CONCERTA Extended-release tablet Ref.[50781] Active ingredients: Methylphenidate

Use with caution in the following circumstances

Depression and Psychosis

CONCERTA should not be used to treat severe depression or for the prevention or treatment of normal fatigue states.

Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. In the case of emergent psychiatric symptoms or exacerbation of pre-existing psychiatric disorders, methylphenidate should not be given unless the benefits outweigh the risks to the patient.

Development 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.

In psychotic patients administration of methylphenidate may exacerbate symptoms of behaviour disturbance and thought disorder.

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking or mania in patients without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate.

Suicidal tendency

Patients with emergent suicidal ideation or behaviour during treatment for ADHD should be evaluated immediately by their physician. Consideration should be given to the exacerbation of an underlying psychiatric condition and to a possible causal role of methylphenidate treatment. Treatment of an underlying psychiatric condition may be necessary and consideration should be given to a possible discontinuation of methylphenidate.

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 Depression and Psychosis above and section 4.2 Dose and method of administration). Patients should be monitored for symptoms at every adjustment of dose, then at least every 6 months and at every visit.

Tics and worsening of Tourette’s syndrome

Methylphenidate is associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported. It is recommended that the family history be assessed, and that the patient is clinically evaluated for tics or Tourette’s syndrome before initiating methylphenidate. Regular monitoring for the emergence or worsening of tics or Tourette’s syndrome during treatment with methylphenidate is recommended at every dose adjustment and every visit, and treatment discontinued if clinically appropriate.

Drug Dependence

Patients should be carefully monitored for the risk of diversion, misuse and abuse of methylphenidate. CONCERTA should be given cautiously to patients with a history of drug or alcohol dependence. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour.

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 nonstimulant treatment should be considered.

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.

Drug Screening

CONCERTA contains methylphenidate which may induce a false positive laboratory test for amphetamines, particularly with immunoassay screen test.

Potential for Gastrointestinal Obstruction

CONCERTA tablet is non-deformable and does not appreciably change in shape in the GIT. 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. Due to the prolonged-release design of the tablet, CONCERTA should only be used in patients who are able to swallow the tablet whole.

Sudden Death and Pre-existing Structural Cardiac Abnormalities

Although a causal relationship has not been established, sudden death has been reported in patients with structural cardiac abnormalities treated with ADHD drugs with stimulant effects. These treatments should be used with caution in patients with 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.

Hypertension and Cardiovascular Conditions

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.

In the laboratory clinical trials in children both CONCERTA 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. In placebo-controlled studies in adults, mean increases in resting pulse rate of approximately 4 to 6 bpm were observed with CONCERTA at endpoint vs. a mean change of roughly -2 to 3 bpm with placebo. Mean changes in blood pressure at endpoint ranged from about -1 to 1 mm Hg (systolic) and 0 to 1 mm Hg (diastolic) for CONCERTA and from -1 to 1 mm Hg (systolic) and -2 to 0 mm Hg (diastolic) for placebo. Therefore, caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate.

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.

The use of methylphenidate is contraindicated in certain pre-existing cardiovascular disorders unless specialist paediatric cardiac advice has been obtained

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 Contraindications for cerebrovascular conditions in which methylphenidate treatment in 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 requiring immediate medical attention (sometimes including surgical intervention, have been reported with methylphenidate products, including CONCERTA, in both paediatric and adult patients (see section 4.8 Undesirable effects). Priapism can develop after some time on methylphenidate, often subsequent to an increase in dose. Priapism has also appeared during a period of methylphenidate withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained erections or frequent and painful erections should seek immediate medical attention.

Cerebrovascular disorders

Cerebrovascular disorders (including cerebral vasculitis and cerebral hemorrhage) have been reported with the use of CONCERTA (see section 4.8 Undesirable effects). Consider cerebrovascular disorders as a possible diagnosis in any patient who develops new neurological symptoms that are consistent with cerebral ischemia during CONCERTA therapy. These symptoms could include severe headache, unilateral weakness or paralysis, and impairment of coordination, vision, speech, language, or memory. If a cerebrovascular disorder is suspected during treatment, discontinue CONCERTA immediately. Early diagnosis may guide subsequent treatment. In patients with pre-existing cerebrovascular disorders (e.g., aneurysm, vascular malformations/anomalies), treatment with CONCERTA is not recommended.

Aggression, anxiety and agitation

Aggressive behaviour, marked anxiety, or agitation are often observed in patients with ADHD, and have been reported in patients treated with CONCERTA (see section 4.8 Undesirable effects). Anxiety led to discontinuation of CONCERTA in some patients. It is recommended to monitor patients beginning treatment with CONCERTA for the appearance of, or worsening of, aggressive behaviour, marked anxiety, or agitation.

Haematologic Monitoring

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

Increased intraocular pressure and glaucoma

There have been reports of a transient elevation of intraocular pressure (IOP) associated with methylphenidate treatment. It is recommended to prescribe CONCERTA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Patients with a history of abnormally increased IOP or open-angle glaucoma, and patients at risk for acute angle-closure glaucoma (e.g., patients with significant hyperopia) must be closely monitored.

CONCERTA is not recommended in patients with acute angle-closure glaucoma.

Use in patients with renal impairment

There is no experience with the use of CONCERTA in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of CONCERTA.

Use in patients with hepatic impairment

There is no experience with the use of CONCERTA in patients with hepatic insufficiency.

Use in children

The safety and efficacy of CONCERTA in children under 6 years old have not been established.

Long-term use (more than 12 months) in children and adolescents: The safety and efficacy of long term use of methylphenidate has not been systematically evaluated in controlled trials. Methylphenidate treatment should not and need not, be indefinite. Methylphenidate treatment is usually discontinued during or after puberty. Patients on long-term therapy (i.e. over 12 months) must have careful ongoing monitoring according to the guidance under section 4.2 Dose and method of administration and section 4.4 Special warnings and precautions for use for hypertension and cardiovascular conditions, growth, 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) in children and adolescents with ADHD should periodically re-evaluate the long term usefulness of the drug for the individual patient with trial periods off medication to assess the patient’s functioning without pharmacotherapy. It is recommended that methylphenidate is de-challenged at least once yearly to assess the child’s condition (preferably during times of school holidays). Improvement may be sustained when the drug is either temporarily or permanently discontinued.

Growth: Moderately reduced weight gain and growth retardation have been reported with the long-term use of methylphenidate in children.

The effects of methylphenidate on final height and final weight are currently unknown and being studied.

Growth should be monitored during methylphenidate treatment: height, weight and appetite should be recorded at least 6 monthly with maintenance of a growth chart. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Use in the elderly

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

Pharmacokinetic interaction

It is not known how methylphenidate may effect plasma concentrations of concomitantly administered drugs. Therefore, caution is recommended at combining methylphenidate with other drugs, 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.

Pharmacodynamic interactions

Use with drugs that elevate blood pressure

Caution is advised in patients being treated with methylphenidate with any other drug that can also elevate blood pressure (see also sections on cardiovascular and cerebrovascular conditions in section 4.4 Special warnings and precautions for use).

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 Contraindications).

Anti-hypertensive drugs

Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. It is recommended to monitor blood pressure and adjust the dosage of the antihypertensive drug as needed (see section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Use with alcohol

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

Use with halogenated anaesthetics

Concomitant use of halogenated anaesthetics and CONCERTA may increase the risk of sudden blood pressure and heart rate increase during surgery. It is recommended to avoid use of CONCERTA in patients being treated with anaesthetics on the day of surgeryUse with domapinergic drugs

Caution is recommended when administering methylphenidate with dopaminergic drugs, including antipsychotics. Because a predominant action of methylphenidate is to increase extracelluar 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 serotonergic drugs

There have been reports of serotonin syndrome following coadministration of methylphenidate with serotonergic drugs. If concomitant use of CONCERTA with a serotonergic drug is warranted, prompt recognition of the symptoms of serotonin syndrome is important. CONCERTA must be discontinued as soon as possible if serotonin syndrome is suspected.

Use with antipsychotic drugs

Because a predominant action of methylphenidate is to increase extracellular dopamine levels, CONCERTA may be associated with pharmacodynamic interactions when co-administered with some antipsychotics. Caution is warranted in patients receiving both CONCERTA and an antipsychotic, as extrapyramidal symptoms could emerge when these drugs are administered concomitantly or when adjusting the dosage of one or both drugs.

Use in pregnancy

Category B3.

The safety of methylphenidate for use during human pregnancy has not been established, and no studies are available on the use of CONCERTA in pregnant women. There is a limited amount of data from the use of methylphenidate in pregnant women.

Medicines should only be prescribed in pregnancy when the expected benefits to the mother outweigh any potential risks to the mother and foetus. If possible, medicines should be used at the lowest effective dose for the shortest possible duration. Careful consideration and discussion of the risks and benefits of the medicines should be taken in the management of pregnant women or women intending to become pregnant. Women of child-bearing potential should be fully informed of the risks and benefits of the use of methylphenidate during pregnancy.

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

Oral administration of methylphenidate to rabbits during the period of organogenesis has produced teratogenic effects at doses of 200 mg/kg/day, associated with systemic exposure (plasma AUC) approximately 5-6 fold that in humans receiving the maximal recommended dose. The exposure at the no-effect dose in rabbits (60 mg/kg/day) was less than human exposure. Teratogenic effects were not seen in rats at oral methylphenidate doses up to 75 mg/kg/day, associated with systemic exposure of 21-25 fold that in humans receiving the maximal dose. Oral administration of methylphenidate to rats from early pregnancy until weaning was associated with maternal toxicity, reduced offspring weight and marginal alterations in neuromotor performance in offspring at a maternal dose of 30 mg/kg/day, approximately 3-6 fold the maximum recommended clinical dose on a mg/m² basis.

Breast-feeding

Methylphenidate has been detected in human milk. Based on 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. Caution should be exercised if CONCERTA is administered to a breast-feeding woman.

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.

Oral administration of methylphenidate to rats from early pregnancy until weaning was associated with maternal toxicity, reduced offspring weight and marginal alterations in neuromotor performance in offspring at a maternal dose of 30 mg/kg/day, approximately 3-6 fold the maximum recommended clinical dose on a mg/m² basis.

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.

Methylphenidate can cause dizziness, drowsiness and visual disturbances including difficulties with accommodation, diplopia and blurred vision and may impair the ability of the patient to operate potentially hazardous machinery or vehicles. Patients should be cautioned accordingly until they are reasonably certain that CONCERTA does not adversely affect their ability to engage in such activities.

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of methylphenidate based on the comprehensive assessment of the available adverse event information. A causal relationship with methylphenidate cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trial Data

Double-Blind Data – Adverse Drug Reactions Reported at ≥1% Frequency

Adverse Drug Reactions (ADRs) in either the paediatric or adult double-blind studies (Table 2 and Table 3) may be relevant for both patient populations.

Paediatric Patients

The safety of CONCERTA was evaluated in 639 paediatric patients (children and adolescents) with ADHD who participated in 4 placebo-controlled, double-blind clinical trials. The information presented in this section was derived from pooled data.

Adverse Drug Reactions (ADRs) reported by ≥1% of CONCERTA-treated children and adolescent subjects and more frequently than placebo in these trials are shown in Table 2.

Table 2. Adverse Drug Reactions Reported by ≥1% of CONCERTA-Treated Children and Adolescent Subjects and More Frequently than Placebo in 4 Placebo-Controlled, DoubleBlind Clinical Trials:

^* Terms of Initial insomnia (CONCERTA=0.6%) and Insomnia (CONCERTA=2.2%) are combined into Insomnia

The majority of ADRs were mild to moderate in severity.

Adult Patients

The safety of CONCERTA was evaluated in 905 adult subjects with ADHD who participated in 3 placebocontrolled, double-blind clinical trials. The information presented in this section was derived from pooled data.

Adverse Drug Reactions (ADRs) reported by ≥1% of CONCERTA-treated adult subjects in these trials are shown in Table 3.

Table 3. Adverse Drug Reactions Reported by ≥1% of CONCERTA-Treated Adult Subjects in 3 Placebo-Controlled, Double-Blind Clinical Trials:

The majority of ADRs were mild to moderate in severity.

Open-Label Data – Adverse Drug Reactions Reported at ≥1% Frequency

The safety of CONCERTA was evaluated in 3782 paediatric and adult subjects with ADHD who participated in 12 open-label clinical trials. The information presented in this section was derived from pooled data.

Adverse Drug Reactions (ADRs) reported by ≥1% of CONCERTA-treated subjects in these trials and not listed in Table 2 and Table 3 are shown in Table 4.

Table 4. Adverse Drug Reactions Reported by ≥1% of CONCERTA-Treated Subjects in 12 Open-Label Clinical Trials:

The majority of ADRs were mild to moderate in severity.

Double Blind and Open-Label Data – Adverse Drug Reactions Reported at <1% Frequency

Additional ADRs that occurred in <1% of CONCERTA-treated paediatric and adult subjects in the double-blind and open-label clinical datasets are listed in Table 5.

Table 5. Adverse Drug Reactions Reported by <1% of CONCERTA-Treated Pediatric and Adult Subjects in Either Double-Blind or Open-Label Clinical Trials:

The majority of ADRs were mild to moderate in severity.

Postmarketing Data

ADRs identified during postmarketing experience with CONCERTA are included in Table 6. The frequencies are provided according to the following convention: Very common ≥1/10, Common ≥1/100 and <1/10, Uncommon ≥1/1000 and <1/100, Rare ≥1/10000 and <1/1000, Very rare <1/10000, including isolated reports

Table 6. Adverse Drug Reactions Identified During Postmarketing Experience with CONCERTA by Frequency Category Estimated from Spontaneous Reporting Rates:

NEC = not elsewhere classified
^* The adverse reaction libido disorder includes terms apart from those associated with decreases in libido

Not applicable.