Equasym^® 5 mg , 10 mg, 20 mg tablets

One tablet contains 5 mg, 10 mg, 20 mg of methylphenidate hydrochloride

For excipients, see section 6.1.

Tablet.

Tablet with breakline, 'Medeva' and strength embossed on one side.

Methylphenidate is indicated as part of a comprehensive treatment programme for attention-deficit hyperactivity disorder (ADHD) in children over 6 years of age when remedial measures alone prove insufficient. The decision to treat as well as follow-up must be under supervision of a specialist in childhood behavioural disorders. Diagnosis should be made according to DSM-IV criteria or the guidelines in ICD-10.

Additional information on the safe use of the product:

ADHD is also known as attentiondeficit disorder (ADD).

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

Methylphenidate treatment is not indicated in all children with this syndrome and the decision to use the drug must be based on a very thorough assessment of the severity of the child's symptoms in relation to the child's age and the persistence of the symptoms.

Adults: Not applicable.

Elderly: Not applicable

Children: (less than 6 years of age). Equasym is not indicated in children less than 6 years of age.

Children: (over 6 years). Begin with 5 mg once or twice daily (e.g. at breakfast and lunch), increasing the dose and frequency of administration if necessary by weekly increments of 510 mg in the daily dose. Doses above 60 mg daily are not recommended. The total daily dose should be administered in divided doses.

The last doses should, in general, not be given within 4 hours before bedtime in order to prevent disturbances in falling asleep. However, if the effect of the drug wears off too early in the evening, disturbed behaviour and/or inability to go to sleep may recur. A small evening dose may help to solve this problem. The pros and cons of a small evening dose versus disturbances in falling asleep should be considered.

Note: If improvement of symptoms is not observed after appropriate dosage adjustment over a onemonth period, the drug should be discontinued. Methylphenidate should be discontinued periodically to assess the child's condition. Drug treatment is usually discontinued during or after puberty.

The presence of marked anxiety, agitation or tension is a contraindication to the use of Equasym as it may aggravate these symptoms. Equasym is also contra-indicated in patients with diagnosis or a family history of motor tics, Tourette's syndrome or other movement disorders.

Methylphenidate is contra-indicated in patients with known drug dependence or history of drug dependence or alcoholism, severe depression, schizophrenic symptoms, anorexia nervosa, psychopathological personality structure, history of aggression, or suicidal tendency.

It is also contra-indicated in patients with severe hypertension, hyperthyroidism, angina pectoris, cardiac arrhythmia, glaucoma, thyrotoxicosis, or known hypersensitivity to the active substance or to any of the excipients.

Methylphenidate is contraindicated in concomitant use, or use within the last two weeks, of MAO inhibitors.

Warnings: Equasym should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.

Clinical experience suggests that Equasym may exacerbate symptoms of behavioural disturbance and thought disorder in psychotic children.

Chronic abuse of Equasym 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.

Whether treatment with methylphenidate during childhood does increase the likelihood of addiction for substances in later life is debated.

Precautions: Treatment with Equasym is not indicated in all cases of Attention-Deficit-Hyperactivity disorders, and should be considered only after detailed history taking and evaluation. The decision to prescribe Equasym should depend on an assessment of the severity and persistence of symptoms and their appropriateness to the child's age and not simply on the presence of one or more abnormal behavioural characteristics. Where these symptoms are associated with acute stress reactions, treatment with Equasym is usually not indicated.

Reduced weight gain and growth retardation have been reported with the long term use of stimulants in children. Careful monitoring of growth is recommended during extended treatment with methylphenidate. Usually patients catch up when treatment is discontinued. Whether drug holidays are beneficial in this respect is debated by experts.

Blood pressure should be monitored at appropriate intervals in all patients taking Equasym.

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

Equasym should be used with caution in patients with epilepsy as clinical experience has shown that it can cause an increase in seizure frequency in a small number of patients. If seizure frequency rises, methylphenidate should be discontinued.

The long term safety and efficacy profiles of methylphenidate are not fully known. Patients requiring long term therapy should therefore be carefully monitored and complete and differential blood counts and a platelet count performed periodically.

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

In theory, there is a possibility that the clearance of methylphenidate might be affected by urinary pH, either being increased with acidifying agents or decreased with alkalising agents. This should be considered when methylphenidate is given in combination with agents that alter urinary pH.

This medicinal product contains lactose. Therefore, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Females of child-bearing potential should not use methylphenidate unless clearly necessary (see section 4.6, Pregnancy and Lactation,- (Section 5.3, Preclinical Safety Data).

Human pharmacological studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, some anticonvulsants (phenobarbitone, phenytoin, primidone), phenylbutazone and tricyclic antidepressants. The dosage of these drugs may have to be reduced. Equasym should be used cautiously in patients being treated with pressor agents. Equasym should not be used in patients being treated (currently or within the last 2 weeks) with MAO inhibitors.

Methylphenidate may also decrease the antihypertensive effect of guanethidine.

Alcohol may exacerbate the CNS adverse reactions of psychoactive drugs, including methylphenidate. It is therefore advisable for patients to abstain from alcohol during treatment.

There are no adequate data from the use of methylphenidate in pregnant women.

Studies in animals have shown reproductive toxicity (teratogenic effects) of methylphenidate (see Section 5.3 Preclinical Safety Data). The potential risk for humans is unknown.

Methylphenidate should not be used during pregnancy unless clearly necessary.

It is not known whether methylphenidate or its metabolites pass into breast milk but for safety reasons breast-feeding mothers should not use Equasym.

Equasym may cause dizziness and drowsiness. It is therefore advisable to exercise caution when driving, operating machinery or engaging in other potentially hazardous activities.

Frequency estimate: very common 10%; common 1% to <10%; uncommon 0.1% to <1%; rare 0.01% to <0.1%; very rare <0.01%.

Nervousness and insomnia are very common adverse reactions occurring at the beginning of treatment but can usually be controlled by reducing the dosage and/or omitting the afternoon or evening dose.

Decreased appetite is also common but usually transient.

Central and peripheral nervous system:

Common: Headache, drowsiness, dizziness, dyskinesia, irritability.

Rare: Difficulties in visual accommodation, and blurred vision.

Very rare: Hyperactivity, convulsions, muscle cramps, choreo-athetoid movements, tics or exacerbation of pre-existing tics, and Tourette's syndrome have been reported. Isolated cases of toxic psychosis (some with visual and tactile hallucinations), transient depressed mood, cerebral arteritis and/or occlusion.

Very rare reports of poorly documented neuroleptic malignant syndrome (NMS) have been received. In most of these reports patients were also receiving other medications. It is uncertain what role methylphenidate played in these cases.

Gastrointestinal tract:

Common: Abdominal pain, nausea and vomiting. These usually occur at the beginning of treatment and may be alleviated by concomitant food intake. Dry mouth.

Very rare: Abnormal liver function, ranging from transaminase elevation to hepatic coma.

Cardiovascular system:

Common: Tachycardia, palpitations, arrhythmias, changes in blood pressure and heart rate (usually an increase).

Rare: Angina pectoris.

Skin and appendages

Common: Rash, pruritus, urticaria, fever, arthralgia, scalp hair loss.

Very rare: Thrombocytopenic purpura, exfoliative dermatitis and erythema multiforme.

Blood:

Very rare: Leucopenia, thrombocytopenia, anaemia.

Miscellaneous:

Rare: Reduced weight gain and growth retardation during prolonged use with stimulants in children have been observed.

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 Equasym overdosage.

Management consists of appropriate supportive measures, preventing self-injury and protecting the patient from external stimuli that would aggravate over-stimulation already present. If the signs and symptoms are not too severe and the patient is conscious, gastric contents may be evacuated by induction of vomiting or gastric lavage. In the presence of severe intoxication, a carefully titrated dose of a shortacting barbiturate 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 for hyperpyrexia.

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

Pharmacotherapeutic group: Psychoanaleptics, Psychostimulants and Nootropics, Centrally acting Sympathomimetics, ATC code: N06B A04.

Mode of action: Methylphenidate is a CNS stimulant. The mode of action is not completely understood. Methylphenidate is an indirect sympatheticomimetic. The pharmacological properties are amphetamine-like.

MAO-enzyme inhibition may result in an increased catecholamine concentration.

Absorption: The active substance methylphenidate hydrochloride is rapidly and almost completely absorbed from the tablets. Owing to extensive firstpass metabolism its systemic availability amounts to only 30% (11-51%) of the dose. Ingestion together with food accelerates its absorption, but has no influence on the amount absorbed. Peak plasma concentrations of approximately 40 nmol/litre (11 ng/ml) are attained, on average, 1-2 hours after administration of 0.30 mg/kg. The peak plasma concentrations, however, show considerable intersubject variability. The area under the plasma concentration curve (AUC), as well as the peak plasma concentration, is proportional to the dose.

Distribution: In the blood, methylphenidate and its metabolites become distributed in the plasma (57%) and the erythrocytes (43%). Methylphenidate and its metabolites have a low plasma proteinbuilding rate (1033%). The apparent distribution volume has been calculated as 13.1 litres/kg.

Biotransformation: Biotransformation of methylphenidate is rapid and extensive. Peak plasma concentrations of 2-phenyl -2-piperidyl acetic acid (PPAA) are attained approximately 2 hours after administration of methylphenidate and are 30 - 50 times higher than those of the unchanged substance. The half-life of PPAA is roughly twice as long as that of methylphenidate, and the mean systemic clearance is 0.17 litres/h/kg. Only small amounts of hydroxylated metabolites (e.g. hydroxymethylphenidate and hydroxyritalinic acid) are detectable. Therapeutic activity seems to be principally due to the parent compound.

Elimination: Methylphenidate is eliminated from the plasma with a mean halflife of 2 hours, and the calculated mean systemic clearance is 10 litres/h/kg. Within 4896 hours 7897% of the dose administered is excreted in the urine and 13% in the faeces in the form of metabolites. Unchanged methylphenidate appears in the urine only in small quantities (<1%). The bulk of the dose is excreted in the urine as 2phenyl2piperidyl acetic acid (PPAA, 6086%).

Characteristics in patients: There are no apparent differences in the pharmacokinetic behaviour of methylphenidate in hyperactive children and healthy adult volunteers.

Elimination data from patients with normal renal function suggest that renal excretion of the unchanged methylphenidate would hardly be diminished at all in the presence of impaired renal function. However, renal excretion of PPAA may be reduced.

There is evidence that methylphenidate may be a teratogen in two species. Spina bifida and limb malformations have been reported in rabbits whilst in the rat, equivocal evidence of induction of abnormalities of the vertebrae was found.

Methylphenidate did not affect reproductive performance or fertility at low multiples of the clinical dose.

In life-time rat and mouse carcinogenicity studies, increased numbers of malignant liver tumours were noted in male mice only. The significance of this finding to humans is unknown.

Anhydrous Lactose

Magnesium Stearate

Microcrystalline Cellulose

Sodium Starch Glycollate

Not applicable.

3 years

Do not store above 25^oC. Store in the original package

PVC/Aluminium blisters of 30 tablets.

PVC/Aluminium blisters of 20 and 50 tablets.

Not all pack sizes may be marketed.

No special requirements.

Shire Pharmaceuticals Ireland Limited

5 Riverwalk

Citywest Business Campus

Dublin 24

Ireland

5 mg: 27303/001, 10 mg: 27303/002, 20 mg: 27303/003

22 February 2000 / 15 June 2009

17 June 2009