Focalin

1 INDICATIONS AND USAGE Focalin XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies ( 14 )] . Limitations of Use The use of Focalin XR 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 ), Use in Specific Populations ( 8.4 )]. Focalin XR is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) ( 1 ). Limitations of Use The use of Focalin XR 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 • Patients new to methylphenidate: Recommended starting dose is 5 mg once daily for pediatric patients and 10 mg once daily for adults with or without food in the morning ( 2.2 ). • Patients currently on methylphenidate: Focalin XR dosage is half (1/2) the current total daily dosage of methylphenidate ( 2.2 ). • Patients currently on Focalin (dexmethylphenidate) immediate-release tablets: Give the same daily dose of Focalin XR ( 2.2 ). • Titrate weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients ( 2.2 ). • Maximum recommended daily dose: 30 mg in pediatric patients and 40 mg in adults ( 2.2 ). • Capsules may be swallowed whole or opened and the entire contents sprinkled on applesauce ( 2.3 ). 2.1 Pretreatment Screening Prior to treating patients with Focalin XR, 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 Focalin XR [see Warnings and Precautions ( 5.10 )] . 2.2 Recommended Dosage Patients New to Methylphenidate The recommended starting dosage of Focalin XR for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate are: • Pediatric patients: Start with 5 mg orally once daily in the morning with or without food. • Adult patients: Start with 10 mg orally once daily in the morning with or without food. Patients Currently on Methylphenidate The recommended starting dose of Focalin XR for patients currently using methylphenidate is half (1/2) the total daily dose of racemic methylphenidate. Patients currently using Focalin (dexmethylphenidate) immediate-release tablets may be given the same daily dose of Focalin XR. Titration Schedule The dose may be titrated weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients. The dose should be individualized according to the needs and response of the patient. Daily doses above 30 mg in pediatrics and 40 mg in adults have not been studied and are not recommended. 2.3 Administration Instructions Focalin XR is administered orally and may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day. 2.4 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue Focalin XR. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

4 CONTRAINDICATIONS • Hypersensitivity to methylphenidate or other components of Focalin XR. Hypersensitivity reactions, such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions ( 6.1 )] . • Concomitant treatment with monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions ( 7.1 )] . • Known hypersensitivity to methylphenidate or other components of Focalin XR ( 4 ). • Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 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 Focalin XR, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing Focalin XR ( 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: Careful observation for digital changes is necessary during Focalin XR 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 treatment interrupted ( 5.7 ). • Acute Angle Closure Glaucoma: Focalin XR-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist ( 5.8 ). • Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe Focalin XR 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 ( 5.9 ). • Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating Focalin XR, 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 ( 5.10 ). 5.1 Abuse, Misuse, and Addiction Focalin XR has a high potential for abuse and misuse. The use of Focalin XR exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Focalin XR 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 Focalin XR, 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 Focalin XR, 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 Focalin XR in a safe place, preferably locked, and instruct patients to not give Focalin XR to anyone else. Throughout Focalin XR 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 Focalin XR 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 cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Some patients may have larger increases. Monitor all Focalin XR-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 mood episode in patients. Prior to initiating Focalin XR treatment, screen patients for risk factors for developing 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 to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing Focalin XR. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. 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). Focalin XR-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 Focalin XR, 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 at and at the therapeutic dosage 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 Focalin XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for Focalin XR-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients Focalin XR 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. In a 7-week, double-blind, placebo-controlled study of Focalin XR, the mean weight gain was greater for pediatric patients (ages 6 to 17 years) receiving placebo (+ 0.4 kg) than for patients receiving Focalin XR (- 0.5 kg). Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients 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 Focalin XR-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 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, Focalin XR-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 and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions ( 6.2 )]. Prescribe Focalin to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor Focalin XR-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.10 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. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions ( 6.2 )]. Before initiating Focalin XR, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor Focalin -treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

7 DRUG INTERACTIONS • Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ). 7.1 Clinically Important Drug Interactions With Focalin XR Table 5 presents clinically important drug interactions with Focalin XR. Table 5: Clinically Important Drug Interactions With Focalin XR Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including Focalin XR, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 )]. Intervention Concomitant use of Focalin XR with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical impact Focalin XR may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5.3 )]. Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical impact Concomitant use of halogenated anesthetics and Focalin XR may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of Focalin XR in patients being treated with anesthetics on the day of surgery. Risperidone Clinical impact Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS) Intervention Monitor for signs of EPS

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 , 9.3 )] • Known hypersensitivity to methylphenidate or other ingredients of Focalin XR [see Contraindications ( 4 )] • Hypertensive Crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications ( 4 ), 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 )] • 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 )] • Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.8 )] • Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.9 )] • Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.10 )] The most common adverse reactions (greater than or equal to 5% and twice the rate of placebo): • Pediatric patients 6 to 17 years: dyspepsia, decreased appetite, headache, and anxiety ( 6.1 ). • Adults: dry mouth, dyspepsia, headache, pharyngolaryngeal pain, and anxiety ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Studies with Focalin XR in Pediatric Patients with ADHD The safety data in this section is based on data from a 7-week controlled clinical study of Focalin XR in 100 (103 randomized) pediatric patients with ADHD ages 6 to 17 years (ages 6 to 12, n = 86; ages 13 to 17, n = 17). This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of Focalin XR 5 mg to 30 mg/day who met The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for ADHD [see Clinical Studies ( 14.1 )] . Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dyspepsia, decreased appetite, headache, and anxiety. Adverse Reactions Leading to Discontinuation: 50 of 684 (7.3%) pediatric patients treated with Focalin (dexmethylphenidate) immediate-release tablets experienced an adverse reaction that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each). Table 1 enumerates adverse reactions for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible Focalin XR doses of 5–30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with Focalin XR and for which the incidence in patients treated with Focalin XR was at least twice the incidence in placebo-treated patients. Table 1: Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) With ADHD Abbreviation: ADHD, attention deficit hyperactivity disorder. System organ class Adverse reaction Focalin XR N = 53 Placebo N = 47 Gastrointestinal disorders 38% 19% Dyspepsia 8% 4% Metabolism and nutrition disorders 34% 11% Decreased appetite 30% 9% Nervous system disorders 30% 13% Headache 25% 11% Psychiatric disorders 26% 15% Anxiety 6% 0% Table 2 below enumerates the incidence of dose-related adverse reactions that occurred during a fixed-dose, double-blind, placebo-controlled trial in pediatric patients with ADHD taking Focalin XR up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with Focalin XR for which the incidence was at least 5% and greater than the incidence among placebo-treated patients. Table 2: Dose-Related Adverse Reactions in Pediatric Patients (6 to 17 years of age) With ADHD Abbreviation: ADHD, attention deficit hyperactivity disorder. System organ class Adverse reaction Focalin XR 10 mg/day N = 64 Focalin XR 20 mg/day N = 60 Focalin XR 30 mg/day N = 58 Placebo N = 63 Gastrointestinal disorders 22% 23% 29% 24% Vomiting 2% 8% 9% 0% Metabolism and nutritional disorders 16% 17% 22% 5% Anorexia 5% 5% 7% 0 Psychiatric disorders 19% 20% 38% 8% Insomnia 5% 8% 17% 3% Depression 0 0 3% 0 Mood swings 0% 0% 3% 2% Other adverse reactions Irritability 0% 2% 5% 0% Nasal congestion 0% 0% 5% 0% Pruritus 0% 0% 3% 0% Adverse Reactions in Studies with Focalin XR in Adult Patients with ADHD The safety data in this section is based on data from a 5-week controlled clinical study of Focalin XR in 218 adult patients (221 randomized) with ADHD ages 18 to 60 years. In this study, 101 adult patients were treated for at least 6 months. This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of Focalin XR 20 mg, 30 mg, or 40 mg daily who met DSM-IV criteria for ADHD [see Clinical Studies ( 14.2 )] . Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dry mouth, dyspepsia, headache, anxiety, and pharyngolaryngeal pain. Adverse Reactions Leading to Discontinuation: During the double-blind phase of the study, 10.7% of the Focalin XR-treated patients and 7.5% of the placebo-treated patients discontinued due to adverse reactions. Three patients (1.8%) in the Focalin XR discontinued due to insomnia and jittery respectively; and two patients (1.2%) in the Focalin XR discontinued due to anorexia and anxiety, respectively. Table 3 enumerates adverse reactions for the placebo-controlled, parallel-group study in adults with ADHD at fixed Focalin XR doses of 20, 30, or 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a Focalin XR dose group and for which the incidences in patients treated with Focalin XR appeared to increase with dose. Table 3: Dose-Related Adverse Reactions in Adult Patients (18 to 60 years of age) With ADHD System organ class Adverse reaction Focalin XR 20 mg N = 57 Focalin XR 30 mg N = 54 Focalin XR 40 mg N = 54 Placebo N = 53 Gastrointestinal disorders 28% 32% 44% 19% Dry mouth 7% 20% 20% 4% Dyspepsia 5% 9% 9% 2% Nervous system disorders 37% 39% 50% 28% Headache 26% 30% 39% 19% Psychiatric disorders 40% 43% 46% 30% Anxiety 5% 11% 11% 2% Respiratory, thoracic, and mediastinal disorders 16% 9% 15% 8% Pharyngolaryngeal pain 4% 4% 7% 2% Two other adverse reactions occurring in clinical trials with Focalin XR at a frequency greater than placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness (6% and 2%, respectively). Table 4 summarizes changes in vital signs and weight that were recorded in the adult study (N = 218) of Focalin XR in the treatment of ADHD. Table 4: Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment–Adults Focalin XR 20 mg (N = 57) Focalin XR 30 mg (N = 54) Focalin XR 40 mg (N = 54) Placebo (N = 53) Pulse (bpm) 3.1 ± 11.1 4.3 ± 11.7 6 ± 10.1 -1.4 ± 9.3 Diastolic BP (mmHg) -0.2 ± 8.2 1.2 ± 8.9 2.1 ± 8 0.3 ± 7.8 Weight (kg) -1.4 ± 2 -1.2 ± 1.9 -1.7 ± 2.3 -0.1 ± 3.9 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal: rhabdomyolysis Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis Adverse Reactions Reported With All Ritalin and Focalin Formulations The following adverse reactions associated with the use of all Ritalin and Focalin formulations were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Infections and Infestations: nasopharyngitis Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, depression Nervous System Disorders: headache, dizziness, tremor, dyskinesia, including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Eye Disorders: blurred vision, difficulties in visual accommodation Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris Respiratory, Thoracic, and Mediastinal Disorders: cough Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis, trismus Investigations: weight loss (adult ADHD patients) Vascular Disorders: peripheral coldness, Raynaud's phenomenon Additional Adverse Reactions Reported with Other Methylphenidate Products The list below shows adverse reactions not listed with Ritalin and Focalin formulations that have been reported with other methylphenidate products based on clinical trials data and post-marketing spontaneous reports. Blood and Lymphatic Disorders: pancytopenia Immune System Disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas Psychiatric Disorders: affect lability, mania, disorientation, libido changes Nervous System Disorders: migraine, motor and verbal tics Eye Disorders: diplopia, increased intraocular pressure, mydriasis Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders: diarrhea, constipation Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption Musculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitching Renal and Urinary Disorders: hematuria Reproductive System and Breast Disorders: gynecomastia General Disorders: fatigue, hyperpyrexia Urogenital Disorders: priapism

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Focalin XR, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . Risk Summary Dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants during pregnancy (see Clinical Considerations) . Embryo-fetal development studies in rats showed delayed fetal skeletal ossification at doses up to 5 times the maximum recommended human dose (MRHD) of 20 mg/day given to adults based on plasma levels. A decrease in pup weight in males was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 5 times the MRHD of 20 mg/day given to adults based on plasma levels (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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 Focalin XR, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses 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, dexmethylphenidate was administered orally at doses of up to 20 and 100 mg/kg/day, respectively, during the period of organogenesis. No evidence of malformations was found in either the rat or rabbit study; however, delayed fetal skeletal ossification was observed at the highest dose level in rats. When dexmethylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 20 mg/kg/day, post-weaning body weight gain was decreased in male offspring at the highest dose, but no other effects on postnatal development were observed. At the highest doses tested, plasma levels [area under the curves (AUCs)] of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1 times, respectively, those in adults dosed with 20 mg/day. Plasma levels in adults were comparatively similar to plasma levels in adolescents. Racemic methylphenidate has been shown to cause malformations (increased incidence of fetal spina bifida) in rabbits when given in doses of 200 mg/kg/day throughout organogenesis.