Methylphenidate retard mylan

Overdose

When treating patients with overdose, allowances must be made for the delayed release of methylphenidate from formulations with extended durations of action.

Signs and Symptoms

Acute overdose, mainly due to overstimulation of the central and sympathetic nervous systems, may result in vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.

Treatment

There is no specific antidote to methylphenidate overdosage.

Treatment consists of appropriate supportive measures.

The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. The efficacy of activated charcoal has not been established.

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

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

Contraindications

QuilliChew ER is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of QuilliChew ER. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products.

QuilliChew ER is contraindicated during concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (MAOI), because of the risk of hypertensive crisis.

Methylphenidate Retard Mylan is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of Methylphenidate Retard Mylan. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products.

Methylphenidate Retard Mylan is contraindicated during concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (MAOI), because of the risk of hypertensive crisis.

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- Glaucoma

- Phaeochromocytoma

- During treatment with non-selective, irreversible monoamine oxidase (MAO) inhibitors, or within a minimum of 14 days of discontinuing those drugs, due to the risk of hypertensive crisis

- 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

Incompatibilities

Not applicable.

Undesirable effects

The following are discussed in more detail in other sections of the labeling:

• Known hypersensitivity to methylphenidate products or other ingredients of QuilliChew ER
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors
• Drug Dependence
• Serious Cardiovascular Reactions
• Blood Pressure and Heart Rate Increases
• Psychiatric Adverse Reactions
• Priapism
• Peripheral Vasculopathy, including Raynaud's phenomenon
• Long-Term Suppression of Growth
• Risks in Phenylketonuria

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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.

Commonly reported (≥ 2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: appetite decreased, weight decreased, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, blood pressure increased, heart rate increased, tachycardia, palpitations, hyperhidrosis, and pyrexia.

There is limited experience with QuilliChew ER in controlled trials. The safety data in this section is based on data from a laboratory classroom study conducted in 90 pediatric subjects (ages 6 to 12 years) with ADHD. The study consisted of a 6-week dose optimization period, followed by a randomized, double-blind, parallel group treatment period with the individually optimized dose of QuilliChew ER or placebo.

The most common (≥ 2% in the QuilliChew ER group and greater than placebo) adverse reactions reported in the double-blind, randomized, placebo-controlled phase in patient optimized to doses of QuilliChew ER 20 to 60 mg/day are described in Table 1.

Table 1: Common Adverse Reactions Occurring in ≥ 2% of Subjects on QuilliChew ER and Greater than Placebo During the Double-Blind Period of the ADHD Laboratory Classroom Study

The following adverse reactions have been identified during post-approval use of methylphenidate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are as follows:

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole

Eye Disorders: Diplopia, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Hyperpyrexia

Hepatobiliary Disorders: Severe hepatocellular injury

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC

Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs

Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Libido changes, Mania

Urogenital System: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders: Raynaud's phenomenon

The following are discussed in more detail in other sections of the labeling:

• Known hypersensitivity to methylphenidate products or other ingredients of Methylphenidate Retard Mylan
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors
• Drug Dependence
• Serious Cardiovascular Reactions
• Blood Pressure and Heart Rate Increases
• Psychiatric Adverse Reactions
• Priapism
• Peripheral Vasculopathy, including Raynaud's phenomenon
• Long-Term Suppression of Growth
• Risks in Phenylketonuria

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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.

Commonly reported (≥ 2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: appetite decreased, weight decreased, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, blood pressure increased, heart rate increased, tachycardia, palpitations, hyperhidrosis, and pyrexia.

There is limited experience with Methylphenidate Retard Mylan in controlled trials. The safety data in this section is based on data from a laboratory classroom study conducted in 90 pediatric subjects (ages 6 to 12 years) with ADHD. The study consisted of a 6-week dose optimization period, followed by a randomized, double-blind, parallel group treatment period with the individually optimized dose of Methylphenidate Retard Mylan or placebo.

The most common (≥ 2% in the Methylphenidate Retard Mylan group and greater than placebo) adverse reactions reported in the double-blind, randomized, placebo-controlled phase in patient optimized to doses of Methylphenidate Retard Mylan 20 to 60 mg/day are described in Table 1.

Table 1: Common Adverse Reactions Occurring in ≥ 2% of Subjects on Methylphenidate Retard Mylan and Greater than Placebo During the Double-Blind Period of the ADHD Laboratory Classroom Study

The following adverse reactions have been identified during post-approval use of methylphenidate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are as follows:

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole

Eye Disorders: Diplopia, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Hyperpyrexia

Hepatobiliary Disorders: Severe hepatocellular injury

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC

Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs

Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Libido changes, Mania

Urogenital System: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders: Raynaud's phenomenon

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

Frequency estimate:

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

†Frequency derived from clinical trials in children and adolescent and reported at a higher frequency in clinical trials in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Preclinical safety data

Carcinogenicity

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.

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

Pregnancy-embryonal/foetal development

Methylphenidate is not considered to be teratogenic in rats and rabbits. Foetal toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.

Therapeutic indications

QuilliChew ER is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

Methylphenidate Retard Mylan is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

Attention-Deficit/Hyperactivity Disorder (ADHD)

Concerta XL is indicated as part of a comprehensive treatment programme for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. Treatment must be under the supervision of a specialist in childhood behavioural disorders. Diagnosis should be made according to the current DSM criteria or ICD guidelines and should be based on a complete history and evaluation of the patient. Diagnosis cannot be made solely on the presence of one or more symptom.

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.

Concerta XL treatment is not indicated in all children with ADHD and the decision to use the drug 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. The use of methylphenidate should always be used in this way according to the licensed indication and according to prescribing/diagnostic guidelines.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: centrally acting sympathomimetics: ATC code: N06BA04

Mechanism of action

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.

Clinical efficacy and safety

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.

Eight hundred ninety-nine (899) adults with ADHD aged 18 to 65 years were evaluated in three double-blind, placebo-controlled studies of 5 to 13 weeks duration. Some short-term efficacy has been demonstrated for Concerta XL in a dosage range of 18 to 72 mg/day, but this has not been consistently shown beyond 5 weeks. In one study, in which response was defined as at least a 30% reduction from baseline in Conners' Adult ADHD Rating Scales (CAARS) ADHD Symptoms total score at Week 5 (endpoint) and analysed assuming subjects with missing data at their final visit were non-responders, a significantly higher proportion of patients responded to treatment with Concerta XL at doses of 18, 36, or 72 mg/day compared to placebo. In the two other studies, when analysed assuming subjects with missing data at their final visit were non-responders, there were numerical advantages for Concerta XL compared to placebo but a statistically significant difference in the proportion of patients meeting predefined response criteria was not demonstrated between Concerta XL and placebo.

Pharmacokinetic properties

Following a single oral dose of 40 mg QuilliChew ER under fasting conditions, plasma methylphenidate reached maximal concentration (Cmax) at a median time of 5 hours after dosing. Compared to an immediate-release formulation of methylphenidate chewable tablet (40 mg in 2 equal doses of 20 mg, 6 hours apart), methylphenidate mean peak concentration and exposure (AUCinf) was about 20% and 11% lower, respectively, after single dose administration of 40 mg QuilliChew ER (Figure 2).

Figure 2: Mean Methylphenidate Plasma Concentration-Time Profiles After Administration of 40 mg QuilliChew ER or Methylphenidate Immediate-Release Chewable Tablets (IRCT, 2 Equal Doses of 20 mg, 6 Hours Apart) Under Fasted Conditions in Healthy Volunteers

Food Effect

High-fat meal had no effect on the time to peak concentration, and increased Cmax and systemic exposure (AUCinf) of methylphenidate by about 20% and 4%, respectively, after a single dose administration of 40 mg QuilliChew ER.

Plasma methylphenidate concentrations decline monophasically following oral administration of QuilliChew ER.

The mean plasma terminal elimination half-life of methylphenidate was about 5.2 hours in healthy volunteers following a single 40 mg dose administration.

Metabolism

In humans, methylphenidate is metabolized primarily via de-esterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity.

Excretion

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

At 40% alcohol concentration, there was about 90% release methylphenidate from QuilliChew ER 40 mg tablet within half an hour. The results with the 40 mg chewable tablet strength are considered representative of the other available tablet strengths.

Following a single oral dose of 40 mg Methylphenidate Retard Mylan under fasting conditions, plasma methylphenidate reached maximal concentration (Cmax) at a median time of 5 hours after dosing. Compared to an immediate-release formulation of methylphenidate chewable tablet (40 mg in 2 equal doses of 20 mg, 6 hours apart), methylphenidate mean peak concentration and exposure (AUCinf) was about 20% and 11% lower, respectively, after single dose administration of 40 mg Methylphenidate Retard Mylan (Figure 2).

Figure 2: Mean Methylphenidate Plasma Concentration-Time Profiles After Administration of 40 mg Methylphenidate Retard Mylan or Methylphenidate Immediate-Release Chewable Tablets (IRCT, 2 Equal Doses of 20 mg, 6 Hours Apart) Under Fasted Conditions in Healthy Volunteers

Food Effect

High-fat meal had no effect on the time to peak concentration, and increased Cmax and systemic exposure (AUCinf) of methylphenidate by about 20% and 4%, respectively, after a single dose administration of 40 mg Methylphenidate Retard Mylan.

Plasma methylphenidate concentrations decline monophasically following oral administration of Methylphenidate Retard Mylan.

The mean plasma terminal elimination half-life of methylphenidate was about 5.2 hours in healthy volunteers following a single 40 mg dose administration.

Metabolism

In humans, methylphenidate is metabolized primarily via de-esterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity.

Excretion

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

At 40% alcohol concentration, there was about 90% release methylphenidate from Methylphenidate Retard Mylan 40 mg tablet within half an hour. The results with the 40 mg chewable tablet strength are considered representative of the other available tablet strengths.

Absorption

Methylphenidate is readily absorbed. Following oral administration of Concerta XL to adults the drug overcoat dissolves, providing an initial maximum drug 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: Cmax 3.7 ± 1.0 (ng/mL), Tmax 6.8 ± 1.8 (h), AUCinf 41.8 ± 13.9 (ng.h/mL), and t½ 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 drug accumulation. The AUC and t1/2 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, Cmax and AUCinf 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.

Biotransformation

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.

Elimination

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 AUCinf 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 AUCinf 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): Cmax 6.0 ± 1.3, 11.3 ± 2.6, and 15.0 ± 3.8 ng/mL, respectively, Tmax 9.4 ± 0.02, 8.1 ± 1.1, 9.1 ± 2.5 h, respectively, and AUC0-11.5 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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

CNS stimulants, including QuilliChew ER, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy.

Stroke and myocardial infarction have occurred in adults treated with CNS stimulants at recommended doses. Sudden death has occurred in children and adolescents with structural cardiac abnormalities and other serious cardiac problems, and in adults taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during treatment with QuilliChew ER.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing QuilliChew ER. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulanttreated patients, compared to 0 in placebo-treated patients.

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including QuilliChew ER, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation of digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.

Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including QuilliChew ER. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Phenylalanine can be harmful to patients with phenylketonuria (PKU). QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame. Each 20 mg, 30 mg, and 40 mg extended-release chewable tablet contains 3 mg, 4.5 mg, and 6 mg phenylalanine, respectively. Before prescribing QuilliChew ER in patients with PKU, consider the combined daily amount of phenylalanine from all sources, including QuilliChew ER.

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Advise patients and their caregivers that QuilliChew ER is a federally controlled substance, and it can be abused and lead to dependence. Instruct patients that they should not give QuilliChew ER to anyone else. Advise patients to store QuilliChew ER in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired QuilliChew ER through a medicine take-back program if available.

Advise patients that QuilliChew ER should be taken by mouth once daily in the morning with or without food.

Advise patients, caregivers, and family members that there is a potential for serious cardiovascular risks including sudden death, myocardial infarction, and stroke with QuilliChew ER use. Instruct patients to contact a health care provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease.

Advise patients that QuilliChew ER can elevate blood pressure and heart rate.

Advise patients that QuilliChew ER, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania.

Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism.

• Instruct patients beginning treatment with QuilliChew ER about the risk of peripheral vasculopathy, including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.
• Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.
• Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking QuilliChew ER.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Advise patients, families, and caregivers that QuilliChew ER can cause slowing of growth and weight loss.

Advise patients to avoid alcohol while taking QuilliChew ER extended-release chewable tablets. Consumption of alcohol while taking QuilliChew ER may result in a more rapid release of the dose of methylphenidate.

Advise patients with phenylketonuria that QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame.

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the maximum recommended human dose on a mg/m basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.

Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 5 times the maximum recommended human dose on a mg/m² basis.

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in an in vivo mouse bone marrow micronucleus assay.

Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 8-fold the maximum recommended human dose on a mg/m² basis.

There are limited published studies and small case series that report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. There are clinical considerations. No teratogenic effects were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses 2 and 11 times, respectively, the maximum recommended human dose (MRHD). However, spina bifida was observed in rabbits at a dose 40 times the MRHD.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Fetal/Neonatal Adverse Reactions

CNS stimulant medications, such as QuilliChew ER, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.

Animal Data

In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m² basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m² basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m² basis).

Limited published literature reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QuilliChew ER and any potential adverse effects on the breastfed infant from QuilliChew ER or from the underlying maternal condition.

Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

The safety and effectiveness of QuilliChew ER have been established in pediatric patients ages 6 to 17 years. Use of QuilliChew ER in these age groups is based on one adequate and well-controlled clinical study in pediatric patients 6 to 12 years old, pharmacokinetic data in adolescents and adults, and safety information from other methylphenidate-containing products. The long-term efficacy of methylphenidate in pediatric patients has not been established. Safety and efficacy in pediatric patients below the age of 6 years have not been established.

Growth should be monitored during treatment with CNS stimulants, including QuilliChew ER. Children who are not growing or gaining weight as expected may need to have their treatment interrupted.

Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the maximum recommended human dose (MRHD) on a mg/m² basis.

In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When these animals were tested as adults (postnatal weeks 13–14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m² basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (12 times the MRHD on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

QuilliChew ER has not been studied in patients over the age of 65 years.

Included as part of the PRECAUTIONS section.

CNS stimulants, including Methylphenidate Retard Mylan, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy.

Stroke and myocardial infarction have occurred in adults treated with CNS stimulants at recommended doses. Sudden death has occurred in children and adolescents with structural cardiac abnormalities and other serious cardiac problems, and in adults taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during treatment with Methylphenidate Retard Mylan.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing Methylphenidate Retard Mylan. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulanttreated patients, compared to 0 in placebo-treated patients.

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including Methylphenidate Retard Mylan, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation of digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.

Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including Methylphenidate Retard Mylan. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Phenylalanine can be harmful to patients with phenylketonuria (PKU). Methylphenidate Retard Mylan extended-release chewable tablets contain phenylalanine, a component of aspartame. Each 20 mg, 30 mg, and 40 mg extended-release chewable tablet contains 3 mg, 4.5 mg, and 6 mg phenylalanine, respectively. Before prescribing Methylphenidate Retard Mylan in patients with PKU, consider the combined daily amount of phenylalanine from all sources, including QuilliChew ER.

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Advise patients and their caregivers that Methylphenidate Retard Mylan is a federally controlled substance, and it can be abused and lead to dependence. Instruct patients that they should not give Methylphenidate Retard Mylan to anyone else. Advise patients to store Methylphenidate Retard Mylan in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired Methylphenidate Retard Mylan through a medicine take-back program if available.

Advise patients that Methylphenidate Retard Mylan should be taken by mouth once daily in the morning with or without food.

Advise patients, caregivers, and family members that there is a potential for serious cardiovascular risks including sudden death, myocardial infarction, and stroke with Methylphenidate Retard Mylan use. Instruct patients to contact a health care provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease.

Advise patients that Methylphenidate Retard Mylan can elevate blood pressure and heart rate.

Advise patients that Methylphenidate Retard Mylan, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania.

Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism.

• Instruct patients beginning treatment with Methylphenidate Retard Mylan about the risk of peripheral vasculopathy, including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.
• Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.
• Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Methylphenidate Retard Mylan.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Advise patients, families, and caregivers that QuilliChew ER can cause slowing of growth and weight loss.

Advise patients to avoid alcohol while taking QuilliChew ER extended-release chewable tablets. Consumption of alcohol while taking Methylphenidate Retard Mylan may result in a more rapid release of the dose of methylphenidate.

Advise patients with phenylketonuria that Methylphenidate Retard Mylan extended-release chewable tablets contain phenylalanine, a component of aspartame.

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the maximum recommended human dose on a mg/m basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.

Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 5 times the maximum recommended human dose on a mg/m² basis.

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in an in vivo mouse bone marrow micronucleus assay.

Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 8-fold the maximum recommended human dose on a mg/m² basis.

There are limited published studies and small case series that report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. There are clinical considerations. No teratogenic effects were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses 2 and 11 times, respectively, the maximum recommended human dose (MRHD). However, spina bifida was observed in rabbits at a dose 40 times the MRHD.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Fetal/Neonatal Adverse Reactions

CNS stimulant medications, such as Methylphenidate Retard Mylan, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.

Animal Data

In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m² basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m² basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m² basis).

Limited published literature reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Methylphenidate Retard Mylan and any potential adverse effects on the breastfed infant from Methylphenidate Retard Mylan or from the underlying maternal condition.

Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

The safety and effectiveness of Methylphenidate Retard Mylan have been established in pediatric patients ages 6 to 17 years. Use of Methylphenidate Retard Mylan in these age groups is based on one adequate and well-controlled clinical study in pediatric patients 6 to 12 years old, pharmacokinetic data in adolescents and adults, and safety information from other methylphenidate-containing products. The long-term efficacy of methylphenidate in pediatric patients has not been established. Safety and efficacy in pediatric patients below the age of 6 years have not been established.

Growth should be monitored during treatment with CNS stimulants, including Methylphenidate Retard Mylan. Children who are not growing or gaining weight as expected may need to have their treatment interrupted.

Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the maximum recommended human dose (MRHD) on a mg/m² basis.

In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When these animals were tested as adults (postnatal weeks 13–14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m² basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (12 times the MRHD on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

Methylphenidate Retard Mylan has not been studied in patients over the age of 65 years.

Methylphenidate treatment is not indicated in all children with ADHD and the decision to use the drug 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.

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.4. for cardiovascular status, 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 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 child's condition (preferably during times of school holidays). Improvement may be sustained when the medicinal product is either temporarily or permanently discontinued.

Use in adults

Safety and efficacy have not been established for the initiation of treatment in adults or the routine continuation of treatment beyond 18 years of age. If treatment withdrawal has not been successful when an adolescent has reached 18 years of age continued treatment into adulthood may be necessary. The need for further treatment of these adults should be reviewed regularly and undertaken annually.

Use in the elderly

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

Use in children under 6 years of age

Methylphenidate should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.

Cardiovascular status

Patients who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden cardiac or unexplained death or malignant arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further specialist cardiac evaluation if initial findings suggest such history or disease. Patients who develop symptoms such as palpitations, exertional chest pain, unexplained syncope, dyspnoea or other symptoms suggestive of cardiac disease during methylphenidate treatment should undergo a prompt specialist cardiac evaluation.

Analyses of data from clinical trials of methylphenidate in children and adolescents with ADHD showed that patients using methylphenidate may commonly experience changes in diastolic and systolic blood pressure of over 10 mmHg relative to controls.

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.

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

Sudden death has been reported in association with the use of stimulants of the central nervous system at usual doses in children, some of whom had structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone may carry an increased risk of sudden death, stimulant products are not recommended in children or adolescents with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant medicine.

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

Cerebral vasculitis appears to be a very rare idiosyncratic reaction to methylphenidate exposure. There is little evidence to suggest that patients at higher risk can be identified and the initial onset of symptoms may be the first indication of an underlying clinical problem. Early diagnosis, based on a high index of suspicion, may allow the prompt withdrawal of methylphenidate and early treatment. The diagnosis should therefore be considered in any patient who develops new neurological symptoms that are consistent with cerebral ischemia during methylphenidate therapy. These symptoms could include severe headache, numbness, weakness, paralysis, and impairment of coordination, vision, speech, language or memory.

Treatment with methylphenidate is not contraindicated in patients with hemiplegic cerebral palsy.

Psychiatric disorders

Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. 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 children and adolescents without prior history of psychotic illness or mania can be caused by methylphenidate at usual doses. If manic or psychotic symptoms occur, consideration should be given to a possible causal role for methylphenidate, and discontinuation of treatment may be appropriate.

Aggressive or hostile behaviour

The emergence or worsening of aggression or hostility can be caused by treatment with stimulants. Aggression has been reported in patients treated with methylphenidate. 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. Family history should be assessed and clinical evaluation for tics or Tourette's syndrome in children 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. Methylphenidate is also associated with the worsening of pre-existing anxiety, agitation or tension, and anxiety led to discontinuation of methylphenidate in some patients. Clinical evaluation for anxiety, agitation or tension should precede use of methylphenidate and patients should be regularly monitored for the emergence or worsening of these symptoms during treatment, at every adjustment of dose and then at least every 6 months or every visit.

Forms of bipolar disorder

Particular care should be taken in using methylphenidate to treat ADHD in patients with comorbid bipolar disorder (including untreated Type I Bipolar Disorder or other forms of bipolar disorder) because of concern for possible precipitation of a mixed/manic episode in such patients.). Patients should be monitored for symptoms at every adjustment of dose, then at least every 6 months and at every visit.

Growth

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

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.

Seizures

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

Priapism

Prolonged and painful erections have been reported in association with methylphenidate products, mainly in association with a change in the methylphenidate treatment regimen. Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

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.

Excipients: 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.

Choice of methylphenidate formulation

The choice of formulation of methylphenidate-containing product will have to be decided by the treating specialist on an individual basis and depends on the intended duration of effect.

Drug screening

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

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.

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 drugs 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 drug 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.

Effects on ability to drive and use machines

Methylphenidate can cause dizziness, drowsiness and visual disturbances including difficulties with accommodation, diplopia and blurred vision. It may have a moderate influence on the ability to drive and use machines. Patients should be warned of these possible effects and advised that if affected, they should avoid potentially hazardous activities such as driving or operating machinery.

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

- The medicine is likely to affect your ability to drive

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

- It is an offence to drive while under the influence of this medicine.

Dosage (Posology) and method of administration

Prior to treating children, adolescents, and adults with CNS stimulants including QuilliChew ER, assess for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam).

Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for QuilliChew ER use.

The recommended starting dose of QuilliChew ER for patients 6 years and above is 20 mg once daily orally in the morning. The dose may be titrated up or down weekly in increments of 10 mg, 15 mg or 20 mg. The 10 mg and 15 mg doses can each be achieved by breaking in half the functionally scored 20 mg and 30 mg tablets, respectively. Daily doses above 60 mg have not been studied and are not recommended. As with any CNS stimulant, during titration of QuilliChew ER, the prescribed dose should be adjusted, if necessary, until a welltolerated, therapeutic dose is achieved.

Pharmacological treatment of ADHD may be needed for extended periods. Health care providers should periodically re-evaluate the long-term use of QuilliChew ER, and adjust dosage as needed.

QuilliChew ER should be orally administered once daily in the morning with or without food.

If switching from other methylphenidate products, discontinue that treatment, and titrate with QuilliChew ER using the above titration schedule.

Do not substitute for other methylphenidate products on a milligram-per-milligram basis, because of different methylphenidate base compositions and differing pharmacokinetic profiles.

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. QuilliChew ER should be periodically discontinued to assess the child's condition. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Prior to treating children, adolescents, and adults with CNS stimulants including Methylphenidate Retard Mylan, assess for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam).

Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for Methylphenidate Retard Mylan use.

The recommended starting dose of Methylphenidate Retard Mylan for patients 6 years and above is 20 mg once daily orally in the morning. The dose may be titrated up or down weekly in increments of 10 mg, 15 mg or 20 mg. The 10 mg and 15 mg doses can each be achieved by breaking in half the functionally scored 20 mg and 30 mg tablets, respectively. Daily doses above 60 mg have not been studied and are not recommended. As with any CNS stimulant, during titration of Methylphenidate Retard Mylan, the prescribed dose should be adjusted, if necessary, until a welltolerated, therapeutic dose is achieved.

Pharmacological treatment of ADHD may be needed for extended periods. Health care providers should periodically re-evaluate the long-term use of Methylphenidate Retard Mylan, and adjust dosage as needed.

Methylphenidate Retard Mylan should be orally administered once daily in the morning with or without food.

If switching from other methylphenidate products, discontinue that treatment, and titrate with Methylphenidate Retard Mylan using the above titration schedule.

Do not substitute for other methylphenidate products on a milligram-per-milligram basis, because of different methylphenidate base compositions and differing pharmacokinetic profiles.

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. Methylphenidate Retard Mylan should be periodically discontinued to assess the child's condition. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Treatment must be initiated under the supervision of a specialist in childhood and/or adolescent behavioural disorders.

Pre-treatment screening

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.

Ongoing monitoring

- 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 should be recorded at least 6 monthly with maintenance of a growth chart;

- 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.

Posology

Dose titration

Careful dose titration is necessary at the start of treatment with Concerta XL. Dose titration should be started at the lowest possible dose. A 27 mg dosage strength is available for those who wish to prescribe between the 18 mg and 36 mg dosages.

Other strengths of this medicinal product and other methylphenidate-containing products may be available.

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

The maximum daily dosage of Concerta XL is 54 mg.

Patients New to Methylphenidate: Clinical experience with Concerta XL is limited in these patients. 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

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

Long-term (more than 12 months) use 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. 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 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 child's condition (preferable during times of school holidays). Improvement may be sustained when the medicinal product is either temporarily or permanently discontinued.

Dose reduction and discontinuation

Treatment must be stopped if the symptoms do not improve after appropriate dosage adjustment over a one-month period. If paradoxical aggravation of symptoms or other serious adverse events occur, the dosage should be reduced or discontinued.

Adults

In adolescents whose symptoms persist into adulthood and who have shown clear benefit from treatment, it may be appropriate to continue treatment into adulthood. However, start of treatment with Concerta XL in adults is not appropriate.

Elderly

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

Children under 6 years of age

Methylphenidate should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.

Method of administration

Concerta XL must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.

Concerta XL may be administered with or without food.

Concerta XL is taken once daily in the morning.

Special precautions for disposal and other handling

No special requirements.