Concerta

Concerta

methylphenidate

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Methylphenidate HCl.
Description
Each extened-release tablet also contains the following excipients: Butylated hydroxytoluene, carnauba wax, cellulose acetate, hypromellose, lactose, phosphoric acid, poloxamer, polyethylene glycol, polyethylene oxides, povidone, propylene glycol, sodium chloride, stearic acid, succinic acid, synthetic iron oxides, titanium dioxide and triacetin.
Action
Pharmacology: Pharmacodynamics: Methylphenidate hydrochloride is a central nervous system stimulant. The mode of therapeutic action in ADHD is not known. Methylphenidate is thought to block the re-uptake of norepinephrine and dopamine into the presynaptic neuron 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.
Pharmacokinetics: Absorption: Methylphenidate is readily absorbed. Following oral administration of Concerta to adults, plasma methylphenidate concentrations increase rapidly reaching an initial maximum at about 1-2 hrs, then increase gradually over the next several hours. Peak plasma concentrations are achieved at about 6-8 hrs after which a gradual decrease in plasma levels of methylphenidate begins. Concerta once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate 3 times daily. The relative bioavailability of Concerta once daily and methylphenidate 3 times daily in adults is comparable.
The mean pharmacokinetic parameters in 36 adults following the administration of Concerta 18 mg once daily and methylphenidate hydrochloride 5 mg 3 times daily are summarized in Table 1.

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No differences in the pharmacokinetics of Concerta were noted following single and repeated once daily dosing indicating no significant drug accumulation. The AUC and half-life following repeated once daily dosing are similar to those following the 1st dose of Concerta.
Dose Proportionality: Following administration of Concerta in single doses of 18, 36 and 54 mg/day to healthy adults, Cmax and AUC(0-∞) of d-methylphenidate were proportional to the dose, whereas l-methylphenidate Cmax and AUC(0-∞) increased disproportionately with respect to dose. Following administration of Concerta, plasma concentrations of the l-isomer were approximately 1/40th the plasma concentrations of the d-isomer.
In healthy adults, single and multiple dosing of once daily Concerta doses from 54-144 mg/day resulted in linear and dose proportional increases in Cmax and AUC for total methylphenidate (MPH) and its major metabolite, (α)-phenylpiperidine acetic acid (PPAA). The single dose and steady-state (day 4) clearance and half-life parameters were similar, indicating that there was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54-144 mg/day, both after single dose and upon multiple dosing.
In a multiple-dose study in adolescent ADHD patients aged 13-16 years administered 18-72 mg/day of Concerta, mean Cmax and AUCτ of d- and total methylphenidate increased proportionally with respect to dose.
Distribution: Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The t½ of methylphenidate in adults following oral administration of Concerta was approximately 3.5 hrs.
Metabolism and Excretion: In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults, the metabolism of Concerta once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate 3 times daily. The metabolism of single and repeated once-daily doses of Concerta is similar.
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.
Food Effects: In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of Concerta when administered after a high-fat breakfast. There is no evidence of dose dumping in the presence or absence of food.
Special Populations: Gender: In healthy adults, the mean dose-adjusted AUC(0-∞) values for Concerta were 36.7 ng·hr/mL in men and 37.1 ng·hr/mL in women, with no differences noted between the 2 groups.
Race: In adults receiving Concerta, dose-adjusted AUC(0-∞) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.
Age: The pharmacokinetics of Concerta has not been studied in children <6 years.
Renal Insufficiency: 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.
Hepatic Insufficiency: There is no experience with the use of Concerta in patients with hepatic insufficiency.
Toxicology: Preclinical Safety Data: In a lifetime carcinogenicity study carried out in mice, methylphenidate hydrochloride 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 is considerably higher than the recommended human dose on a mg/kg basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumours. The mouse strain used is sensitive to the development of hepatic tumours and the significance of these results to humans is unknown.
A similar lifetime study in the rat at a methylphenidate hydrochloride dose of up to 45 mg/kg/day showed no evidence of carcinogenicity.
In a 24-week study in transgenic mouse strain p53+/-, there was no evidence of carcinogenicity methylphenidate hydrochloride at doses of up to 74 mg/kg/day.
No adverse toxicologic effects were seen in 2 separate 30-day oral dosing studies in dogs with Concerta at doses up to 72 mg/day (up to 8.6 mg/kg/day) and 144 mg/day (up to 22 mg/kg/day), respectively.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchange and chromosome aberrations were increased in an in vitro test on cultured ovary cells of Chinese hamster. Methylphenidate was negative in vivo in the mouse bone marrow micronucleus assay.
All other safety data relevant to the prescriber have been included in the appropriate section.
Indications/Uses
Treatment of attention deficit hyperactivity disorder (ADHD). The efficacy of Concerta in the treatment of ADHD was established in controlled trials of children and adolescents 6-17 years and adults 18-65 years who met DSM-IV criteria for ADHD.
Concerta should be used as a part of a comprehensive treatment program where remedial measures alone prove insufficient. A comprehensive treatment program for the treatment of ADHD may include other measures (psychological, educational, social) for patients with this disorder. Diagnosis must be made according to DSM-IV criteria or the guidelines in ICD-10 and should be based on a complete history and evaluation of the patient.
Concerta treatment is not indicated in all patients with ADHD and the decision to use the drug must be based on a very thorough assessment of the severity of the patient's symptoms. Stimulants are not intended for use in the patient who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful.
Specific etiology of this syndrome is unknown and there is no single diagnostic test. Adequate diagnosis requires the use of medical and special psychological, educational and social resources. Learning may or may not be impaired.
Dosage/Direction for Use
Administer orally once daily. As the effect has been shown to be present 12 hrs after dosing, Concerta should be taken once daily in the morning.
Concerta must be swallowed whole with the aid of liquid and must not be chewed, divided or crushed (see Precautions). It may be administered with or without food (see Pharmacokinetics under Actions).
Patients New to Methylphenidate: The recommended starting dose of Concerta for patients who are not currently taking methylphenidate, or stimulants other than methylphenidate, is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults.
Patients Currently Using Methylphenidate: The recommended dose of Concerta for patients who are currently taking methylphenidate 2 or 3 times daily, at doses of 10-60 mg/day, is provided in Table 2.

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Clinical judgment should be used when selecting the dose for patients currently taking methylphenidate in other regimens.
Dose Titration: Dosage should be individualized according to the needs and responses of the patient. Doses may be increased in 18-mg increments at weekly intervals. Daily dosages >54 mg in children, 72 mg in adolescents and 108 mg in adults have not been studied and are not recommended.
Maintenance/Extended Treatment: The long-term use of methylphenidate has not been systematically evaluated in controlled trials. The physician who elects to use Concerta for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient's functioning without pharmacotherapy.
Dose Reduction and Discontinuation: If paradoxical aggravation of symptoms or other adverse reactions occur, the dosage should be reduced, or if necessary, Concerta should be discontinued.
Children: Use of Concerta in patients <6 years has not been studied in controlled trials. Concerta should not be used in patients <6 years.
Elderly: Use of Concerta in the elderly patients >65 years has not been studied in controlled trials.
Overdosage
Symptoms: Signs and symptoms of Concerta overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: Vomiting, agitation, muscle twitching, convulsions, grand mal convulsion, confusional state, hallucination (auditory and/or visual), hyperhidrosis, headache, pyrexia, tachycardia, palpitations, increased heart rate, sinus arrhythmias, hypertension, mydriasis and dry mouth.
Treatment: Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for pyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Concerta overdosage has not been established.
The prolonged release of methylphenidate from Concerta should be considered when treating patients with overdose.
Contraindications
In patients with marked anxiety, tension and agitation, since Concerta may aggravate these symptoms; known hypersensitivity to methylphenidate or other components of Concerta; glaucoma; family history or diagnosis of Tourette's syndrome; during treatment with monoamine oxidase inhibitors (MAOIs), and also within a minimum of 14 days following discontinuation of a MAOI (hypertensive crises may result) (see Interactions).
Special Precautions
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.
Central nervous system stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Therefore, clinical evaluation for tics in patients should precede use of stimulant medication. Family history should be assessed.
Although a causal relationship has not been established, suppression of growth (ie, weight gain, and/or height) has been reported with the long-term use of stimulants in children. Therefore, patients requiring long-term therapy should be carefully monitored. Patients who are not growing or gaining weight as expected should have their treatment interrupted.
Concerta must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided or crushed. The medication is contained within a non-absorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
Because Concerta tablet is non-deformable and does not appreciably change in shape in the gastrointestinal tract, Concerta should ordinarily not be administered to patients with preexisting severe gastrointestinal 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 non-deformable controlled-release formulations. Due to the controlled-release design of the tablet, Concerta should only be used in patients who are able to swallow the tablet whole.
Concerta should not be used to treat severe depression and/or for the prevention or treatment of normal fatigue states.
Psychotic (eg, hallucinations) or manic symptoms have been reported in patients without a prior history of psychotic illness or mania during treatment with Concerta at usual doses. If such symptoms occur, consideration should be given to a possible causal role of Concerta and discontinuation of treatment may be appropriate (see Adverse Reactions).
Patients beginning treatment with Concerta should be monitored for the appearance or worsening of aggressive behavior. Aggression is frequently associated with ADHD; however, emergence or worsening of aggression has been reported during treatment with Concerta (see Adverse Reactions).
Concerta should be given with caution in the following conditions: Clinical experience suggests that in psychotic patients, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder.
In the laboratory classroom clinical trials in children, both Concerta and methylphenidate administered 3 times daily increased resting pulse rate by an average of 2-6 beats per minute (bpm) and produced average increases of systolic and diastolic blood pressure of roughly 1-4 mmHg during the day, relative to placebo. In placebo-controlled studies in adults, mean increases in resting pulse rate of approximately 4-6 bpm were observed with Concerta at endpoint versus a mean change of roughly -2 to 3 bpm with placebo. Mean changes in blood pressure at endpoint ranged from about -1 to 1 mmHg (systolic) and 0-1 mmHg (diastolic) for Concerta and from -1 to 1 mmHg (systolic) and -2 to 0 mmHg (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. Blood pressure (especially for patients with hypertension) and heart rate should be monitored at appropriate intervals in patients taking Concerta.
Concerta should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.
There is some clinical evidence that methylphenidate may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and very rarely, in absence of history of seizures and no prior EEG evidence of seizures. In the presence of seizures, Concerta should be discontinued.
Symptoms of visual disturbances have been encountered in rare cases. Difficulties with accommodation and blurring of vision have been reported.
Periodic hematologic monitoring (complete blood count, differential and platelet counts) is advised during prolonged therapy.
Effects on the Ability to Drive or Operate Machinery: Stimulants 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.
Use in pregnancy: The safety of methylphenidate for use during human pregnancy has not been established. No studies are available on the use of Concerta in pregnant women. Concerta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Methylphenidate hydrochloride has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times the maximum recommended human dose on a mg/kg basis.
Teratogenic effects were not seen in rats at methylphenidate hydrochloride doses up to 30 mg/kg/day, resulting in an approximate systemic exposure to methylphenidate of 9-12 times that seen in trials in volunteers and patients with the maximum recommended dose of Concerta, based on pharmacokinetic data.
Methylphenidate did not impair fertility in mice that received up to 160 mg/kg/day methylphenidate hydrochloride in an 18-week continuous breeding study.
Use in lactation: It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Concerta is administered to a nursing woman.
Use in children: Concerta should not be used in patients <6 years. Sufficient data on the safety of long-term use of methylphenidate is not yet available.
Use in the elderly: Use of Concerta in elderly patients >65 years has not been studied in controlled trials.
Use In Pregnancy & Lactation
Use in pregnancy: The safety of methylphenidate for use during human pregnancy has not been established. No studies are available on the use of Concerta in pregnant women. Concerta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Methylphenidate hydrochloride has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times the maximum recommended human dose on a mg/kg basis.
Teratogenic effects were not seen in rats at methylphenidate hydrochloride doses up to 30 mg/kg/day, resulting in an approximate systemic exposure to methylphenidate of 9-12 times that seen in trials in volunteers and patients with the maximum recommended dose of Concerta, based on pharmacokinetic data.
Methylphenidate did not impair fertility in mice that received up to 160 mg/kg/day methylphenidate hydrochloride in an 18-week continuous breeding study.
Use in lactation: It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Concerta is administered to a nursing woman.
Adverse Reactions
Clinical Trial Data: Double-Blind Data: Adverse Drug Reactions Reported at ≥1% Frequency: Adverse drug reactions (ADRs) in either the pediatric or adult double-blind adverse drug reaction tables may be relevant for both patient populations.
Pediatric Patients: The safety of Concerta was evaluated in 639 pediatric 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 reported by ≥1% of Concerta-treated subjects in these trials are shown in Table 3.

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The majority of ADRs were mild to moderate in severity.
Adult Patients: The safety of Concerta was evaluated in 627 adult patients with ADHD who participated in 2 placebo-controlled, double-blind clinical trials. The information presented in this section was derived from pooled data.
Adverse drug reactions reported by ≥1% of Concerta-treated patients in these trials are shown in Table 4.

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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 3590 pediatric and adult subjects with ADHD who participated in 11 open-label clinical trials. The information presented in this section was derived from pooled data.
Adverse drug reactions reported by ≥1% of Concerta-treated subjects in these trials and not listed in Tables 3 and 4 are shown in Table 5.

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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 subjects in the double-blind and open-label clinical datasets are as follows: Blood and Lymphatic System Disorders: Leukopenia.
Psychiatric Disorders: Anger, hypervigilance, altered mood, mood swings, sleep disorder, tearfulness, tic.
Nervous System Disorders: Lethargy, somnolence, psychomotor hyperactivity.
Eye Disorders: Dry eyes.
Vascular Disorders: Hypertension.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea.
Skin and Subcutaneous Tissue Disorders: Macular rash.
Reproductive System and Breast Disorders: Erectile dysfunction.
Investigations: Cardiac murmur.
The majority of ADRs were mild to moderate in severity.
Post-Marketing Data: ADRs identified during post-marketing experience with Concerta are included in the following texts. The frequencies are provided according to the following convention: Very common: ≥1/10; common ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10,000 to <1/1000; very rare <1/10,000, including isolated reports.
The following ADRs are presented by frequency category based on incidence in clinical trials, when known: Blood and Lymphatic System Disorders: Not Known: Pancytopenia, thrombocytopenia, thrombocytopenic purpura.
Immune System Disorders: Uncommon: Hypersensitivity reactions eg, angioedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticarias, pruritus NEC, rashes, eruptions and exanthemas NEC.
Psychiatric Disorders: Rare: Disorientation, auditory and visual hallucinations, mania. Not Known: Hallucinations.
Nervous System Disorders: Uncommon: Dyskinesia. Not Known: Convulsions, grand mal convulsions.
Eye Disorders: Rare: Diplopia, mydriasis, visual disturbance.
Cardiac Disorders: Rare: Angina pectoris, extrasystoles, ventricular extrasystoles. Not Known: Bradycardia, supraventricular tachycardia.
Vascular Disorders: Not Known: Raynaud's phenomenon.
Skin and Subcutaneous Tissue Disorders: Uncommon: Alopecia, erythema.
Musculoskeletal, Connective Tissue and Bone Disorders: Uncommon: Myalgia, arthralgia, muscle twitching.
General Disorders and Administration Site Conditions: Uncommon: Chest pain and discomfort. Not Known: Decreased drug effect, hyperpyrexia, decreased therapeutic response.
Investigations: Uncommon: Increased hepatic enzyme. Rare: Increased blood bilirubin. Not Known: Increased blood alkaline phosphatase, decreased platelet count, abnormal white blood cell count.
Note: The frequency category “not known” is used for ADRs for which no valid estimate of the incidence rate can be derived from clinical trials.
Drug Interactions
Concerta should not be used in patients being treated (currently or within the preceeding 2 weeks) with MAOIs (see Contraindications).
Because of possible increases on blood pressure, Concerta should be used cautiously with vasopressor agents.
Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone) and some antidepressants (tricyclics and selective serotonin re-uptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.
Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally-acting α2-agonists has not been systematically evaluated.
Incompatibilities: None known.
Storage
Do not store above 25°C. Keep the container tightly closed.
ATC Classification
N06BA04 - methylphenidate ; Belongs to the class of centrally-acting sympathomimetics. Used as CNS stimulant.
Presentation/Packing
XR tab 18 mg (capsule-shaped, yellow, with "alza 18" printed on one side in black ink) x 30's. 27 mg (capsule-shaped, gray, with "alza 27" printed on one side in black ink) x 30's. 36 mg (capsule-shaped, white, with "alza 36" printed on one side in black ink) x 30's.
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