Concerta

Concerta

methylphenidate

Manufacturer:

Johnson & Johnson
Full Prescribing Info
Contents
Methylphenidate HCl.
Description
18 mg tablet: Each tablet contains 18 mg of methylphenidate hydrochloride.
36 mg tablet: Each tablet contains 36 mg of methylphenidate hydrochloride.
Excipients/Inactive Ingredients: 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
Pharmacotherapeutic group: Centrally-acting sympathomimetics. ATC code: N06BA04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known. Methylphenidate is thought to block the reuptake 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 to 2 hours, then increase gradually over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours after which a gradual decrease in plasma levels of methylphenidate begins. CONCERTA once daily minimizes the fluctuations betvveen peak and trough concentrations associated with immediate-release methylphenidate three times daily. The relative bioavailability of CONCERTA once daily and methylphenidate three 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 three times daily are summarized in Table 1. (See 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 t½ following repeated once daily dosing are similar to those following the first dose of CONCERTA.
Dose proportionality: Following administration of CONCERTA in single doses of 18, 36, and 54 mg/day to adults, C-max and AUC-(0-inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC(0-inf) 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 to 144 mg/day resulted in linear and dose proportional increases in Cmax and AUCinf for total methylphenidate (MPH) and its major metabolite, (alpha)-phenyl-piperidine 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 to 144 mg/day, both after single dose and upon multiple dosing.
In a multiple-dose study in adolescent ADHD patients aged 13 to 16 years administered 18 to 72 mg/day of CONCERTA, mean Cmax and AUCTAU of d- and total methylphenidate increased proportionally with respect 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 was approximately 3.5 h.
Metabolism: In humans, methylphenidate is metabolized primarily by deesterification to (alpha)-phenyl-piperidine acetic acid (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 three times daily. The metabolism of single and repeated once daily doses of CONCERTA is similar.
Elimination: 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.
Alcohol effect: An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the CONCERTA 18 mg tablet dosage form. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg tablet strength are considered representative of the other available tablet strength.
Special populations: Gender: In healthy adults, the mean dose-adjusted AUC(0-inf) values for CONCERTA 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 adults receiving CONCERTA, dose-adjusted AUC(0-inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.
Age: The pharmacokinetics of CONCERTA has not been studied in children less than 6 years of age.
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: 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 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 tumors. The mouse strain used is sensitive to the development of hepatic tumors, 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 the transgenic mouse strain p53+/-, there was no evidence of carcinogenicity at methylphenidate hydrochloride doses of up to 74 mg/kg/day.
No adverse toxicologic effects were seen in two 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
CONCERTA is indicated for the 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 aged 6 to 17 and adults aged 18 to 65 who met DSM-IV criteria for ADHD.
A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, eg. in social, academic, or occupational functioning, and be present in two or more settings, eg. school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; "on the go;" excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.
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 the current DSM criteria or ICD guidelines.
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 exhibits symptoms secondary to environmental factors and/or 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
Adults: Patients New to Methylphenidate: The recommended starting dosage 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 dosage of CONCERTA for patients who are currently taking methylphenidate twice daily or three times daily, at dosages of 10 to 60 mg/day is provided in the following table: (See 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: The 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 above 54 mg in children and 72 mg in adolescents and in adults 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 events occur, the dosage should be reduced or, if necessary, the drug should be discontinued.
Special Populations: Pediatrics (under 6 years of age): Use of CONCERTA in patients under six years of age has not been studied in controlled trials. CONCERTA should not be used in patients under six years old.
Elderly (over 65 years of age): Use of CONCERTA in patients over 65 years of age has not been studied in controlled trials.
Administration: CONCERTA is administered orally once daily. As the effect has been shown to be present 12 hours after dosing, the product should be taken in the morning.
CONCERTA must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed (see Dose administration under Precautions).
CONCERTA may be administered with or without food (see Pharmacology: Pharmacokinetics: Food effects under Actions).
Overdosage
Signs and 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, convulsion, grand mal convulsion, confusional state, hallucination (auditory and/or visual), hyperhidrosis, headache, pyrexia, tachycardia, palpitations, heart rate increased, sinus arrhythmia, hypertension, mydriasis, and dry mouth. Additional signs and symptoms of methylphenidate overdosage may include tremors, hypperreflexia, euphoria and delirium.
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. 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
CONCERTA is contraindicated: in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms;
in patients known to be hypersensitive to methylphenidate or other components of the product;
in patients with glaucoma;
during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result) (see Interactions).
Warnings
Drug Dependence: 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.
Special Precautions
Structural cardiac abnormalities: Although a causal relationship has not been established, sudden death has been reported in patients with structural cardiac abnormalities treated with ADHD drugs with stimulant effects. These treatments should be used with caution in patients with structural cardiac abnormalities.
Patients under six years old: CONCERTA should not be used in patients under six years old. Sufficient data on the safety of long-term use of methylphenidate is not yet available.
Motor and verbal tics, and worsening of Tourette's syndrome: Central nervous system (CNS) stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported. It is recommended that the family history be assessed, and that the patient is clinically evaluated for tics or Tourette's syndrome before initiating methylphenidate. Regular monitoring for the emergence or worsening of tics or Tourette's syndrome during treatment with methylphenidate is recommended at every dose adjustment and every visit, and treatment discontinued if clinically appropriate.
Long-term use: Although a causal relationship has not been established, suppression of growth (i.e., 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.
Dose administration: CONCERTA 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, 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 the CONCERTA tablet is non-deformable and does not appreciably change in shape in the GI 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.
Psychotic or manic symptoms: Clinical experience suggests that in psychotic patients, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder.
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients.
Treatment emergent psychotic or manic symptoms, eg. Hallucinations, delusional thinking or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptpms occur, consideration should be given to a possible causal role of the stimulant and discontinuation of treatment may be appropriate.
Aggressive behavior: Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.
Priapism: Prolonged and painful erections requiring immediate medical attention (sometimes including surgical intervention), have been reported with methylphenidate products, including CONCERTA in both pediatric and adult patients (see Adverse Reactions). Priapism can develop after some time on methylphenidate, often subsequent to an increase in dose. Priapism has also appeared during a period of methyphenidate withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained erections or frequent and painful erections should seek immediate medical attention.
Conditions requiring caution: CONCERTA should be given with caution in the following conditions: Psychotic patients: Clinical experience suggests that in psychotic patients, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder.
Underlying medical conditions that might be compromised by increases in blood pressure or heart rate: Use cautiously in patients with hypertension. Cardiovascular status and blood pressure should be monitored at appropriate intervals in patients taking CONCERTA, especially patients with hypertension. In the laboratory classroom clinical trials in children, both CONCERTA and methylphenidate tid increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In placebo-controlled studies in adults, mean increases in resting pulse rate of apporoximately 4 to 6 bpm were observed with CONCERTA at endpoint vs. a mean change of roughly -2 to 3 bpm with placebo. Mean changes in blood pressure at endpoint ranged from about -1 to 1 mm Hg (systolic) and 0 to 1 mm Hg (diastolic) for CONCERTA and from -1 to 1 mm Hg (Systolic) and 2 to 0 mm Hg (diastolic) for placebo. Therefore, caution is indicated in treating patients whose underlying medical conditions might be compromised by increase in blood pressure or heart rate, eg. those with preexisting hypertension, heart failure, recent myocardial infarction, or hyperthyroidism.
Children, adolescents or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.
History of drug dependence or alcoholism: 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.
History of seizure or prior EEG abnormalities: There is some clinical evidence that methylphenidate may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in absence of history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.
Visual disturbances: Symptoms of visual disturbances have been encountered in rare cases. Difficulties with accommodation and blurring of vision have been reported.
Hematologic monitoring: Periodic hematologic monitoring (Complete Blood Count, differential, and platelet counts) is advised during prolonged therapy.
Drug Abuse and Dependence: Controlled Substance Class: CONCERTA, like other methylphenidate products, is classified as a Schedule II controlled substance.
Abuse, Dependence, and Tolerance: See Warnings for boxed warning containing drug abuse and dependence information.
Effects on Ability to Drive and Use Machines: 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 & Lactation
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 nine to twelve times that seen in trials in volunteers and patients with the maximum recommended dose of CONCERTA, based on pharmacokinetic data.
Breast-feeding: 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 breast-feeding woman.
Fertility: Methylphenidate did not impair fertility in mice that received up to 160 mg/kg/day methylphenidate hydrochloride in an 18-week Continuous Breeding study.
Adverse Reactions
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of methylphenidate hydrochloride based on the comprehensive assessment of the available adverse event information. A causal relationship with methylphenidate hydrochloride cannot be reliably established in individual cases.
Further, 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.
Clinical Trial Data: Double-blind data - adverse reactions reported at ≥1% frequency: Adverse reactions in either the pediatric or adult double-blind adverse drug reactions tables may be relevant for both patient populations.
Pediatric Patients: The safety of CONCERTA was evaluated in 639 patients with ADHD who participated in 4 placebo-controlled, double-blind clinical trials. The information presented in this section was derived from pooled data.
Adverse reactions reported by ≥1% of CONCERTA-treated children and adolescent patients in these trials are shown in Table 3. (See Table 3.)


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The majority of adverse reactions were mild to moderate in severity.
Adult Patients: The safety of CONCERTA was evaluated in 905 adult patients with ADHD who participated in 3 placebo-controlled, double-blind clinical trials. The information presented in this section was derived from pooled data.
Adverse reactions reported by ≥1% of CONCERTA-treated adult patients in these trials are shown in Table 4. (See Table 4.)


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The majority of adverse reactions were mild to moderate in severity.
Open-label data - adverse reactions reported at ≥1% frequency: The safety of CONCERTA was evaluated in 3782 pediatric and adult patients with ADHD who participated in 12 open-label clinical trials. The information presented in this section was derived from pooled data.
Adverse reactions reported by ≥1% of CONCERTA-treated patients in these trials and not listed in Tables 3 and 4 are shown in Table 5. (See Table 5.)


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The majority of adverse reactions were mild to moderate in severity.
Double blind and open-label data - adverse reactions reported at <1% frequency: Additional adverse reactions that occurred in <1% of CONCERTA-treated pediatric and adult patients in the double-blind and open-label clinical datasets are listed in Table 6. (See Table 6.)


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The majority of adverse reactions were mild to moderate in severity.
Postmarketing data: Adverse reactions identified during postmarketing experience with CONCERTA are included in Table 7. In this table, the frequencies are provided according to the following convention: Very common ≥1/10 (≥10%); Common ≥1/100 and <1/10 (≥1% and <10%); Uncommon ≥1/1000 and <1/100 (≥0.1% and <1%); Rare ≥1/10000 and <1/1000 (≥0.01 and <0.1%); Very rare <1/10000 (<0.01%), including isolated reports; Not known: Cannot be estimated from the available data. (See Table 7.)


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Drug Interactions
CONCERTA should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors (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 reuptake 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.
Caution For Usage
Instructions for use/handling: No special requirements.
Incompatibilities: None known.
Storage
Do not store above 30°C (86°F).
Keep the container tightly closed.
Shelf-Life: 2 years (24 months).
ATC Classification
N06BA04 - methylphenidate ; Belongs to the class of centrally-acting sympathomimetics. Used as CNS stimulant.
Presentation/Packing
XR captab 18 mg (yellow with "alza 18" printed on one side in black ink) x 30's. 36 mg (white with "alza 36" printed on one side in black ink) x 30's.
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