WARNING: 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.

CONCERTA is indicated for the treatment of Attention Deficit Hyperactivity Disorder
(ADHD) in children 6 years of age and older, adolescents, and adults up to the age of
65 [see Clinical Studies (14)].

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, e.g., in social, academic, or occupational functioning, and be present in two or
more settings, e.g., 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.

Special Diagnostic Considerations
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. The diagnosis must be based upon a
complete history and evaluation of the patient and not solely on the presence of the required
number of DSM-IV characteristics.

Need for Comprehensive Treatment Program
CONCERTA is indicated as an integral part of a total treatment program for ADHD that
may include other measures (psychological, educational, social). Drug treatment may not be
indicated for all patients with ADHD. Stimulants are not intended for use in patients 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. When remedial measures alone are insufficient,
the decision to prescribe stimulant medication will depend upon the physician's assessment
of the chronicity and severity of the patient’s symptoms.

CONCERTA should be administered orally once daily in the morning with or without
food.
CONCERTA must be swallowed whole with the aid of liquids, and must not be chewed,
divided, or crushed [see Patient Counseling Information (17)].

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 (see Table 1).
Table 1. CONCERTA Recommended Starting Doses and Dose Ranges
Patient Age                                          Recommended Starting Dose                            Dose Range
Children 6-12 years of age                            18 mg/day                                              18 mg - 54 mg/day
Adolescents 13-17 years of age                    18 mg/day                                              18 mg - 72 mg/day                                                                                                                                      not to exceed 2 mg/kg/day
Adults 18-65 years of age                           18 or 36 mg/day                                      18 mg - 72 mg/day

 

Patients Currently Using Methylphenidate
The recommended dose of CONCERTA for patients who are currently taking
methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in
Table 2. Dosing recommendations are based on current dose regimen and clinical judgment.
Conversion dosage should not exceed 72 mg daily.

Table 2. Recommended Dose Conversion from Methylphenidate Regimens to CONCERTA
Previous Methylphenidate Daily Dose                                                            Recommended CONCERTA                                                                                                                                  Starting Dose
5 mg Methylphenidate twice daily or three times daily                             18 mg every morning
10 mg Methylphenidate twice daily or three times daily                           36 mg every morning
15 mg Methylphenidate twice daily or three times daily                           54 mg every morning
20 mg Methylphenidate twice daily or three times daily                           72 mg every morning

Other methylphenidate regimens: Clinical judgment should be used when selecting the
starting dose.

Dose Titration
Doses may be increased in 18 mg increments at weekly intervals for patients who have not
achieved an optimal response at a lower dose. Daily dosages above 54 mg in children and
72 mg in adolescents have not been studied and are not recommended. Daily dosages above
72 mg in adults are not recommended.

A 27 mg dosage strength is available for physicians who wish to prescribe between the
18 mg and 36 mg dosages.

Maintenance/Extended Treatment
There is no body of evidence available from controlled trials to indicate how long the patient
with ADHD should be treated with CONCERTA. It is generally agreed, however, that
pharmacological treatment of ADHD may be needed for extended periods.

The effectiveness of CONCERTA for long-term use, i.e., for more than 7 weeks, 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. Improvement may be sustained
when the drug is either temporarily or permanently discontinued.

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

Hypersensitivity to Methylphenidate Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with CONCERTA. Therefore, CONCERTA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see Adverse Reactions (6.6)]. Agitation CONCERTA is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. Glaucoma CONCERTA is contraindicated in patients with glaucoma. Tics CONCERTA is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome [see Adverse Reactions (6.4)]. Monoamine Oxidase Inhibitors CONCERTA is contraindicated 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 Drug Interactions (7.1)].

Serious Cardiovascular Events
Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious
Heart Problems

Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses
in children and adolescents with structural cardiac abnormalities or other serious heart
problems. Although some serious heart problems alone carry an increased risk of sudden
death, stimulant products generally should not be used in children or adolescents with
known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm
abnormalities, or other serious cardiac problems that may place them at increased
vulnerability to the sympathomimetic effects of a stimulant drug.

Adults
Sudden deaths, stroke, and myocardial infarction have been reported in adults taking
stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult
cases is also unknown, adults have a greater likelihood than children of having serious
structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities,
coronary artery disease, or other serious cardiac problems. Adults with such abnormalities
should also generally not be treated with stimulant drugs.

Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mm
Hg) and average heart rate (about 3 to 6 bpm) [see Adverse Reactions (6.5)], and individuals
may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate
and blood pressure. Caution is indicated in treating patients whose underlying medical
conditions might be compromised by increases in blood pressure or heart rate, e.g., those
with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular
arrhythmia.

Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications
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.

Psychiatric Adverse Events
Preexisting Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought
disorder in patients with a preexisting psychotic disorder.
 

Bipolar Illness
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. Prior to initiating treatment with a stimulant, patients with comorbid depressive
symptoms should be adequately screened to determine if they are at risk for bipolar disorder;
such screening should include a detailed psychiatric history, including a family history of
suicide, bipolar disorder, and depression.

Emergence of New Psychotic or Manic Symptoms
Treatment-emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking,
or mania in patients without a prior history of psychotic illness or mania can be caused by
stimulants at usual doses. If such symptoms occur, consideration should be given to a
possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In
a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms
occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or
amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0
in placebo-treated patients.

Aggression
Aggressive behavior or hostility is often observed in patients 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.

Seizures
There is some clinical evidence that stimulants 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 patients without a history of seizures and no prior EEG
evidence of seizures. In the presence of seizures, the drug should be discontinued.
 

Priapism
Prolonged and painful erections, sometimes requiring surgical intervention, have been
reported with methylphenidate products, including CONCERTA, in both pediatric and
adult patients [see Adverse Reactions (6.6)]. Priapism was not reported with drug initiation
but developed after some time on the drug, often subsequent to an increase in dose.
Priapism has also appeared during a period of drug withdrawal (drug holidays or during
discontinuation). Patients who develop abnormally sustained or frequent and painful
erections should seek immediate medical attention.

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

Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized
to either methylphenidate or nonmedication treatment groups over 14 months, as well as in
naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated children
over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children
(i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth
rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight
over 3 years), without evidence of growth rebound during this period of development.
Published data are inadequate to determine whether chronic use of amphetamines may cause
similar suppression of growth; however, it is anticipated that they likely have this effect as
well. Therefore, growth should be monitored during treatment with stimulants, and patients
who are not growing or gaining height or weight as expected may need to have their
treatment interrupted.
 

Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant
treatment.

Potential for Gastrointestinal Obstruction
Because the CONCERTA tablet is nondeformable and does not appreciably change in
shape in the GI tract, CONCERTA should not ordinarily be administered to patients with
preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example:
esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due
to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic
intestinal pseudo-obstruction, or Meckel’s diverticulum). There have been rare reports of
obstructive symptoms in patients with known strictures in association with the ingestion of
drugs in nondeformable controlled-release formulations. Due to the controlled-release
design of the tablet, CONCERTA should be used only in patients who are able to swallow
the tablet whole [see Patient Counseling Information ].

Hematologic Monitoring
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

 

PATIENT COUNSELING INFORMATION

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

 

Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including
Raynaud’s Phenomenon]
Instruct patients beginning treatment with CONCERTA about the risk of peripheral
vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms:
fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to
red.

Instruct patients to report to their physician any new numbness, pain, skin color change, or
sensitivity to temperature in fingers or toes.
Instruct patients to call their physician immediately with any signs of unexplained
wounds appearing on fingers or toes while taking CONCERTA.
Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain
patients.

 

General Considerations
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with methylphenidate and
should counsel them in its appropriate use. A patient Medication Guide is available for
CONCERTA. The prescriber or health professional should instruct patients, their families,
and their caregivers to read the Medication Guide and should assist them in understanding
its contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete text
of the Medication Guide is reprinted at the end of this document.

Administration Instructions
Patients should be informed that CONCERTA should 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.

MAO Inhibitors
CONCERTA should not be used in patients being treated (currently or within the
preceding 2 weeks) with MAO inhibitors [see Contraindications (4.5)].

Vasopressor Agents
Because of possible increases in blood pressure, CONCERTA should be used cautiously
with vasopressor agents [see Warnings and Precautions (5.1)].

Coumarin Anticoagulants, Antidepressants, and Selective Serotonin
Reuptake Inhibitors
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.

Pregnancy
Pregnancy Category C

Methylphenidate has been shown to have teratogenic effects in rabbits when given in doses
of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum
recommended human dose on a mg/kg and mg/m2 basis, respectively.

A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to
30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose
of CONCERTA® on a mg/kg and mg/m2 basis, respectively. The approximate plasma
exposure to methylphenidate plus its main metabolite PPAA in pregnant rats was 1-2 times
that seen in trials in volunteers and patients with the maximum recommended dose of
CONCERTA based on the AUC.

The safety of methylphenidate for use during human pregnancy has not been established.
There are no adequate and well-controlled studies in pregnant women. CONCERTA
should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus.

Labor and Delivery
The effect of CONCERTA on labor and delivery in humans is unknown.

Nursing Mothers
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.

In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled
methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was
observed in milk and levels were generally similar to those in plasma.
 

Pediatric Use
CONCERTA should not be used in children under six years, since safety and efficacy in
this age group have not been established. Long-term effects of methylphenidate in children
have not been well established.

Geriatric Use
CONCERTA has not been studied in patients greater than 65 years of age.

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.

The following are discussed in more detail in other sections of the labeling:
• Drug Dependence [see Box Warning]
• Hypersensitivity to Methylphenidate [see Contraindications (4.1)]
• Agitation [see Contraindications (4.2)]
• Glaucoma [see Contraindications (4.3)]
• Tics [see Contraindications (4.4)]
• Monoamine Oxidase Inhibitors [see Contraindications (4.5) and Drug Interactions (7.1)]
• Serious Cardiovascular Events [see Warnings and Precautions (5.1)]
• Psychiatric Adverse Events [see Warnings and Precautions (5.2)]
• Seizures [see Warnings and Precautions (5.3)]
• Priapism [see Warnings and Precautions (5.4)]
• Long-Term Suppression of Growth [see Warnings and Precautions (5.6)]
• Visual Disturbance [see Warnings and Precautions (5.7)]
• Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.8)]
• Hematologic Monitoring [see Warnings and Precautions (5.9)]

The most common adverse reaction in double-blind clinical trials (>5%) in pediatric patients
(children and adolescents) was abdominal pain upper. The most common adverse reactions
in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry
mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis
[see Adverse Reactions (6.1)].

The most common adverse reactions associated with discontinuation (≥1%) from either
pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure
increased [see Adverse Reactions (6.3)].

The development program for CONCERTA included exposures in a total of 3906
participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated
in 6 controlled clinical studies and 11 open-label clinical studies (see Table 3). Safety was
assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing
physical examinations and laboratory analyses.

Table 3. CONCERTA Exposure in Double-Blind and Open-Label Clinical Studies
Patient Population                                                     N                                                Dose Range
Children                                                                      2216                                      18 to 54 mg once daily
Adolescents                                                               502                                        18 to 72 mg once daily
Adults                                                                         1188                                        18 to 108 mg once daily

Adverse events during exposure were obtained primarily by general inquiry and recorded by
clinical investigators using their own terminology. Consequently, to provide a meaningful
estimate of the proportion of individuals experiencing adverse events, events were grouped
in standardized categories using MedDRA terminology.

The stated frequencies of adverse events represent the proportion of individuals who
experienced, at least once, a treatment-emergent adverse event of the type listed. An event
was considered treatment-emergent if it occurred for the first time or worsened while
receiving therapy following baseline evaluation.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse
events that were considered to be reasonably associated with the use of CONCERTA based
on the comprehensive assessment of the available adverse event information. A causal
association for CONCERTA often 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
clinical trials of another drug and may not reflect the rates observed in clinical practice.

The majority of adverse reactions were mild to moderate in severity.

Commonly Observed 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.

Children and Adolescents
Table 4 lists the adverse reactions reported in 1% or more of CONCERTA-treated children
and adolescent subjects in 4 placebo-controlled, double-blind clinical trials.

Table 4. Adverse Reactions Reported by ≥1% of CONCERTA-Treated Children and Adolescent

Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of CONCERTA

System/Organ Class Adverse Reaction	CONCERTA (n=321) %	Placebo (n=318) %
Gastrointestinal Disorders Abdominal pain upper Vomiting	6.2 2.8	3.8 1.6
General Disorders and Administration Site Conditions Pyrexia	2.2	0.9
Infections and Infestations Nasopharyngitis	2.8	2.2
Nervous System Disorders Dizziness	1.9	0
Psychiatric Disorders Insomnia*	2.8	0.3
Respiratory, Thoracic and Mediastinal Disorders Cough Oropharyngeal pain	1.9 1.2	0.9 0.9

*Terms of Initial insomnia (CONCERTA®=0.6%) and Insomnia (CONCERTA®=2.2%) are

combined into Insomnia.

The majority of adverse reactions were mild to moderate in severity.
Adults

Table 5 lists the adverse reactions reported in 1% or more of CONCERTA-treated adults in
2 placebo-controlled, double-blind clinical trials.

Table 5. Adverse Reactions Reported by ≥1% of CONCERTA-Treated Adult Subjects in
2 Placebo-Controlled, Double-Blind Clinical Trials*

System/Organ Class Adverse Reaction	CONCERTA (n=415) %	Placebo (n=212) %
Cardiac Disorders Tachycardia Palpitations	4.8 3.1	0 0.9
Ear and Labyrinth Disorders Vertigo	1.7	0
Eye Disorders Vision blurred	1.7	0.5
Gastrointestinal Disorders Dry mouth Nausea Dyspepsia Vomiting Constipation	14.0 12.8 2.2 1.7 1.4	3.8 3.3 0.9 0.5 0.9
General Disorders and Administration Site Conditions Irritability	5.8	1.4
Infections and Infestations Upper respiratory tract infection	2.2	0.9
Investigations Weight decreased	6.5	3.3
Metabolism and Nutrition Disorders Decreased appetite Anorexia	25.3 1.7	6.6 0
Musculoskeletal and Connective Tissue Disorders Muscle tightness	1.9	0
Nervous System Disorders Headache Dizziness Tremor Paresthesia Sedation Tension headache	22.2 6.7 2.7 1.2 1.2 1.2	15.6 5.2 0.5 0 0 0.5
Psychiatric Disorders Insomnia Anxiety Initial insomnia Depressed mood Nervousness Restlessness Agitation Aggression Bruxism Depression Libido decreased Affect lability Confusional state Tension	12.3 8.2 4.3 3.9 3.1 3.1 2.2 1.7 1.7 1.7 1.7 1.4 1.2 1.2	6.1 2.4 2.8 1.4 0.5 0 0.5 0.5 0.5 0.9 0.5 0.9 0.5 0.5
Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal pain	1.7	1.4
Skin and Subcutaneous Tissue Disorders Hyperhidrosis	5.1	0.9

* Included doses up to 108 mg.

The majority of ADRs were mild to moderate in severity.

Other Adverse Reactions Observed in CONCERTA Clinical Trials
This section includes adverse reactions reported by CONCERTA-treated subjects in
double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all
adverse reactions reported by CONCERTA-treated subjects who participated in open-label
and postmarketing clinical trials.

Blood and Lymphatic System Disorders: Leukopenia

Eye Disorders: Accommodation disorder, Dry eye

Vascular Disorders: Hot flush

Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea

General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling
jittery, Thirst

Infections and Infestations: Sinusitis

Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac
murmur, Heart rate increased

Musculoskeletal and Connective Tissue Disorders: Muscle spasms

Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence

Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack,
Sleep disorder, Tearfulness, Tic

Reproductive System and Breast Disorders: Erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Skin and Subcutaneous Tissue Disorders: Rash, Rash macular

Vascular Disorders: Hypertension

Discontinuation Due to Adverse Reactions
Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to
discontinuation occurred in 2 CONCERTA patients (0.6%) including depressed mood
(1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including
headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor
hyperactivity (1, 0.3%), and tic (1, 0.3%).

In the 2 placebo-controlled studies of adults, 25 CONCERTA patients (6.0%) and 6
placebo patients (2.8%) discontinued due to an adverse reaction. Those events with an
incidence of >0.5% in the CONCERTA patients included anxiety (1.7%), irritability
(1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood
pressure increased and depressed mood had an incidence of >0.5% (0.9%).
In the 11 open-label studies of children, adolescents, and adults, 266 CONCERTA patients
(7.0%) discontinued due to an adverse reaction. Those events with an incidence of
>0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite
(0.7%), and tic (0.6%).

Tics
In a long-term uncontrolled study (n=432 children), the cumulative incidence of new onset
of tics was 9% after 27 months of treatment with CONCERTA.
In a second uncontrolled study (n=682 children) the cumulative incidence of new-onset tics
was 1% (9/682 children). The treatment period was up to 9 months with mean treatment
duration of 7.2 months.

Blood Pressure and Heart Rate Increases
In the laboratory classroom clinical trials in children (Studies 1 and 2), both CONCERTA
once daily and methylphenidate three times daily increased resting pulse by an average of 2
to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly
1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled adolescent trial
(Study 4), 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,
respectively). Mean increases from baseline in blood pressure at the end of the double-blind
phase 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 one placebo-controlled study in adults
(Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse
rate were observed with CONCERTA at the end of the double-blind treatment vs. an
increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood
pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -
0.7 to 2.2 mm Hg (diastolic) for CONCERTA and was 1.1 mm Hg (systolic) and -1.8 mm
Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean
changes from baseline in resting pulse rate were observed for CONCERTA and placebo at
the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively). Mean
changes from baseline in blood pressure at the end of the double–blind treatment for
CONCERTA 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 (5.1]).

Postmarketing Experience
The following additional adverse reactions have been identified during postapproval 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, Extrasystoles, Supraventricular
tachycardia, Ventricular extrasystoles

Eye Disorders: Diplopia, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased

Hepatobiliary disorders: Hepatocellular injury, Acute hepatic failure

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

Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic
enzyme increased, Platelet count decreased, White blood cell count abnormal

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

Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia

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

Reproductive System and Breast Disorders: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders: Raynaud’s phenomenon

DRUG ABUSE AND DEPENDENCE
Controlled Substance
Methylphenidate is a Schedule II controlled substance under the Controlled Substances Act.
 

Abuse
As noted in the Box Warning, 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.

In two placebo-controlled human abuse potential studies, 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 stimulant use to assess relative abuse
potential. For the purpose of this assessment, the response for each of the subjective
measures was defined as the maximum effect within the first 8 hours after dose
administration.

In one study (n=40), both CONCERTA (108 mg) and 60 mg IR MPH compared to placebo
produced statistically significantly greater responses on the five subjective measures
suggestive of abuse potential. In comparisons between the two active treatments, however,
CONCERTA® (108 mg) produced variable responses on positive subjective measures that
were either statistically indistinguishable from (Abuse Potential, Drug Liking,
Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than
(Stimulation – Euphoria) responses produced by 60 mg IR MPH.

In another study (n=49), both doses of CONCERTA (54 mg and 108 mg) and both doses of
IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared
to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses
of CONCERTA® (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg),
respectively, CONCERTA® produced statistically significantly lower subjective responses
on these two scales than IR MPH. CONCERTA® (108 mg) produced responses that were
statistically indistinguishable from the responses on these two scales produced by IR MPH
(50 mg). Differences in subjective responses to the respective doses should be considered in
the context that only 22% of the total amount of methylphenidate in CONCERTA® tablets is
available for immediate release from the drug overcoat [see System Components and
Performance (11.1)].

Although these findings reveal a relatively lower response to CONCERTA® on subjective
measures suggestive of abuse potential compared to IR MPH at roughly equivalent total
MPH doses, the relevance of these findings to the abuse potential of CONCERTA® in the
community is unknown.

Dependence
As noted in the Box Warning, 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.

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, hallucinations (auditory and/or visual), hyperhidrosis, headache, pyrexia,
tachycardia, palpitations, heart rate increased, sinus arrhythmia, hypertension,
rhabdomyolysis, mydriasis, and dry mouth.

Recommended 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.

Poison Control Center
As with the management of all overdosage, the possibility of multiple-drug ingestion
should be considered. The physician may wish to consider contacting a poison control
center for up-to-date information on the management of overdosage with methylphenidate.

Mechanism of Action
Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of
therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.
Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the
presynaptic neuron and increase the release of these monoamines into the extraneuronal
space.
 

Pharmacodynamics
Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is
more pharmacologically active than the l-isomer.

Absorption
Methylphenidate is readily absorbed. Following oral administration of CONCERTA,
plasma methylphenidate concentrations increase rapidly, reaching an initial maximum 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). The relative bioavailability of CONCERTA once daily and methylphenidate
three times daily in adults is comparable.

Figure 1. Mean methylphenidate plasma concentrations in 36 adults, following a single dose of
CONCERTA 18 mg once daily and immediate-release methylphenidate 5 mg three times daily
administered every 4 hours.

 

The mean single-dose pharmacokinetic parameters in 36 healthy adults following the
administration of CONCERTA 18 mg once daily and methylphenidate 5 mg three times
daily are summarized in Table 6.
Table 6. Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults

Parameters	CONCERTA (18 mg once daily) (n=36)	Methylphenidate (5 mg three times daily) (n=35)
Cmax (ng/mL)	3.7 ± 1.0	4.2 ± 1.0
Tmax (h)	6.8 ± 1.8	6.5 ± 1.8
AUCinf (ng•h/mL)	41.8 ± 13.9	38.0 ± 11.0
t½ (h)	3.5 ± 0.4	3.0 ± 0.5

The pharmacokinetics of CONCERTA were evaluated in healthy adults following singleand
multiple-dose administration (steady state) of doses up to 144 mg/day. The mean
half-life was about 3.6 hours. No differences in the pharmacokinetics of CONCERTA
were noted following single and repeated once-daily dosing, indicating no significant drug
accumulation. The AUC and t1/2 following repeated once-daily dosing are similar to those
following the first dose of CONCERTA in a dose range of 18 to 144 mg.

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 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 1/40 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, 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 in adolescent ADHD patients aged 13 to 16 administered their
prescribed dose (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 and adolescents decline biexponentially
following oral administration. The half-life of methylphenidate in adults and adolescents
following oral administration of CONCERTA® was approximately 3.5 hours.

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 three 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.

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 strengths.

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
Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in adolescents compared to children). Some of these differences could be explained by bodyweight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses.
The pharmacokinetics of CONCERTA have 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.

NONCLINICAL TOXICOLOGY

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 30 times and
4 times the maximum recommended human dose of CONCERTA on a mg/kg and mg/m2
basis, respectively. 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 22 times and 5 times the maximum recommended human dose of
CONCERTA on a mg/kg and mg/m2 basis, respectively.
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 80-fold and 8-fold the highest recommended
human dose of CONCERTA on a mg/kg and mg/m2 basis, respectively.

 

CLINICAL STUDIES
CONCERTA was demonstrated to be effective in the treatment of Attention Deficit
Hyperactivity Disorder (ADHD) in 4 randomized, double-blind, placebo-controlled studies
in children and adolescents and 2 double-blind placebo-controlled studies in adults who
met the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD.

Children
Three double-blind, active- and placebo-controlled studies were conducted in 416 children
aged 6 to 12 years. The controlled studies compared CONCERTA given once daily (18,
36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg
total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and
2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary
comparison of interest in all three trials was CONCERTA versus placebo.
Symptoms of ADHD were evaluated by community schoolteachers using the
Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant
reduction in the Inattention/Overactivity subscale versus placebo was shown consistently

across all three controlled studies for CONCERTA. The scores for CONCERTA and
placebo for the three studies are presented in Figure 2.

Figure 2. Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with
CONCERTA once daily (18, 36, or 54 mg) and placebo. 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 were evaluated by laboratory schoolteachers using
the SKAMP* laboratory school rating scale. The combined results from these two studies
demonstrated statistically significant improvements in attention and behavior in patients
treated with CONCERTA versus placebo that were maintained through 12 hours after
dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for CONCERTA
and placebo.
*Swanson, Kotkin, Agler, M-Fynn, and Pelham

 

Figure 3. Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention
(Studies 1 and 2)

 

Adolescents
In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving
177 patients, CONCERTA was demonstrated to be effective in the treatment of ADHD in
adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day). Of 220 patients
who entered an open 4-week titration phase, 177 were titrated to an individualized dose
(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
dose of CONCERTA (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week
double-blind phase. At the end of this phase, mean scores for the investigator rating on the
ADHD Rating Scale demonstrated that CONCERTA was statistically significantly
superior to placebo.
 

Adults
Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to
65 years. The controlled studies compared CONCERTA administered once daily and
placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to
108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18,
36, and 72 mg/day).
Study 5 demonstrated the effectiveness of CONCERTA in the treatment of ADHD in
adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from
baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of
226 patients who entered the 7-week trial, 110 were randomized to CONCERTA and 116
were randomized to placebo. Treatment was initiated at 36 mg/day and patients continued
with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific
improvement criteria with acceptable tolerability. At the final study visit, mean change

scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that
CONCERTA was statistically significantly superior to placebo.
Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group,
dose-response study (5-week duration) with 3 fixed-dose groups (18, 36, and 72 mg).
Patients were randomized to receive CONCERTA administered at doses of 18 mg (n=101),
36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). All three doses of CONCERTA
were statistically significantly more effective than placebo in improving CAARS (Conners’
Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with
ADHD.

REFERENCES
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.
4th ed. Washington, DC: American Psychiatric Association, 1994.

CONCERTA is a central nervous system (CNS) stimulant. CONCERTA is available in
four tablet strengths. Each extended-release tablet for once-a-day oral administration
contains 18, 27, 36, or 54 mg of methylphenidate HCl USP and is designed to have a
12-hour duration of effect. Chemically, methylphenidate HCl is d,l (racemic) methyl
α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C14H19NO2•HCl. Its
structural formula is:

 

Methylphenidate HCl USP is a white, odorless crystalline powder. Its solutions are acid to
litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble
in chloroform and in acetone. Its molecular weight is 269.77.
CONCERTA also contains the following inert 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.

System Components and Performance
CONCERTA uses osmotic pressure to deliver methylphenidate HCl at a controlled rate.
The system, which resembles a conventional tablet in appearance, comprises an
osmotically active trilayer core surrounded by a semipermeable membrane with an

immediate-release drug overcoat. The trilayer core is composed of two drug layers
containing the drug and excipients, and a push layer containing osmotically active
components. There is a precision-laser drilled orifice on the drug-layer end of the tablet. In
an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves
within one hour, providing an initial dose of methylphenidate. Water permeates through the
membrane into the tablet core. As the osmotically active polymer excipients expand,
methylphenidate is released through the orifice. The membrane controls the rate at which
water enters the tablet core, which in turn controls drug delivery. Furthermore, the drug
release rate from the system increases with time over a period of 6 to 7 hours due to the
drug-concentration gradient incorporated into the two drug layers of CONCERTA. The
biologically inert components of the tablet remain intact during gastrointestinal transit and
are eliminated in the stool as a tablet shell along with insoluble core components. It is
possible that CONCERTA extended-release tablets may be visible on abdominal x-rays
under certain circumstances, especially when digital enhancing techniques are utilized.

Not applicable.

2 years

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

CONCERTA (methylphenidate HCl) Extended-release Tablets are available in 18 mg, 27
mg, 36 mg, and 54 mg dosage strengths. The 18 mg tablets are yellow and imprinted with
“alza 18”. The 27 mg tablets are gray and imprinted with “alza 27”. The 36 mg tablets are
white and imprinted with “alza 36”. The 54 mg tablets are brownish-red and imprinted with
“alza 54”. All four dosage strengths are supplied in bottles containing 100 tablets.

18 mg 100-count bottle NDC 50458-585-01
27 mg 100-count bottle NDC 50458-588-01
36 mg 100-count bottle NDC 50458-586-01
54 mg 100-count bottle NDC 50458-587-01

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.