2.1 Pretreatment Screening

Prior to treating patients with CONCERTA, assess:

• For the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
• The family history for tics or Tourette' syndrome and clinically evaluate patients for motor or verbal tics or Tourette's syndrome [see Warnings and Precautions (5.11)].

2.2 Important Administration Instructions

Administer CONCERTA orally once daily in the morning with or without food.

Swallow CONCERTA whole with liquids. Do not split, crush, or chew the extended-release tablets because doing so will compromise the extended-release characteristics of CONCERTA and may compromise the effectiveness or safety of CONCERTA.

2.3 Recommended CONCERTA Dosage in Patients New to Methylphenidate

See Table 1 for the recommended once-daily dosage of CONCERTA in patients who were not taking a methylphenidate product. In patients who have not achieved an optimal response at a lower dosage, increase the CONCERTA dosage in 18 mg increments at weekly intervals. However, if a slower titration is recommended for patients who have not achieved an optimal response taking 18 mg of CONCERTA once daily, increase their daily dosage to 27 mg once per day.

2.4 Recommended CONCERTA Dosage in Patients Switching from Another Methylphenidate Product

See Table 2 for the recommended starting dosage of CONCERTA in patients switching from an immediate-release methylphenidate product administered twice daily or three times daily (total daily dosage of 10 to 60 mg/day).

In patients who have not achieved an optimal response at a lower dosage, increase the CONCERTA dosage in 18 mg increments at weekly intervals. The maximum recommended dosage in pediatric patients 6 to 12 years of age is 54 mg/day, and the maximum recommended dosage in patients 13–65 years old is 72 mg/day.

2.5 Dosage Reduction and Discontinuation

If paradoxical aggravation of ADHD symptoms or CONCERTA-associated adverse reactions occur, reduce the CONCERTA dosage or, if necessary, discontinue CONCERTA.

If ADHD improvement is not observed after appropriate dosage modification over a one-month period, discontinue CONCERTA.

5.1 Abuse, Misuse, and Addiction

CONCERTA has a high potential for abuse and misuse. The use of CONCERTA exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence (9.1, 9.2)]. Misuse and abuse of CNS stimulants, including CONCERTA, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection.

Before prescribing CONCERTA, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store CONCERTA in a safe place, preferably locked, and instruct patients to not give CONCERTA to anyone else. Throughout CONCERTA treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2 Risks to Patients with Serious Cardiac Disease

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.

Avoid CONCERTA use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3 Increased Blood Pressure and Heart Rate

CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mm Hg) and heart rate (mean increase approximately 3 to 6 beats per minute) [see Adverse Reactions (6)]. Some patients may have larger increases.

Monitor all CONCERTA-treated patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions

Exacerbation of Psychosis in Patients with a Psychotic Disorder

CNS stimulants, including CONCERTA, may exacerbate behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder

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

New Psychotic or Manic Symptoms in Patients without a History of a Bipolar or Psychotic Disorder

CNS stimulants (including CONCERTA), at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. 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 stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing CONCERTA.

5.5 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in adult and pediatric male patients [see Adverse Reactions (6)]. Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate after some time, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).

CONCERTA-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon

CNS stimulants, including CONCERTA, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon [see Adverse Reactions (6.2)]. Signs and symptoms of these cases of peripheral vasculopathy were usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms of peripheral vasculopathy generally improved after CNS stimulant dosage reduction or discontinuation.

During CONCERTA treatment, carefully assess for digital changes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for CONCERTA-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.7 Long-Term Suppression of Growth in Pediatric Patients

CONCERTA is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)]. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

Pediatric patients 7 to 13 years of age who received methylphenidate for 7 days per week for over 14 months to over 36 months had 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 development period.

Closely monitor growth (weight and height) in CONCERTA-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.8 Risk of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing

Because CONCERTA extended-release tablets are nondeformable and do not appreciably change in shape in the gastrointestinal (GI) tract, CONCERTA should not ordinarily be administered to patients with pre-existing severe pathologic or iatrogenic GI narrowing. There have been rare reports of obstructive GI symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable modified-release dosage forms.

CONCERTA should be used only in patients who are able to swallow the extended-release tablets whole [see Dosage and Administration (2.2)].

5.9 Acute Angle Closure Glaucoma

There have been reports of angle closure glaucoma associated with methylphenidate treatment.

Although the mechanism is not clear, CONCERTA-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

5.10 Increased Intraocular Pressure and Glaucoma

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6)].

Prescribe CONCERTA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor CONCERTA-treated patients with a history of abnormally increased IOP or open angle glaucoma.

5.11 Motor and Verbal Tics, and Worsening of Tourette's Syndrome

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions (6)]. Worsening of Tourette's syndrome has also been reported.

Before initiating CONCERTA, assess the family history for tics or Tourette' syndrome and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor CONCERTA-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue CONCERTA treatment if clinically appropriate.

6.1 Clinical Trial Experience

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 clinical trials of another drug and may not reflect the rates observed in clinical practice. The data below is based on a total of 3,906 patients in clinical studies who received CONCERTA. Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3].

The most common adverse reactions (≥5%) in double-blind clinical trials were:

• Pediatric patients: upper abdominal pain [see Table 4].
• Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis [see Table 5].

The most common adverse reactions associated with CONCERTA discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure.

Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.

Adverse Reactions in Pediatric Patients Aged 6 years and Older

Table 4 displays adverse reactions reported in 2% or more of CONCERTA-treated pediatric patients ages 6 and older with ADHD in 4 placebo-controlled, double-blind clinical trials.

Adverse Reactions in Adults

Table 5 lists the adverse reactions reported in 2% or more of CONCERTA-treated adults with ADHD in 2 placebo-controlled, double-blind clinical trials.

Other Adverse Reactions Observed in Clinical Trials of CONCERTA

The following adverse reactions occurred in less than 2% of CONCERTA-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials.

• Blood and Lymphatic System Disorders: Leukopenia
• Cardiac Disorders: Cardiac murmur, Hypertension, Heart rate increased
• Ear and Labyrinth Disorders: Vertigo
• Eye Disorders: Accommodation disorder, Dry eye, Vision blurred
• Gastrointestinal Disorders: Abdominal discomfort/pain, Constipation, Diarrhea, Vomiting
• General Disorders and Administration Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst
• Hepatobiliary Disorders: Hepatic enzymes increased
• Infections and Infestations: Sinusitis
• Metabolism and Nutrition Disorders: Anorexia
• Musculoskeletal and Connective Tissue Disorders: Muscle spasms, Muscle tightness
• Nervous System Disorders: Lethargy, Paresthesia, Psychomotor hyperactivity, Sedation, Somnolence, Tension headache
• Psychiatric Disorders: Affect lability, Aggression, Anger, Bruxism, Confusional state, Depression, Hypervigilance, decreased libido, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tension, Tic
• Reproductive System and Breast Disorders: Erectile dysfunction
• Respiratory, Thoracic and Mediastinal Disorders: Cough, Dyspnea, Oropharyngeal pain
• Skin and Subcutaneous Tissue Disorders: Rash
• Vascular Disorders: Hot flush

Discontinuation Due to Adverse Reactions

In the 2 placebo-controlled studies in adults with ADHD, 25 (6%) CONCERTA-treated patients and 6 (3%) placebo-treated patients discontinued due to an adverse reaction. In the CONCERTA group, adverse reactions leading to discontinuation with an incidence of >0.5% were anxiety (1.7%), irritability (1.4%), increased blood pressure (1%), and nervousness (0.7%). In the placebo group, adverse reactions leading to discontinuation with an incidence of >0.5% were increased blood pressure (0.9%) and depressed mood (0.9%).

In the 11 open-label studies in patients 6 to 65 years of age with ADHD, 266 (7%) CONCERTA-treated patients discontinued due to an adverse reaction including insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).

Blood Pressure and Heart Rate Increases

• In the 1-week treatment, controlled trials in pediatric patients 6 to 12 years of age with ADHD (Studies 1 and 2) [see Clinical Studies (14.2)], both the CONCERTA once daily group and the methylphenidate three times daily group increased resting pulse by an average of 2 to 6 beats per minute (bpm) and increased the average systolic and diastolic blood pressure roughly 1 to 4 mm Hg during the day, relative to placebo.
• In the randomized withdrawal portion of the double-blind, placebo-controlled trial with pediatric patients 13 to 17 years of age with ADHD (Study 4) [see Clinical Studies (14.3)], mean increases from baseline in resting pulse rate were observed with CONCERTA and placebo at the end of the double-blind phase (5 and 3 beats/minute (bpm), respectively). At the end of four weeks of treatment, mean increases from baseline in blood pressure for CONCERTA and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively.
• In the 7-week dose-titration, placebo-controlled study in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (14.4)], mean changes from baseline in resting pulse rate were 3.6 in CONCERTA-treated patients and -1.6 for placebo-treated patients after 7 weeks of treatment. Mean changes from baseline in blood pressure after 7 weeks of treatment in CONCERTA-treated and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.3)].
• In the 5-week fixed-dose, placebo-controlled trial in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (14.4)], dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with CONCERTA-treated patients and 2.7 bpm with placebo-treated patients at the end of 5 weeks. Mean changes from baseline in standing blood pressure after 5 weeks of treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for CONCERTA-treated patients and 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo-treated patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of CONCERTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

• Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura
• Cardiac Disorders: Angina pectoris, Bradycardia, Supraventricular tachycardia, Ventricular extrasystoles
• Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis
• General Disorders and Administration Site Conditions: Chest pain, Drug effect decreased, Hyperpyrexia
• Hepatobiliary Disorders: Hepatocellular injury, Acute hepatic failure, Blood bilirubin increased
• Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Exanthemas NEC
• Investigations: Blood alkaline phosphatase increased, Platelet count decreased,
• Musculoskeletal and Connective Tissue Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis
• Nervous System Disorders: Convulsion, Grand mal convulsion, Stroke in pediatric patients, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics
• Psychiatric Disorders: Disorientation, Hallucination, Mania, Logorrhea
• Reproductive System and Breast Disorders: Priapism
• Skin and Subcutaneous Tissue Disorders: Alopecia, Bullous conditions, Erythema, Exfoliative conditions, Pruritus, Urticarias
• Vascular Disorders: Raynaud's phenomenon

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD drugs, including CONCERTA, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/.

Risk Summary

Published studies and post-marketing reports on methylphenidate use during pregnancy have inconsistent findings about a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the fetus associated with the use of central nervous system (CNS) stimulants during pregnancy (see Clinical Considerations).

No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits throughout organogenesis at doses up to 4 and 16 times, respectively, the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m2 basis. However, spina bifida was observed in rabbits at a dose 54 times the MRHD given to adults. A slight decrease in body weight was observed in pregnant rats at the highest dose of 30 mg/kg/day (4 times the MRHD given to adults).

In a pre- and postnatal development study in which rats were treated with oral administration of methylphenidate throughout pregnancy and lactation, a decrease in pup body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD given to adults on a mg/m2 basis) (see Data).

The background risk of major birth defects and miscarriage in those with ADHD is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions: CNS stimulants, such as CONCERTA, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of a therapeutic dosage of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine dependent mothers.

Data

Animal Data: In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses up to 30 and 200 mg/kg/day, respectively, during the period of organogenesis.

Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 54 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (16 times the MRHD given to adults on a mg/m2 basis).

There was no evidence of changes in morphological development in rats, although a reduction in maternal body weight was observed at the highest dose of 30 mg/kg/day (4 times the MRHD of 72 mg/day given to adults (on a mg/m2 basis). The no effect level for maternal body weight in rats is 5 mg/day (equal to the MRHD for adults on a mg/m2 basis); and the no effect level for embryo-fetal development is 30 mg/kg/day (4 times the MRHD for adults on a mg/m2 basis).

When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 30 mg/kg/day, decreases in offspring body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD of 72 mg/day, given to adults on a mg/m2 basis). The no effect level for pre- and post-natal development in rats was 12.5 mg/kg/day (2 times the MRHD given to adults on a mg/m2 basis).

8.2 Lactation

Risk Summary

Limited published literature, based on breast milk sampling from a small number of methylphenidate-treated lactating women, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted methylphenidate dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant or 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 CONCERTA and any potential adverse effects on the breastfed child from CONCERTA or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding infants of CONCERTA-treated lactating women for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

8.4 Pediatric Use

The safety and effectiveness of CONCERTA for the treatment of ADHD have been established in pediatric patients 6 years of age and older. The safety and effectiveness of CONCERTA have not been established in pediatric patients below the age of 6 years.

In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Growth (weight and height) should be monitored in pediatric patients during treatment with CNS stimulants, including CONCERTA. Pediatric patients who are not growing or gaining weight as expected may need to have their CONCERTA treatment interrupted [see Warnings and Precautions (5.7)].

Juvenile Animal Toxicity Data

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 4 times the MRHD of 54 mg/day given to pediatric patients 6 to 12 years of age on a mg/m2 basis.

In a 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 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 54 mg/day given to pediatric patients 6 to 12 years of age on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (9 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.4 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use

CONCERTA is not indicated for use in patients greater than 65 years of age.

9.1 Controlled Substance

CONCERTA contains methylphenidate, a Schedule II controlled substance.

9.2 Abuse

CONCERTA has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of CONCERTA may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including CONCERTA, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Studies of Abuse Potential with CONCERTA

In two placebo- and active-controlled, crossover human abuse potential (HAP) studies, the relative abuse potential of single oral doses of CONCERTA were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational CNS stimulant use. In these studies, the response for each of the abuse-related subjective measures was defined as the maximum effect within the first 8 hours after treatment administration. When evaluating these results, consider that 22% of the total methylphenidate amount in CONCERTA (methylphenidate hydrochloride) extended-release tablets is available for immediate release and the remaining 78% is available for extended-release over 24 hours.

• In the first HAP study (n=40), single dose administration of CONCERTA 108 mg (1.5 times the maximum recommended adult dose of CONCERTA), IR MPH 60 mg (2 times the maximum recommended adult dose of IR MPH), or placebo were administered to subjects in a cross-over design. CONCERTA 108 mg and IR MPH 60 mg produced responses on the subjective measures of Drug Liking and Abuse Potential that were statistically similar, and both were statistically significantly greater than the responses to placebo. However, on subjective measures of Euphoria, CONCERTA 108 mg produced responses that were statistically less than those produced by IR MPH 60 mg.
• In the second HAP study (n=49), a single dose of CONCERTA 108 mg (1.5 times the maximum recommended adult dose of CONCERTA), CONCERTA 54 mg (0.75 times the maximum recommended adult dose of CONCERTA), IR MPH 90 mg (3 times the maximum recommended adult dose of IR MPH), 50 mg (1.7 times the maximum recommended adult dose of IR MPH), or placebo were administered to subjects in a cross-over design. The three active treatments each produced responses on the subjective measure of Drug Liking that were statistically significantly greater than responses to placebo. IR MPH produced greater responses on Drug Liking compared to CONCERTA when similar doses were compared (50 mg vs. 54 mg, and 90 mg vs. 108 mg, respectively), consistent with the extended-release properties of CONCERTA. However, there were no significant differences in response between CONCERTA 108 mg and IR MPH 50 mg on the subjective measures of Drug Liking and Euphoria.

The clinical significance of the differences in response between CONCERTA and IR MPH on subjective measures of abuse potential as reported in these HAP studies is unknown.

9.3 Dependence

Physical Dependence

CONCERTA may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal signs and symptoms after abrupt discontinuation or dosage reduction following prolonged use of CNS stimulants including CONCERTA included dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

CONCERTA may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

10.1 Clinical Effects of Overdose

Overdose of CNS stimulants is characterized by the following sympathomimetic effects:

• Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.
• CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur.
• Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.

10.2 Overdose Management

Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of CONCERTA should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

12.1 Mechanism of Action

Methylphenidate is a central nervous system (CNS) stimulant. The mode of therapeutic action of methylphenidate in the treatment of ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of CONCERTA have not been fully characterized.

12.3 Pharmacokinetics

Absorption

Following oral administration of CONCERTA, plasma methylphenidate concentrations reached an initial maximum concentration at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours, after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of CONCERTA occurred between 6 and 10 hours.

CONCERTA once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily [see Figure 1]. No clinically significant difference in methylphenidate exposures was observed following the administration of either CONCERTA once daily and immediate-release methylphenidate three times daily in adults.

Figure 1. Mean Methylphenidate Plasma Concentrations Following a Single 18 mg CONCERTA dose and Immediate-release Methylphenidate 5 mg Doses (Three Doses Administered Every 4 Hours)

The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of one 18 mg CONCERTA dose and three 5 mg methylphenidate doses every four hours are summarized in Table 7.

The methylphenidate pharmacokinetics were evaluated in healthy adults following single- and multiple-doses (steady state) of CONCERTA (up to 144 mg/day (up to 2 times the maximum recommended dose)). The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of CONCERTA were noted following single and repeated once-daily CONCERTA dosing, indicating no significant drug accumulation. The AUC and t1/2 following repeated once-daily dosing are similar to those following a single 18 to 144 mg 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–inf) of d-methylphenidate were dose proportional, 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 1/40 the plasma concentrations of the d-isomer.

In healthy adults, single and multiple doses (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, α-phenyl-piperidine acetic acid (PPAA). 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, after patients aged 13 to 16 with ADHD were administered their prescribed CONCERTA dose (18 to 72 mg/day), mean Cmax and AUCTAU of d- and total methylphenidate increased proportionally with respect to 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.

Distribution

Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral CONCERTA administration. The half-life of methylphenidate in adults and adolescents following oral CONCERTA administration was approximately 3.5 hours.

Elimination

Metabolism: 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 was similar to that of immediate-release methylphenidate three times daily. The metabolism of single and repeated once-daily doses of CONCERTA was similar.

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.

Alcohol Effect on Methylphenidate Release in CONCERTA

An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the CONCERTA 18 mg extended-release tablets. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg extended-release tablet strength are considered representative of the other available tablet strengths.

Specific Populations

Male and Female Patients:

In healthy adults, the mean dose-adjusted AUC(0–inf) values for CONCERTA were 36.7 ng∙h/mL in males and 37.1 ng∙h/mL in females, with no differences noted between the two groups.

Ethnic Groups:

In adults receiving CONCERTA, dose-adjusted AUC(0–inf) was consistent across ethnic groups; however, the sample size was insufficient to detect ethnic variations in pharmacokinetics.

Pediatric Patients:

Increase in pediatric age was associated with increased apparent oral clearance (CL/F) (58% increase in adolescents compared to younger pediatric patients). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have a lower exposure of total methylphenidate at similar doses.

Patients with Renal Impairment

There is no pharmacokinetic information on the use of CONCERTA in patients with renal impairment.

Patients with Hepatic Impairment

There is no pharmacokinetic information on the use of CONCERTA in patients with hepatic impairment.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

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 (MRHD) of CONCERTA given to adults on a mg/m2 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 increases 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 6 times the MRHD (adults) on a mg/m2 basis.

In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate.

Mutagenesis

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or 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 cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.

Impairment of Fertility

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 up to 160 mg/kg/day, approximately 11 times the MRHD of CONCERTA given to adults on a mg/m2 basis.

14.1 Overview of Clinical Trials

CONCERTA was demonstrated to be effective in the treatment of ADHD in patients who met the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD in the following trials:

• Three trials in pediatric patients 6 to 12 years old (Studies 1, 2, and 3),
• One trial in adolescents (13 to 18 years old),
• Two trials in adults (18 to 65 years old).

14.2 Clinical Trials in Pediatric Patients 6 to 12 Years

Three double-blind, active- and placebo-controlled trials were conducted in 416 pediatric patients 6 to 12 years of age with ADHD: (1) two single-center, crossover trials (patients received each treatment for one week) (Studies 1 and 2) and (2) a multicenter, 4-week, parallel-group comparison trial (Study 3). In these trials, patients were randomized to receive:

• 18 mg, 36 mg, or 54 mg of oral CONCERTA given once daily,
• 5 mg, 10 mg, or 15 mg of oral immediate-release methylphenidate given three times daily (15, 30, or 45 mg total daily dosage) over 12 hours, and
• Placebo

The primary comparison of interest in all three trials was the CONCERTA group versus the placebo group.

ADHD symptoms were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale.

A statistically significant reduction in the Inattention/Overactivity subscale (0 to 15) in the CONCERTA group versus the placebo group was shown in all three trials. The scores for CONCERTA and placebo for the three trials are presented in Figure 2.

Figure 2. Mean Community School Teacher Inattention/Overactivity Subscores in the IOWA Conners Scale in Pediatric Patients 6 to 12 Years with ADHD

Studies 1 and 2 involved a 3-way crossover of 1-week per treatment arm. Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at week 4. Error bars represent the mean plus standard error of the mean.

In Studies 1 and 2, symptoms of ADHD including attentiveness were evaluated by schoolteachers using the Swanson, Kotkin, Agler, M-Fynn, and Pelham (SKAMP) laboratory school rating scale. The combined results from these two trials demonstrated statistically significant improvements in attention and behavior in the CONCERTA group compared to the placebo group. These results were maintained through 12 hours after dosing. Figure 3 presents the schoolteacher SKAMP ratings for the CONCERTA and placebo groups in Studies 1 and 2.

Figure 3. School Teacher SKAMP Ratings (Mean (SEM) of Combined Attention) in Pediatric Patients 6 to 12 Years with ADHD (Studies 1 and 2)

14.3 Clinical Trials in Pediatric Patients 13 to 17 Years

In a randomized-withdrawal, double-blind, multicenter, placebo-controlled trial (Study 4) with 177 pediatric patients 13 to 17 years of age with ADHD, CONCERTA demonstrated effectiveness with a dosage up to 72 mg/day (1.4 mg/kg/day):

• Of 220 patients who entered an open 4-week titration phase, 177 patients were titrated to an individualized CONCERTA dosage (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability.
• Patients who met these criteria were then randomized to receive either their individualized dosage of CONCERTA (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase.

At the end of the double blind phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that the CONCERTA group was statistically significantly superior to the placebo group.

14.4 Clinical Trials in Adults up to 65 Years Old

Two randomized double-blind, placebo-controlled multicenter, parallel-group trials were conducted in 627 adults aged 18 to 65 years with ADHD who received CONCERTA or placebo once daily:

• Study 5 was a 7-week, dose-titration trial where patients were randomized to receive CONCERTA (n=110) or placebo (n=116) once daily. Patients treated with CONCERTA started at 36 mg/day and had incremental increases of 18 mg/day up to 108 mg/day of CONCERTA (titration was based on improvement criteria with acceptable tolerability).
• Study 6 was a 5-week, fixed-dose trial where patients were randomized to receive 18 mg (n=101), 36 mg (n=102), or 72 mg (n=102) of CONCERTA versus placebo (n=96) once daily.

In Study 5, CONCERTA demonstrated efficacy based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that the CONCERTA group was statistically significantly superior to the placebo group.

In Study 6, all three CONCERTA dosages were statistically significantly more effective than placebo in improving Conners' Adult ADHD Rating Scale (CAARS) total scores after five weeks of treatment.

Storage and Handling

Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) [see USP Controlled Room Temperature]. Protect from humidity.