustment may proceed at approximately weekly intervals.

The maximum daily dosage of methylphenidate is 54 mg in children. The maximum daily dosage of methylphenidate is 72 mg in adults.

Posology

Children

Children new to methylphenidate

Methylphenidate may not be indicated in all children with ADHD syndrome. Lower doses of short- acting methylphenidate formulations may be considered sufficient to treat children new to methylphenidate. Careful dose titration by the physician in charge is required in order to avoid unnecessarily high doses of methylphenidate. The recommended starting dose of methylphenidate for children who are not currently taking methylphenidate, or for children who are on stimulants other than methylphenidate, is 18 mg once daily.

Adults

Adults New to Methylphenidate

Methylphenidate may not be indicated in all adults with ADHD syndrome. Lower doses of short- acting methylphenidate formulations may be considered sufficient to treat adults new to methylphenidate. Careful dose titration by the physician in charge is required in order to avoid unnecessarily high doses of methylphenidate. The recommended starting dose of methylphenidate for adults who are not currently taking methylphenidate, or for adults who are on stimulants other than methylphenidate, is 18 mg once daily.

Patients currently using methylphenidate

The recommended dose of Xenidate XL for patients who are currently taking methylphenidate three times daily at doses of 15 to 60 mg/day is provided in Table 1. Dosing recommendations are based on current dose regimen and clinical judgement.

Table 1: Recommended Dose Conversion from other Methylphenidate hydrochloride Regimens, where available, to Xenidate XL

Previous Methylphenidate hydrochloride Daily Dose

Recommended Xenidate XL Dose

5 mg methylphenidate three times daily

18 mg once daily

10 mg methylphenidate three times daily

36 mg once daily

15 mg methylphenidate three times daily

54 mg once daily

20 mg methylphenidate three times daily

72 mg once daily

If improvement is not observed after appropriate dosage adjustment over a one-month period, the medicinal product should be discontinued.

Long-term (more than 12 months) use

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. In children and adolescents, methylphenidate treatment is usually discontinued during or after puberty. The physician who elects to use methylphenidate for extended periods (over 12 months) in patients 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 patient's condition (for children preferable during times of 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 dosage adjustment over a one-month period. If paradoxical aggravation of symptoms or other serious adverse events occur, the dosage should be reduced, or the medicinal product should be discontinued.

Special populations

Elderly

Methylphenidate should not be used in the elderly. Safety and efficacy has not been established in this age group. Methylphenidate has not been studied in ADHD in patients older than 65 years.

Hepatic impairment

Methylphenidate has not been studied in patients with hepatic impairment.

Renal impairment

Methylphenidate has not been studied in patients with renal impairment.

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.

Method of administration

Xenidate XL is for oral use once daily in the morning.

Xenidate XL may be administered with or without food (see section 5.2).

The tablet can be divided into equal doses. Xenidate XL must be swallowed with sufficient liquid, and must not be chewed or crushed (see section 4.4).

4.3. Contraindications

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

• Glaucoma

• Phaeochromocytoma

• During treatment with non-selective, irreversible monoamine oxidase (MAO) inhibitors, or within a minimum of 14 days of discontinuing those medicinal products, due to the risk of hypertensive crises (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 I) 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 e.g. cerebral aneurysm, vascular abnormalities including vasculitis or stroke

4.4. Special warnings and precautions for use

Methylphenidate treatment is not indicated in all patients with ADHD and the decision to use the medicinal product must be based on a very thorough assessment of the severity and chronicity of the patient's symptoms. When treatment of children is considered, assessment of the severity and chronicity of the child's symptoms should be related to the child's age (6-18 years).

Long-term use (more than 12 months)

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. In children and adolescents, methylphenidate treatment is usually discontinued during or after puberty. Patients on long-term therapy (i.e. over 12 months) must have careful ongoing monitoring according to the guidance in sections 4.2 and 4.4 for cardiovascular status, growth (children), weight, appetite, development of de novo or worsening of pre-existing psychiatric disorders. Psychiatric disorders to monitor for are described below, and include (but are not limited to) motor or vocal tics, aggressive or hostile behaviour, agitation, anxiety, depression, psychosis, mania, delusions, irritability, lack of spontaneity, withdrawal and excessive perseveration.

The physician who elects to use methylphenidate for extended periods (over 12 months) 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 patient's condition (for children preferably during times of school holidays). Improvement may be sustained when the medicinal product is either temporarily or permanently discontinued.

Use in the elderly

Methylphenidate should not be used in the elderly. Safety and efficacy has not been established in this age group. Methylphenidate has not been studied in ADHD in patients older than 65 years.

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 arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further specialist cardiac evaluation if initial findings suggest such history or disease. Patients who develop symptoms such as palpitations, 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. Increases in diastolic and systolic blood pressure values were also observed in clinical trial data from adult ADHD patients. 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 especially when treatment during childhood/adolescence is continued into adulthood. 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 then at least every 6 months.

Methylphenidate should be discontinued in patients under treatment with repeated measures of tachycardia, arrhythmia or increased systolic blood pressure (>95th percentile) and referral to a cardiologist should be considered.

The use of methylphenidate is contraindicated in certain pre-existing cardiovascular disorders unless specialist cardiac advice has been obtained (see section 4.3).

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

Sudden death has been reported in association with the use of stimulants of the central nervous system at usual doses in patients, 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 products are not recommended in patients with known structural cardiac 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.

Adults

Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.

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 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.

Psychiatric disorders

Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. Before the start of treatment with methylphenidate, the patient should be examined for any existing psychiatric disorders and a family history with regard to psychiatric disorders should be obtained (see section 4.2). 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 patients 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. Aggression has been reported in patients treated with methylphenidate (see section 4.8). Patients treated with methylphenidate should be closely monitored for the emergence or worsening of aggressive behaviour or hostility at treatment initiation, at every dose adjustment and then at least every 6 months and every visit. Physicians should evaluate the need for adjustment of the treatment regimen in patients experiencing behaviour changes bearing in mind that upwards or downwards titration may be appropriate. Treatment interruption can be considered.

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 (see section 4.8). Family history should be assessed and clinical evaluation for tics or Tourette's syndrome 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

Anxiety, agitation and tension have been reported in patients treated with methylphenidate (see section 4.8). Methylphenidate is also associated with the worsening of pre-existing anxiety, agitation or tension. Anxiety has led to discontinuation of methylphenidate in some patients. 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 comorbid bipolar disorder (including untreated type I bipolar disorder or other forms of bipolar disorder) because of concern for possible precipitation of a mixed/manic episode in such patients. Prior to initiating treatment with methylphenidate, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Close ongoing monitoring is essential in these patients (see above 'Psychiatric disorders' and section 4.2). Patients should be monitored for symptoms at every adjustment of dose and then at least every 6 months and at every visit.

Growth

Moderately reduced weight gain and growth retardation have been reported with the long-term use of methylphenidate in children. Weight decrease has been reported with methylphenidate treatment in adults (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 every 6 months 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. In adults, weight should be regularly monitored.

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.

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.

Use with serotonergic medicinal products

Serotonin syndrome has been reported following coadministration 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.

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 all be taken into account when deciding on a course of treatment for ADHD.

Caution is called for in emotionally unstable patients, such as those with a history of drug or alcohol dependence, because such patients may increase the dosage on their own initiative.

For some high-risk substance abuse patients, methylphenidate or other stimulants may not be suitable and non-stimulant treatment should be considered.

Withdrawal

Careful supervision is required during medicinal product 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.

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. Athletes must be aware that this medicinal product may cause a positive reaction to 'anti-doping' tests.

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 leukopenia, thrombocytopenia, anaemia or other alterations, including those indicative of serious renal or hepatic disorders, discontinuation of treatment should be considered (see section 4.8).

Potential for gastrointestinal obstruction

Because the methylphenidate tablet is nondeformable 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 drugs in nondeformable prolonged-release formulations.

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.

The tablet can be divided into equal doses. Patients should be informed that Xenidate XL must be swallowed with sufficient liquid. Tablets must not be chewed or crushed.

Xenidate XL contains sucrose and sodium.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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

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

Pharmacokinetic interactions

It is not known how methylphenidate may effect plasma concentrations of concomitantly administered medicinal products. Therefore, caution is recommended at combining methylphenidate with other medicinal products, especially those with a narrow therapeutic window.

Methylphenidate is not metabolised by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l- enantiomers of methylphenidate do not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.

However, there are reports indicating that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g. phenobarbital, phenytoin, primidone) and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). When starting or stopping treatment with methylphenidate, it may be necessary to adjust the dosage of these medicinal products already being taken and establish their plasma concentrations (or for coumarin, coagulation times).

Pharmacodynamic interactions

Antihypertensive 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 and any other active substances 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).

Use with alcohol

Alcohol may exacerbate the adverse CNS effect of psychoactive medicinal products, including methylphenidate. In-vitro data suggest that alcohol concentrations higher than 10% increase the cumulative release of MPH from methylphenidate. The clinical relevance of the finding on the MPH exposure after oral ingestion of methylphenidate in combination with alcohol is not known. It is therefore advisable for patients to abstain from alcohol during treatment.

Use with serotonergic medicinal products

There have been reports of serotonin syndrome following coadministration 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 (see section 4.4). Methylphenidate must be discontinued as soon as possible if serotonin syndrome is suspected.

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 alpha-2 agonists (e.g. clonidine)

Serious, adverse events, including sudden death, have been reported in concomitant use of methylphenidate and clonidine. The long-term safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systematically evaluated.

Use with dopaminergic substances

Caution is recommended when administering methylphenidate with dopaminergic substances, including antipsychotics. Because a predominant action of methylphenidate is to increase extracellular dopamine levels, methylphenidate may be associated with pharmacodynamic interactions when co- administered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) or with dopamine antagonists (including antipsychotics).

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 1000 women who receive 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 case reports.

Studies in animals have only shown evidence of reproductive toxicity at maternally toxic doses (see section 5.3).

Methylphenidate is not recommended for use during pregnancy unless a clinical decision is made that postponing treatment may pose a greater risk to the pregnancy.

Breast-feeding

Methylphenidate excreted in human milk. Based on reports of breast milk sampling from five mothers, methylphenidate concentrations in human milk resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage, and a milk to maternal plasma ratio ranging between 1.1 and 2.7.

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.

Fertility

No human data on the effect of methylphenidate on fertility are available. There were no relevant effects observed in the non-clinical studies.

4.7. Effects on ability to drive and use machines

Methylphenidate can 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.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It may be an offence to drive while under the influence of this medicine.

4.8. Undesirable effects

The table below shows all adverse drug reactions (ADRs) observed during clinical trials of children, adolescents and adults and post-market spontaneous reports with methylphenidate and those, which have been reported with other methylphenidate hydrochloride formulations. If the ADRs with methylphenidate prolonged release tablets and the other methylphenidate formulation frequencies were different, the highest frequency of both databases was used.

The frequency of undesirable effects listed below is defined using the following convention:

Very common:

Common:

Uncommon:

Rare:

Very rare:

Not known:

≥1/10

≥1/100 to <1/10

≥1/1,000 to <1/100

≥1/10,000 to <1/1,000

<1/10,000

cannot be estimated from the available data

System Organ Class

Adverse Reaction

Frequency

Very common

Common

Uncommon

Rare

Very rare

Not known

Infections and infestations

Nasopharyngitis, Upper respiratory tract infection#, Sinusitis#

Blood and lymphatic system disorders

Anaemia†, Leucopenia†, Thrombocytopenia, Thrombocytopenic purpura

Pancytopenia

Immune system disorders

Hypersensitivity reactions such as Angioneurotic oedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, 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, Nervous- ness

Affectlability, 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*†, Disorien- tation, Libido disorder, Confusional state†, Obsessive-compulsive disorder (including trichotillomania and dermatillomania)

Suicidal attempt (including completed suicide)*†, Transient depressed mood*, Abnormal thinking, Apathy†,

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, Paresthaesia#, Tension headache#

Sedation, Tremor†, Lethargy#

Convulsions, Choreo-athetoid movements, Reversible ischaemic neurological deficit, Neuroleptic malignant syndrome (NMS; Reports were poorly documented and in most cases, patients were also receiving other medicinal products, so the role of methylphenidate is unclear).

Cerebro-vascular disorders* † (including vasculitis, cerebral haemorrhages, cerebro-vascular accidents, cerebral occlusion), Grand malconvulsion*, Migraine†, Dysphemia

Eye disorders

Accommod ation disorder#

Blurred vision†, Dry eye#

Difficulties in visual accommodation, Visual impairment, Diplopia

Mydriasis, Increased intraocular pressure, Glaucoma

Ear and labyrinth disorders

Vertigo#

Cardiac disorders*

Arrhythmia, Tachycardia, Palpitations

Chest pain

Angina pectoris

Cardiac arrest, Myocardial infarction

Supra-ventricular 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†

Epistaxis

Gastro-intestinal disorders

Abdominal pain upper, Diarrhoea, Nausea, † Abdominal discomfort, Vomiting, Dry mouth†, Dyspepsia#

Constipation†

Hepatobiliary disorders

Hepatic enzyme inreased

Abnormal liver function, including acute hepatic failure and hepatic coma, Blood alkaline phosphatase increased, Blood bilirubin increased

Skin and subcutaneous tissue disorders

Alopecia, Pruritis, Rash, Urticaria, Hyperhidrosis†

Angioneurotic oedema, Bullons conditions, Exfoliative conditions

Macular rash; Erythema

Erythema multiforme, Exfoliative dermatitis, Fixed drug eruption

Musculo-skeletal 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†, White blood cell count abnormal

*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.

† Adverse drug reaction from clinical trials in adult patients that were reported with a higher frequency than in children and adolescents.

^ Based on the frequency calculated in adult ADHD studies (no cases were reported in the paediatric studies).

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 at: 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 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 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. The efficacy of activated charcoal has not yet been established.

Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.

Efficacy of peritoneal dialysis or extracorporeal haemodialysis for overdose of methylphenidate has not been established.