CONCERTA

1 INDICATIONS AND USAGE CONCERTA is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old. Limitations of Use The use of CONCERTA is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.7) and Use in Specific Populations (8.4) ]. CONCERTA is a CNS stimulant indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old. ( 1 ) Limitations of Use The use of CONCERTA is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.7 , 8.4 ).

2 DOSAGE AND ADMINISTRATION Prior to initiating CONCERTA treatment assess for ( 2.1 ): the presence of cardiac disease for family history of tics or Tourette' syndrome and clinically evaluate patients for motor or verbal tics or Tourette's syndrome Administer once daily in the morning with or without food. Swallow whole with liquids; do not chew, divide, or crush. ( 2.2 ) Recommended dosage in pediatric patients 6 to 17 years of age new to methylphenidate: starting dosage is18 mg once daily. May be increased weekly in 18 mg increments. Maximum dosage for pediatric patients ( 2.3 ): 6 to 12 years: 54 mg once daily 13 to 17 years: 72 mg once daily Recommended dosage in adults (up to 65 years of age) new to methylphenidate: starting dosage is 18 mg or 36 mg once daily. May be increased weekly in 18 mg increments, up to 72 mg once daily. ( 2.3 ) Patients currently using immediate-release methylphenidate: starting CONCERTA dosage is based on current dosage regimen. ( 2.4 ) 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. Table 1: Recommended CONCERTA Dosage in Patients New to Methylphenidate Patient Population Recommended Starting Dosage Dosage Range Pediatric patients 6 to 12 years of age 18 mg once daily 18 mg to 54 mg once daily Pediatric patients 13 to 17 years of age 18 mg once daily 18 mg to 72 mg once daily (not to exceed 2 mg/kg/day) Adults 18 to 65 years of age 18 or 36 mg once daily 18 mg to 72 mg once daily 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). Table 2: Recommended Starting Dosage in Patients Switching from Another Methylphenidate Product Previous Immediate-release Methylphenidate Daily Dosage Recommended CONCERTA Starting Dosage 5 mg twice daily or three times daily 18 mg every morning 10 mg twice daily or three times daily 36 mg every morning 15 mg twice daily or three times daily 54 mg every morning 20 mg twice daily or three times daily 72 mg every morning Only for patients 13–65 years of age. 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.

4 CONTRAINDICATIONS CONCERTA is contraindicated in patients: Known to be hypersensitive to methylphenidate or other components of CONCERTA. Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been reported in patients treated with CONCERTA. [see Adverse Reactions (6) ] . Receiving concomitant monoamine oxidase inhibitors (MAOIs), and within 14 days following discontinuation of treatment with a MAO inhibitor because of the risk of a hypertensive crisis [see Drug Interactions (7) ] . Known hypersensitivity to methylphenidate or other components of CONCERTA ( 4 ) Receiving concomitant monoamine oxidase inhibitors and within 14 days following discontinuation of treatment with a MAO inhibitor ( 4 )

5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease ( 5.2 ). Increased 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 ) Priapism : If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention ( 5.5 ) Peripheral Vasculopathy, including Raynaud's Phenomenon : Carefully assess for digital changes during CONCERTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 5.6 ) 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 CONCERTA treatment interrupted. ( 5.7 ) Risk of Gastrointestinal (GI) Obstruction in Patients with GI Narrowing: Only use in patients able to swallow the extended-release tablet whole, and should not ordinarily be used in patients with pre-existing severe GI narrowing. ( 5.8 ) 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. ( 5.9 ) Increased Intraocular Pressure (IOP) 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. ( 5.10 ) 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 CONCERTA treatment if clinically appropriate. ( 5.11 ) 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.

7 DRUG INTERACTIONS Table 6 describes clinically significant drug interactions with CONCERTA. Table 6: Clinically Significant Drug Interactions Monoamine Oxidase Inhibitors Prevention or Management Concomitant use of CNS stimulants, including CONCERTA, with MAOIs or within 14 days after discontinuing an MAOI is contraindicated [ see Contraindications (4) ]. Mechanism and Clinical Effect(s) Concomitant use of MAOIs and CNS stimulants, including CONCERTA, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Antihypertensive Drugs Prevention or Management Increase monitoring for blood pressure and adjust the dosage of the antihypertensive drug, as needed. Mechanism and Clinical Effect(s) CONCERTA may decrease effectiveness of drugs used to treat hypertension [see Warnings and Precautions 5.3 ]. Halogenated Anesthetics Prevention or Management Avoid use of CONCERTA in patients being treated with anesthetics on the day of surgery. Mechanism and Clinical Effect(s) Concomitant use of halogenated anesthetics and CONCERTA may increase the risk of sudden blood pressure and heart rate increase during surgery. Risperidone Prevention or Management Monitor for signs of extrapyramidal symptoms. Mechanism and Clinical Effect(s) The risk of risperidone-associated extrapyramidal symptoms may increase in patients taking concomitant CONCERTA when there is a change in the CONCERTA or risperidone dosage. Antihypertensive drugs : Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7 ) See additional clinically significant drug interactions, in the DRUG INTERACTIONS section ( 7 ).

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) , Drug Abuse and Dependence (9.2) ] Hypersensitivity Reactions [see Contraindications (4) ] Monoamine Oxidase Inhibitors [see Contraindications (4) , Drug Interactions (7) ] 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) ] Priapism [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.6) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7) ] Risks of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing [see Warnings and Precautions (5.8) ] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.9) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.10) ] Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.11) ] The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients 6 to 17 years: upper abdominal pain. ( 6.1 ) Adults up to 65 years of age: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis. ( 6.1 ) 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 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 ]. Table 3: CONCERTA-treated Patients in Double-Blind and Open-Label Clinical Studies Patient Population N Dosage Range Pediatric patients 6 to 12 years of age 2,216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults up to 65 years of age 1,188 18 to 108 mg once daily 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. Table 4: Most Common Adverse Reactions Reported in ≥ 2% of CONCERTA-treated patients in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials CONCERTA (n=321) Placebo (n=318) Upper abdominal pain 6% 4% Insomnia Initial insomnia (CONCERTA=0.6%) and insomnia (CONCERTA=2.2%) terms were combined into Insomnia. 3% 1% Nasopharyngitis 3% 2% Vomiting 3% 2% Pyrexia 2% 1% 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. Table 5: Most Common Adverse Reactions Reported in ≥ 2% of CONCERTA-treated patients in Adults with ADHD in 2 Placebo-Controlled, Double-Blind Clinical Trials CONCERTA Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage). (n=415) Placebo (n=212) Decreased appetite 25% 7% Headache 22% 16% Dry mouth 14% 4% Nausea 13% 3% Insomnia 12% 6% Anxiety 8% 2% Decreased weight 7% 3% Dizziness 7% 5% Irritability 6% 1% Tachycardia 5% 0% Hyperhidrosis 5% 1% Depressed mood 4% 1% Initial insomnia 4% 3% Restlessness 3% 0% Palpitations 3% 1% Nervousness 3% 1% Tremor 3% 1% Upper respiratory tract infection 2% 1% Agitation 2% 1% Dyspepsia 2% 1% 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 basis). The no effect level for maternal body weight in rats is 5 mg/day (equal to the MRHD for adults on a mg/m 2 basis); and the no effect level for embryo-fetal development is 30 mg/kg/day (4 times the MRHD for adults on a mg/m 2 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/m 2 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/m 2 basis).