CONCERTA (methylphenidate hydrochloride 36 mg) Dailymed

• CONCERTA should be taken once daily in the morning and swallowed whole with the aid of liquids. CONCERTA should not be chewed or crushed. CONCERTA may be taken with or without food. ( 2.2)
• For children and adolescents new to methylphenidate, the recommended starting dosage is 18 mg once daily. Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 54 mg/day in children and 72 mg/day in adolescents. ( 2.3)
• For adult patients new to methylphenidate, the recommended starting dose is 18 or 36 mg/day. Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 72 mg/day for adults. ( 2.3)
• For patients currently using methylphenidate, dosing is based on current dose regimen and clinical judgment. ( 2.4)

2.1 Pretreatment Screening

Prior to treating patients with CONCERTA, assess:

• for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating CONCERTA [see Warnings and Precautions (5.13)].

2.2 Recommended Dosage

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)] .

2.3 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

2.4 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.

2.5 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.

2.6 Dosage Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue CONCERTA.

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

3 Dosage Forms And Strengths

CONCERTA (methylphenidate HCl) Extended-Release Tablets are available in the following dosage strengths: 18 mg tablets are yellow and imprinted with "alza 18," 27 mg tablets are gray and imprinted with "alza 27," 36 mg tablets are white and imprinted with "alza 36," and 54 mg tablets are brownish-red and imprinted with "alza 54."


Tablets: 18, 27, 36, and 54 mg ( 3)

4 Contraindications

• Known hypersensitivity to the product ( 4.1)
• Do not use CONCERTA in patients currently using or within 2 weeks of using an MAO inhibitor ( 4.2)

4.1 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 (6.5)] .

4.2 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)] .

5 Warnings And Precautions

• Risks to Patients with Serious Cardiac Disease: Avoid in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2)
• Increase in Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3)
• Psychiatric Adverse Reactions: Prior to initiating CONCERTA, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing CONCERTA. ( 5.4)
• Seizures: Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures. ( 5.5)
• Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention ( 5.6)
• Peripheral Vasculopathy, including Raynaud's Phenomenon: Careful observation for digital changes is necessary during CONCERTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 5.7)
• Long-Term Suppression of Growth in Pediatric Patients Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.8)
• Gastrointestinal obstruction with preexisting GI narrowing. ( 5.9)
• Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy. ( 5.10)
• Acute Angle Closure Glaucoma :CONCERTA -treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.11)
• Increased Intraocular Pressure and Glaucoma: 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 patients with a history of increased IOP or open angle glaucoma. ( 5.12)
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating CONCERTA, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. ( 5.13)

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. CONCERTA can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (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 doses 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 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases.

Monitor all CONCERTA-treated patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions

Exacerbation of Pre-existing Psychosis

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

New Psychotic or Manic Symptoms

CNS stimulants, 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 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.

5.6 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients [see Adverse Reactions (6.5)] . Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, 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.

5.7 Peripheral Vasculopathy, including Raynaud's Phenomenon

CNS 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, 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 generally improved after dosage reduction or discontinuation of the CNS stimulant.

Careful observation for digital changes is necessary during CONCERTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for CONCERTA-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.8 Long-Term Suppression of Growth in Pediatric Patients

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturaulic subgroups of newly methylphenidate-treated and nonmedication-treated children over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year 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.

5.9 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 (17)] .

5.10 Hematologic Monitoring

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

5.11 Acute Angle Closure Glaucoma

There have been rare 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.

5.12 Increased Intraocular Pressure and Glaucoma

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.5)].

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.

5.13 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 (6.2, 6.5)] . Worsening of Tourette's syndrome has also been reported .

Before initiating CONCERTA, assess the family history 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 treatment if clinically appropriate.

6 Adverse Reactions

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

• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1)]
• Hypersensitivity to Methylphenidate [see Contraindications (4.1)]
• Monoamine Oxidase Inhibitors [see Contraindications (4.2)and Drug Interactions (7.1)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Seizures [see Warnings and Precautions (5.5)]
• Priapism [see Warnings and Precautions (5.6)]
• Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.7)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.8)]
• Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.9)]
• Hematologic Monitoring [see Warnings and Precautions (5.10)]
• Acute Angle Closure Glaucoma [see Warnings and Precautions (5.11)]
• Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.12)]
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.13)]

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 uled. 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.


The most common adverse reaction in double-blind clinical trials (>5%) in 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. ( 6.1and 6.2)

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

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 uls 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	6.2	3.8
  Vomiting	2.8	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 Â
Psychiatric Disorders
  Insomnia Terms of Initial insomnia (CONCERTA=0.6%) and Insomnia (CONCERTA=2.2%) are combined into Insomnia.	2.8	0.3
Respiratory, Thoracic and Mediastinal Disorders
  Cough	1.9	0.9
  Oropharyngeal pain	1.2	0.9

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

Adults

Table 5 uls 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 Included doses up to 108 mg.

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

The majority of ADRs were mild to moderate in severity.

6.2 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

6.3 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%).

6.4 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 (5.3)] .

6.5 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, Increased intraocular pressure, 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, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics

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