4.1. Therapeutic indications

Attention-Deficit/Hyperactivity Disorder (ADHD)

Ambinet XL is indicated as part of a comprehensive treatment programme for attention-deficit/hyperactivity disorder (ADHD) in children aged and over 6 years of age and adults when remedial measures alone prove insufficient.

Treatment must be initiated and supervised by a doctor 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 current DSM 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.

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 in this way according to the licensed indication and according to prescribing/diagnostic guidelines.

Special diagnostic considerations for ADHD in adults

Diagnosis should be made according to DSM criteria or the guidelines in ICD 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 characterized 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 preexistence of childhood ADHD is required and has to be determined retrospectively (by patients' records or if not available by appropriate and structured instruments/interviews). Third-party corroboration is desirable and Ambinet XL 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

Posology

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

Pre-treatment screening

If required by national practice, in adults new to Ambinet XL, a 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 also 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 6 monthly 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

General aspects

- The regimen that achieves satisfactory symptom control with the lowest total daily dose should be employed. The effect occurs within an hour after ingestion if the dose is sufficiently high.

- Children should not take Ambinet XL too late in the morning as it may cause disturbances in sleep.

- For doses not realisable/practicable with this strength, other strengths of this medicinal product and other methylphenidate-containing products are available.

Children

Careful dose titration is necessary at the start of treatment with methylphenidate. Dose titration should be started at the lowest possible dose. This is normally achieved using an immediate-release formulation taken in divided doses. The recommended starting daily dose is 5 mg once daily or twice daily (e.g. at breakfast and lunch), increasing if necessary by weekly increments of 5-10 mg in the daily dose according to tolerability and degree of efficacy observed. Ambinet XL 10 mg once daily may be used in place of immediate-release methylphenidate hydrochloride 5 mg twice daily from the beginning of treatment where the treating physician considers that twice daily dosing is appropriate from the outset and twice daily treatment administration is impracticable.

Ambinet XL consists of an immediate-release component (50% of the dose) and a modified-release component (50% of the dose). Hence Ambinet XL 10 mg yields an immediate-release dose of 5 mg and an extended-release dose of 5 mg methylphenidate hydrochloride. The extended-release portion of each dose is designed to maintain a treatment response through the afternoon without the need for a midday dose. It is designed to deliver therapeutic plasma levels for a period of approximately 8 hours, which is consistent with the school day rather than the whole day (see section 5.2). For example, 20 mg of Ambinet XL is intended to take the place of 10 mg at breakfast and 10 mg at lunchtime of immediate-release methylphenidate hydrochloride.

Patients currently established on an immediate-release methylphenidate hydrochloride formulation may be switched to the milligram equivalent daily dose of Ambinet XL.

If the effect of the medicinal product wears off too early in the evening, disturbed behaviour may recur. A small dose (5 mg) of an immediate-release methylphenidate hydrochloride tablet late in the day may help to solve this problem. In that case, it could be considered that adequate symptom control might be achieved with a twice daily immediate-release methylphenidate regimen. The pros and cons of a small evening dose of immediate-release methylphenidate versus disturbances in falling asleep should be considered.

Treatment should not continue with Ambinet XL if an additional late dose of immediate-release methylphenidate is required, unless it is known that the same extra dose was also required for a conventional immediate-release regimen at equivalent breakfast/lunchtime dose.

The regimen that achieves satisfactory symptom control with the lowest total daily dose should be employed.

The maximum daily dose of methylphenidate hydrochloride in children is 60 mg.

Adults

Continuation of methylphenidate therapy

Adult patients who have shown clear benefit from treatment with Ambinet XL in childhood and/or adolescence may continue treatment with Ambinet XL into adulthood, initially at the same daily dose (mg/day). Whether or not a dose adjustment depending on efficacy and tolerability is necessary or possible must be reviewed regularly.

Adults new to Ambinet XL

Any treatment with methylphenidate requires individual dose titration against efficacy and tolerability because individual response may vary substantially. Initiation of treatment in adults who are new to Ambinet XL therefore requires careful dose titration. Dose titration should be started at the lowest possible dose.

The recommended starting dose is 10 mg daily, which may be increased if necessary by weekly increments of 10 mg in the daily dose according to tolerability and degree of efficacy observed. The total daily dose should be given in two divided doses in the morning and at midday.

The aim of individual titration should be to find the lowest daily dose that achieves satisfactory symptom control.

Compared to children and adolescents, adult patients may require a higher daily dose, based on the patient's body weight.

The maximum daily dose is based on the patient's body weight and must not exceed 1 mg/kg body weight. Regardless of body weight, a maximum daily dose of 80 mg methylphenidate hydrochloride should not be exceeded because limited experience with daily doses greater than 80 mg is available from clinical studies.

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. Methylphenidate treatment can usually be discontinued during or after puberty, when used in children with ADHD. 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.

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.

Elderly

Methylphenidate should not be used in the elderly. Safety and efficacy has not been established in patients older than 60 years of age.

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.

Hepatic impairment

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

Renal impairment

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

Method of administration

Oral use.

Ambinet XL has to be taken with or after a meal in order to obtain sufficiently prolonged action and to avoid high plasma peaks. Methylphenidate hydrochloride is absorbed much faster from Ambinet XL when the medicinal product is taken on an empty stomach. In this case, release may not be adequately sustained. Therefore Ambinet XL should not be administered without food.

Children

Ambinet XL should be given in the morning with or after breakfast.

Adults

Ambinet XL should be given in the morning and at lunchtime with or after the meals.

The capsules may be swallowed whole with the aid of liquids, or alternatively, the capsule may be opened and the capsule contents sprinkled onto a small amount (tablespoon) of applesauce or yoghurt and given immediately, and not stored for future use. Drinking some fluids, e.g. water, should follow the intake of the sprinkles with applesauce. The capsules and the capsule contents must not be crushed or chewed.

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 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 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, cerebral aneurysm, vascular abnormalities including vasculitis or stroke

- A history of pronounced anacidity of the stomach with a pH value above 5.5, in therapy with H2-receptor blockers, proton pump inhibitors or in antacid therapy

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 note, be indefinite. 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 patients older than 60 years of age.

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, exceptional chest pain, unexplained syncope, dyspnoea or other symptoms suggestive of cardiac disease during methylphenidate treatment should undergo a prompt specialist cardiac evaluation.

Analyses of data from clinical trials of methylphenidate in children and adolescents with ADHD showed that patients using methylphenidate may commonly experience changes in diastolic and systolic blood pressure of over 10 mmHg relative to controls. Changes 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. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate. See section 4.3 for conditions in which methylphenidate treatment is contraindicated.

Cardiovascular status should be carefully monitored. Blood pressure and pulse should be recorded on a centile chart at each adjustment of dose, and then at least every 6 months.

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 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 at usual doses in children, some of whom had cardiac structural abnormalities or other serious heart problems. Although some serious heart problems alone may carry an increased risk of sudden death, stimulant products are not recommended in patients with known cardiac structural abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant medicine.

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.

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.

Psychiatric disorders

Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. Prior to initiating treatment with methylphenidate, the patient should be assessed with regard to pre-existing psychiatric disorders and a family history thereof should be established (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. 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 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 comorbid bipolar disorder (including untreated Type I bipolar disorder or other forms of bipolar disorder) because of concern for possible precipitation of a mixed/manic episode in such patients. Prior to initiating treatment with methylphenidate, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Close ongoing monitoring is essential in these patients (see above 'Psychiatric disorders' and section 4.2). Patients should be monitored for symptoms at every adjustment of dose, then at least every 6 months and at every visit.

Growth and weight

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 in children 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. In adults, weight should be regularly monitored.

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.

Seizures

Methylphenidate should be used with caution in patients with epilepsy. Methylphenidate may lower the convulsive threshold in patient with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and rarely in patients without a history of convulsions and no EEG abnormalities. If seizure frequency increases or new onset seizures occur, methylphenidate should be discontinued.

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 drug withdrawal, since this may unmask depression as well as chronic over-activity. Some patients may require long-term follow up.

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

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. In adults, only Ambinet XL should be used.

Caution is advised if long-acting formulations of methylphenidate are used interchangeably due to the differences between these formulations in frequency of dosing, administration with food and plasma drug concentration achieved.

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).

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 a narrow therapeutic window.

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

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

Pharmacodynamic interactions

Anti-hypertensive medicinal products

Methylphenidate may decrease the effectiveness of active substances used to treat hypertension.

Use with medicinal products that elevate blood pressure

Caution is advised in patients being treated with methylphenidate with any other active substance that can also elevate blood pressure (see also sections on cardiovascular and cerebrovascular conditions in section 4.4).

Because of possible hypertensive crisis, methylphenidate is contraindicated in patients being treated (currently or within the preceding 2 weeks) with non-selective, irreversible MAO-inhibitors (see section 4.3).

Use with alcohol

Alcohol may exacerbate the adverse CNS effects of psychoactive active substances, including methylphenidate. In case of very high alcohol concentrations the kinetic profile may change towards a more immediate release-like pattern. 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 alpha-2 agonists (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 active substances

Caution is recommended when administering methylphenidate with dopaminergic active substances, including antipsychotics.

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

Use with other medicines

Ambinet XL must not be taken together with H2 receptor blockers, proton pump inhibitors or antacids, as this could lead to a faster release of the total amount of active substance.

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 receive methylphenidate during the first trimester of pregnancy, compared with non-exposed pregnancies.

Cases of neonatal cardio-respiratory toxicity, specifically fetal tachycardia and respiratory distress have been reported in spontaneous case reports.

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

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

Breast-feeding

Methylphenidate has been found in the breast-milk of a woman treated with methylphenidate.

There is one case report of an infant who experienced an unspecified decrease in weight during the period of exposure but recovered and gained weight after the mother discontinued treatment with methylphenidate. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from methylphenidate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of methylphenidate on fertility are available. In animal studies, no clinically relevant effects on fertility were observed.

4.7. Effects on ability to drive and use machines

Methylphenidate improves attention. However, methylphenidate can cause dizziness, drowsiness and visual disturbances including difficulties with accommodation, diplopia, blurred vision, hallucinations, and other CNS side effects (see section 4.8).

Ambinet XL 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.

4.8. Undesirable effects

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

Frequency estimate:

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)

Infections and infestations

Common

Uncommon

Nasopharyngitis

Gastroenteritis

Blood and lymphatic system disorders

Very rare

Not known

Leukopenia, thrombocytopenia, anaemia, thrombocytopenic purpura

Pancytopenia

Immune system disorders

Uncommon

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

Metabolism and nutrition disorders*

Very common

Common

Decreased appetite**

Anorexia, moderate reduction in weight and height gain during prolonged use in children*

Psychiatric disorders*

Very common

Insomnia, nervousness

Common

Affect lability, aggression*, agitation*, anorexia, anxiety*, depression*, irritability, abnormal behaviour, restlessness**, sleep disorder**, libido decrease***, bruxism***, panic attack***, stress***

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

Uncommon

Rare

Very rare

Not known

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

Suicidal attempt (including completed suicide)*, transient depressed mood*, abnormal thinking, apathy

Delusions*, thought disturbances*, confusional state, dependence, logorrhoea. Cases of abuse and dependence have been described, more often with immediate-release formulations

Nervous system disorders

Very common

Common

Uncommon

Very rare

Not known

Headache

Tremor**, dizziness, dyskinesia, psychomotor hyperactivity, somnolence

Sedation, akathisia***

Convulsions, choreoathetoid 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)

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

Eye disorders

Uncommon

Rare

Not known

Diplopia, blurred vision, dry eye$

Difficulties in visual accommodation, mydriasis, visual disturbance

Ocular hypertension, increased intraocular pressure, glaucoma

Ear and labyrinth disorders

Not known

Tinnitus$

Cardiac disorders*

Common

Uncommon

Rare

Very rare

Not known

Arrhythmias, tachycardia**, palpitations

Chest pain

Angina pectoris

Cardiac arrest, myocardial infarction

Supraventricular tachycardia, bradycardia, ventricular extrasystoles, extrasystoles, cardiac discomfort$

Vascular disorders*

Common

Very rare

Not known

Hypertension, peripheral coldness**

Cerebral arteritis and/or occlusion, Raynaud's phenomenon

Hot flush$, flushing$

Respiratory, thoracic and mediastinal disorders

Common

Not known

Cough, pharyngolaryngeal pain, dyspnoea**

Oropharyngeal pain$, Epistaxis$

Gastrointestinal disorders

Very common

Common

Uncommon

Not known

Nausea**, dry mouth**

Abdominal pain, diarrhoea, stomach discomfort, vomiting, dyspepsia***, toothache*** (these usually occur at the start of treatment and may be alleviated by concomitant intake of food)

Constipation

Retching$

Hepatobiliary disorders

Uncommon

Very rare

Hepatic enzyme elevations

Abnormal liver function including hepatic coma

Skin and subcutaneous tissue disorders

Common

Uncommon

Rare

Very rare

Alopecia, pruritus, rash, urticaria, hyperhidrosis**

Angioneurotic oedema, bullous conditions, exfoliative conditions

Macular rash, erythema

Erythema multiforme, exfoliative dermatitis, fixed drug eruption

Musculoskeletal and connective tissue disorders

Common

Uncommon

Very rare

Not known

Arthralgia

Myalgia, muscle twitching, muscle tightness***

Muscle cramps

Trismus***

Renal and urinary disorders

Uncommon

Not known

Haematuria

Incontinence

Reproductive system and breast disorders

Rare

Not known

Gynaecomastia

Erectile dysfunction, priapism, erection increased and prolonged erection, breast pain$

General disorders and administration site conditions

Common

Very rare

Not known

Pyrexia, growth retardation during prolonged use in children*, feeling of inner restlessness***, fatigue**, thirst***

Sudden cardiac death*

Hyperpyrexia, disturbance in attention$, influenza like illness$, asthenia$, chest discomfort

Investigations

Common

Uncommon

Very rare

Not known

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

Cardiac murmur*, hepatic enzyme increased

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

Blood thyroid stimulating hormone increased$

Social circumstances

Not known

Partner stress$, family stress$

* See section 4.4.

** ADRs 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)

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

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 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 Ambinet XL.

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, dryness of mucous membranes and rhabdomyolysis.

Treatment

There is no specific antidote to Ambinet XL 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 to detoxify the gut include administration of activated charcoal and a cathartic. In the presence of severe intoxication, a carefully titrated dose of a benzodiazepine may be given before performing gastric lavage.

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 hydrochloride has not been established.