CONCERTA^® XL 27 mg prolonged-release tablets.

One prolonged release tablet contains 27 mg of methylphenidate hydrochloride.

Excipients: contains 4.94mg lactose.

For a full list of excipients, see section 6.1.

Prolonged-release Tablet.

Capsule-shaped grey tablet with “alza 27” printed on one side in black ink.

CONCERTA^® XL is indicated as part of a comprehensive treatment programme for Attention Deficit Hyperactivity Disorder (ADHD) in children (over 6 years of age) and adolescents when remedial measures alone prove insufficient. Diagnosis must be made according to DSM-IV criteria or the guidelines in ICD-10 and should be based on a complete history and evaluation of the patient. The specific aetiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and special psychological, educational, and social resources. Learning may or may not be impaired. Medicinal product treatment may not be necessary for all children with this syndrome. Therefore CONCERTA^® XL 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.

Use of CONCERTA^® XL should be limited to patients requiring a product with effects lasting through the day to the evening when taken in the morning. A comprehensive treatment programme for the treatment of ADHD should include other measures (psychological, educational, social) for patients with this disorder. Stimulants are not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential, and psychosocial intervention is often helpful.

Adults: Not applicable.

Elderly: Not applicable.

Children (under 6 years): The safety and efficacy of CONCERTA XL in children under 6 years of age have not been established. Therefore, CONCERTA XL should not be used in children under 6 years of age.

Children (over 6 years of age) and Adolescents: CONCERTA^® XL is administered orally once daily in the morning.

CONCERTA^® XL must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed (see section 4.4.).

CONCERTA^® XL may be administered with or without food (see section 5.2.).

Treatment must be initiated under the supervision of a specialist conversant with childhood and/or adolescence behavioural disorders.

Dosage should be individualised according to the needs and responses of the patient.

Dosage may be adjusted in 18 mg increments to a maximum of 54 mg/day taken once daily in the morning. A 27 mg dosage strength is available for those who wish to prescribe between the 18 mg and 36 mg dosages. In general, dosage adjustment may proceed at approximately weekly intervals.

Patients New to Methylphenidate: Clinical experience with CONCERTA^® XL is limited in these patients (see section 5.1). CONCERTA^® XL may not be indicated in all children with ADHD syndrome. Lower doses of short-acting methylphenidate formulations may be considered sufficient to treat patients 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 CONCERTA^® XL for patients who are not currently taking methylphenidate, or for patients who are on stimulants other than methylphenidate, is 18 mg once daily.

Patients Currently Using Methylphenidate: The recommended dose of CONCERTA^® XL for patients who are currently taking methylphenidate three times daily at doses of 15 to 45 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 CONCERTA^® XL

Daily dosage above 54 mg is not recommended.

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

Maintenance/Extended Treatment: The long-term use of methylphenidate has not been systematically evaluated in controlled trials. The physician who elects to use CONCERTA^® XL for extended periods 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. Improvement may be sustained when the medicinal product is either temporarily or permanently discontinued.

Dose Reduction and Discontinuation: If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the medicinal product should be discontinued. Medicinal product treatment is usually discontinued during or after puberty.

Renal or hepatic impairment: There is no experience with the use of CONCERTA XL in patients with renal insufficiency or hepatic insufficiency (see section 5.2).

CONCERTA^® XL is contraindicated:

• in patients with hypersensitivity to the active substance or to any other excipients;

• in patients with marked anxiety and tension, since the active ingredient may aggravate these symptoms;

• in patients with glaucoma;

• in patients with a family history or diagnosis of Tourette's syndrome;

• in combination with non-selective, irreversible monoamine oxidase inhibitors (MAO), and also within a minimum of 14 days following discontinuation of a non-selective, irreversible MAO inhibitor (hypertensive crises may result) (see section 4.5.)

• in patients with hyperthyroidism;

• in patients with severe angina pectoris;

• in patients with cardiac arrhythmias;

• in patients with severe hypertension;

• in patients who currently exhibit severe depression, anorexia nervosa, psychotic symptoms or suicidal tendency, since the active ingredient might worsen these conditions;

• in patients with known drug dependence or alcoholism;

• in patients during pregnancy (see sections 4.6. and 5.3.).

Pre-existing structural cardiac abnormalities

Sudden death has been reported in association with the use of stimulants of the central nervous system at usual doses in children with structural cardiac abnormalities. Although some structural cardiac abnormalities alone may carry an increased risk of sudden death, stimulant products are not recommended in children or adolescents with known structural cardiac abnormalities.

Hypertension and other cardiovascular conditions

Use cautiously in patients with hypertension. Blood pressure should be monitored at appropriate intervals in patients taking CONCERTA^® XL, especially patients with hypertension. In the laboratory classroom clinical trials, both CONCERTA^® XL and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. Therefore, caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate.

Use in children under 6 years of age

CONCERTA^® XL should not be used in children under 6 years old. The safety and efficacy of CONCERTA^® XL in this age group have not been established.

Potential for gastrointestinal obstruction

Because the CONCERTA^® XL 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 medicinal products in nondeformable prolonged-release formulations.

Due to the prolonged-release design of the tablet, CONCERTA^® XL should only be used in patients who are able to swallow the tablet whole. Patients should be informed that CONCERTA^® XL must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the active ingredient at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

Choice of methylphenidate formulation

The choice between treatment with either CONCERTA^® XL or an immediate release formulation, containing methylphenidate, will have to be decided by the treating physician on an individual basis and depends on the intended duration of effect.

Tics

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Therefore, clinical evaluation for tics in children should precede use of stimulant medication. Family history should be assessed.

Fatigue

It should not be used for the prevention or treatment of normal fatigue states.

Psychosis/Mania

Clinical experience suggests that in psychotic patients, administration of methylphenidate may exacerbate symptoms of behaviour disturbance and thought disorder.

Psychotic (e.g., hallucinations) or manic symptoms have been reported in patients without a prior history of psychotic illness or mania during treatment with CONCERTA^® XL at usual doses. If such symptoms occur, consideration should be given to a possible causal role of CONCERTA^® XL and discontinuation of treatment may be appropriate (see Section 4.8).

Drug dependence

CONCERTA^® XL should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

Seizures

There is some clinical evidence that methylphenidate may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in absence of history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the medicinal product should be discontinued.

Aggression

Patients beginning treatment with CONCERTA^® XL should be monitored for the appearance or worsening of aggressive behaviour. Aggression is frequently associated with ADHD; however, emergence or worsening of aggression has been reported during treatment with CONCERTA^® XL (see Section 4.8).

Haematological monitoring

Periodic full blood count, differential, and platelet counts are advised during prolonged therapy.

Visual disturbance

Symptoms of visual disturbances have been encountered in rare cases.

Difficulties with accommodation and blurring of vision have been reported.

Long term suppression of growth

Sufficient data on the safety of long-term use of methylphenidate in children are not yet available. Although a causal relationship has not been established, suppression of growth (ie, weight gain, and/or height) has been reported with the long-term use of stimulants in children. Therefore, patients requiring long-term therapy should be carefully monitored. Patients who are not growing or gaining weight as expected should have their treatment interrupted temporarily.

Use in sports persons

Sport: This product contains methylphenidate which results in a positive result during drug testing.

Use of contraception

Females of child-bearing potential (females post-menarche) should use effective contraception.

Galactose intolerance

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

CONCERTA^® XL must not be used in patients being treated (currently or within the preceding 2 weeks) with non-selective, irreversible MAO inhibitors (see section 4.3).

Because of possible increases in blood pressure, CONCERTA^® XL should be used cautiously with vasopressor agents (see section 4.4).

Formal drug-drug interaction studies have not been performed with CONCERTA^® XL. Hence, the interaction potential is not fully elucidated. It is not known how methylphenidate may affect plasma concentrations of concomitantly administered medicinal products. Caution is recommended at combination of methylphenidate with other medicinal products, especially those with a narrow therapeutic window. Case reports have indicated that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these medicinal products may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma active ingredient concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.

Halogenated anaesthetics: There is a risk of sudden blood pressure increase during surgery. If surgery is planned, methylphenidate treatment should not be used on the day of surgery.

Alcohol may exacerbate the adverse CNS effect of psychoactive medicinal products, including CONCERTA^® XL. It is therefore advisable for patients to abstain from alcohol during treatment.

Pregnancy

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.). The potential risk for humans is unknown.

From observations in humans there are indications that amfetamines could be harmful to the foetus.

CONCERTA^® XL is contraindicated during pregnancy (see section 4.3).

Females of child-bearing potential (females post-menarche) should use effective contraception.

Lactation

It is not known whether methylphenidate or its metabolites pass into breast milk, but for safety reasons breast-feeding mothers should not use CONCERTA^® XL.

No studies on the effects of CONCERTA^® XL on the ability to drive and use machines have been performed. However, CONCERTA^® XL may cause dizziness. It is therefore advisable to exercise caution when driving, operating machinery, or engaging in other potentially hazardous activities.

The most commonly reported adverse drug reaction is headache occurring in approximately 13% of patients.

Frequency estimate: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1000 to < 1/100); rare ( 1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

¹Reports of suicidal ideation and/or suicide attempt have been received in patients treated with CONCERTA^® XL. The role of CONCERTA^® XL in these cases is uncertain.

Undesirable effects noted with other methylphenidate formulations:

In addition to the above reactions observed with CONCERTA^® XL, the following adverse reactions have been noted with the use of other methylphenidate products:

Nervous system disorders: Choreoathetoid movements, Tourette's syndrome, poorly documented neuroleptic malignant syndrome (NMS).

Hepatobiliary disorders: Hepatic coma.

Vascular disorders: Cerebral arteritis, and/or occlusion.

Miscellaneous: Growth retardation during prolonged use in children.

The prolonged release of methylphenidate from CONCERTA^® XL should be considered when treating patients with overdose.

Signs and Symptoms: Signs and symptoms of acute methylphenidate overdose, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: 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.

Recommended Treatment: Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. 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. 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 CONCERTA^® XL overdose has not been established.

Pharmacotherapeutic group: centrally acting sympathomimetics: ATC code: N06BA04

Methylphenidate HCl is a mild central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of noradrenaline and dopamine into the presynaptic neurone and increase the release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.

In the pivotal clinical studies, CONCERTA^® XL was assessed in 321 patients already stabilised with immediate release preparations (IR) of methylphenidate and in 95 patients not previously treated with IR preparations of methylphenidate.

Clinical studies showed that the effects of CONCERTA^® XL were maintained until 12 hours after dosing when the product was taken once daily in the morning.

Absorption: Methylphenidate is readily absorbed. Following oral administration of CONCERTA^® XL to adults the drug overcoat dissolves, providing an initial maximum active ingredient concentration at about 1 to 2 hours. The methylphenidate contained in the two internal drug layers is gradually released over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours, after which plasma levels of methylphenidate gradually decrease. CONCERTA^® XL taken once daily minimises the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. The extent of absorption of CONCERTA^® XL once daily is generally comparable to conventional immediate release preparations.

Following the administration of CONCERTA^® XL 18 mg once daily in 36 adults, the mean pharmacokinetic parameters were: C_max 3.7 ± 1.0 (ng/mL), T_max 6.8 ± 1.8 (h), AUCinf 41.8 ± 13.9 (ng.h/mL), and t_½ 3.5 ± 0.4 (h).

No differences in the pharmacokinetics of CONCERTA^® XL were noted following single and repeated once daily dosing, indicating no significant active ingredient accumulation. The AUC and t_1/2 following repeated once daily dosing are similar to those following the first dose of CONCERTA^® XL 18 mg.

Following administration of CONCERTA^® XL in single doses of 18, 36, and 54 mg/day to adults, C_max and AUC_(0-inf) of methylphenidate were proportional to dose.

Distribution: Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The half-life of methylphenidate in adults following oral administration of CONCERTA^® XL was approximately 3.5 h. The rate of protein binding of methylphenidate and of its metabolites is approximately 15%. The apparent volume of distribution of methylphenidate is approximately 13 litres/kg.

Metabolism: In humans, methylphenidate is metabolised primarily by de-esterification to alpha-phenyl-piperidine acetic acid (PPA, approximately 50 fold the level of the unchanged substance) which has little or no pharmacologic activity. In adults the metabolism of CONCERTA^® XL once daily as evaluated by metabolism to PPA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once daily doses of CONCERTA^® XL is similar.

Excretion: The elimination half-life of methylphenidate in adults following administration of CONCERTA^® XL was approximately 3.5 hours. After oral administration, about 90% of the dose is excreted in urine and 1 to 3% in faeces, as metabolites within 48 to 96 hours. Small quantities of unchanged methylphenidate are recovered in urine (less than 1%). The main urinary metabolite is alpha-phenyl-piperidine acetic acid (60-90%).

After oral dosing of radiolabelled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose.

Food Effects: In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of CONCERTA^® XL when administered after a high fat breakfast on an empty stomach.

Special Populations

Gender: In healthy adults, the mean dose-adjusted AUC_(0-inf) values for CONCERTA^® XL were 36.7 ng.h/mL in men and 37.1 ng.h/mL in women, with no differences noted between the two groups.

Race: In healthy adults receiving CONCERTA^® XL, dose-adjusted AUC_(0-inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.

Age: The pharmacokinetics of CONCERTA^® XL has not been studied in children younger than 6 years of age. In children 7-12 years of age, the pharmacokinetics of CONCERTA^® XL after 18, 36 and 54 mg were (mean±SD): C_max 6.0±1.3, 11.3±2.6, and 15.0±3.8 ng/mL, respectively, T_max 9.4±0.02, 8.1±1.1, 9.1±2.5 h, respectively, and AUC_0-11.5 50.4±7.8, 87.7±18.2, 121.5±37.3 ng.h/mL, respectively.

Renal Insufficiency: There is no experience with the use of CONCERTA^® XL in patients with renal insufficiency. After oral administration of radiolabelled methylphenidate in humans, methylphenidate was extensively metabolised and approximately 80% of the radioactivity was excreted in the urine in the form of PPA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of CONCERTA^® XL.

Hepatic Insufficiency: There is no experience with the use of CONCERTA^® XL in patients with hepatic insufficiency.

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 (2-5 times) of the therapeutic human dose.

There was no evidence of carcinogenicity in the rat. In mice, methylphenidate caused an increase in hepatocellular adenomas, in animals of both sexes and, in males only, hepatoblastomas. In the absence of exposure data, the significance of these findings to humans is not known.

The weight of evidence from the genotoxicity studies reveals no special hazard for humans.

Butylhydroxytoluene (E321)

Cellulose acetate

Hypromellose (E646)

Phosphoric acid concentrated

Poloxamer 188

Polyethylene oxides 200K and 7000K

Povidone K29-32

Sodium chloride

Stearic acid

Succinic acid

Iron oxide black (E172)

Iron oxide red(E172)

Iron oxide yellow (E172).

Film Coat:

Iron oxide black(E172)

Hypromellose (E464)

Lactose monohydrate

Titanium dioxide (E171)

Triacetin.

Clear Coat:

Carnauba wax

Hypromellose (E464)

Macrogol 400

Printing Ink:

Iron oxide black (E172)

Hypromellose (E646)

Propylene glycol.

Not applicable.

2 years

Keep the bottle tightly closed in order to protect from moisture.

High-density polyethylene (HDPE) bottle with a child-resistant polypropylene closure with one or two silica gel desiccant pouches enclosed.

28 or 30 prolonged-release tablets.

Not all pack sizes may be marketed.

No special requirements.

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PL 00242/0400

09/03/2007

4^th September 2008