Dexmethylphenidate Hydrochloride

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 dexmethylphenidate hydrochloride extended-release capsules, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing dexmethylphenidate hydrochloride extended-release capsules ( 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 dexmethylphenidate hydrochloride extended-release capsules 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 : Dexmethylphenidate hydrochloride extended-release capsules-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 dexmethylphenidate hydrochloride extended-release capsules 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 dexmethylphenidate hydrochloride extended-release capsules, 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 Dexmethylphenidate hydrochloride extended-release capsules have a high potential for abuse and misuse. The use of dexmethylphenidate hydrochloride extended-release capsules exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Dexmethylphenidate hydrochloride extended-release capsules 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 dexmethylphenidate hydrochloride extended-release capsules, 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 dexmethylphenidate hydrochloride extended-release capsules, 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 dexmethylphenidate hydrochloride extended-release capsules in a safe place, preferably locked, and instruct patients to not give dexmethylphenidate hydrochloride extended-release capsules to anyone else. Throughout dexmethylphenidate hydrochloride extended-release capsules 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 dexmethylphenidate hydrochloride extended-release 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 dexmethylphenidate hydrochloride extended-release-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 dexmethylphenidate hydrochloride extended-release 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 dexmethylphenidate hydrochloride extended-release capsules.

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). Dexmethylphenidate hydrochloride extended-release-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 dexmethylphenidate hydrochloride extended-release capsules, 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 postmarketing reports 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 dexmethylphenidate hydrochloride extended-release treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for dexmethylphenidate hydrochloride extended-release-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.7 Long-Term Suppression of Growth in Pediatric Patients Dexmethylphenidate hydrochloride extended-release 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 dexmethylphenidate hydrochloride extended-release capsules, the mean weight gain was greater for pediatric patients (ages 6 to 17 years) receiving placebo (+0.4 kg) than for patients receiving dexmethylphenidate hydrochloride extended-release capsules (-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 dexmethylphenidate hydrochloride extended-release-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, dexmethylphenidate hydrochloride extended-release-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 dexmethylphenidate hydrochloride to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor dexmethylphenidate hydrochloride extended-release-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 dexmethylphenidate hydrochloride extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor dexmethylphenidate hydrochloride-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

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 dexmethylphenidate hydrochloride extended-release capsules [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 Teva at 1-888-838-2872 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 Dexmethylphenidate Hydrochloride Extended-Release Capsules in Pediatric Patients with ADHD The safety data in this section is based on data from a 7-week controlled clinical study of dexmethylphenidate hydrochloride extended-release capsules 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 dexmethylphenidate hydrochloride extended-release capsules 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 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 dexmethylphenidate hydrochloride extended-release capsules doses of 5 to 30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extended-release capsules and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release capsules 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 System organ class Adverse reaction Dexmethylphenidate Hydrochloride Extended-Release Capsules 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% Abbreviation: ADHD, attention deficit hyperactivity disorder. 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 dexmethylphenidate hydrochloride extended-release capsules up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride extended-release capsules 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 System organ class Adverse reaction Dexmethylphenidate Hydrochloride Extended-Release Capsules Dexmethylphenidate Hydrochloride Extended-Release Capsules Dexmethylphenidate Hydrochloride Extended-Release Capsules 10 mg/day 20 mg/day 30 mg/day Placebo N = 64 N = 60 N = 58 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% Abbreviation: ADHD, attention deficit hyperactivity disorder. Adverse Reactions in Studies with Dexmethylphenidate Hydrochloride Extended-Release Capsules in Adult Patients with ADHD The safety data in this section is based on data from a 5-week controlled clinical study of dexmethylphenidate hydrochloride extended-release capsules 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 dexmethylphenidate hydrochloride extended-release capsules 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 dexmethylphenidate hydrochloride extended-release-treated patients and 7.5% of the placebo-treated patients discontinued due to adverse reactions. Three patients (1.8%) in the dexmethylphenidate hydrochloride extended-release discontinued due to insomnia and jittery respectively; and two patients (1.2%) in the dexmethylphenidate hydrochloride extended-release 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 dexmethylphenidate hydrochloride extended-release capsules doses of 20, 30, or 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a dexmethylphenidate hydrochloride extended-release capsules dose group and for which the incidences in patients treated with dexmethylphenidate hydrochloride extended-release capsules 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 Dexmethylphenidate Hydrochloride Extended-Release Capsules, 20 mg Dexmethylphenidate Hydrochloride Extended-Release Capsules, 30 mg Dexmethylphenidate Hydrochloride Extended-Release Capsules, 40 mg Placebo N = 57 N = 54 N = 54 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 dexmethylphenidate hydrochloride extended-release capsules 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 dexmethylphenidate hydrochloride extended-release capsules in the treatment of ADHD. Table 4: Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment–Adults Dexmethylphenidate Hydrochloride Extended-Release Capsules, 20 mg (N = 57) Dexmethylphenidate Hydrochloride Extended-Release Capsules, 30 mg (N = 54) Dexmethylphenidate Hydrochloride Extended-Release Capsules, 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 postmarketing 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 dexmethylphenidate hydrochloride extended-release capsules, 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 dexmethylphenidate hydrochloride extended-release capsules, 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.

8.2 Lactation Risk Summary Dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Limited published literature, based on milk sampling from seven mothers' reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dexmethylphenidate hydrochloride extended-release capsules and any potential adverse effects on the breastfed infant from dexmethylphenidate hydrochloride extended-release capsules or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

8.4 Pediatric Use The safety and effectiveness of dexmethylphenidate hydrochloride extended-release capsules have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of dexmethylphenidate hydrochloride extended-release capsules for the treatment of ADHD have been established in pediatric patients aged 6 to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies ( 14.2 )] . Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including dexmethylphenidate hydrochloride extended-release capsules. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.7 )] . Juvenile Animal Toxicity Data Rats treated with racemic methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, racemic methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day of racemic methylphenidate given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use Dexmethylphenidate hydrochloride extended-release capsules have not been studied in the geriatric population.

12.1 Mechanism of Action Dexmethylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics Dexmethylphenidate is the more pharmacologically active d -enantiomer of racemic methylphenidate. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology At the recommended maximum total daily dosage of 40 mg, dexmethylphenidate hydrochloride extended-release capsules do not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics Absorption Dexmethylphenidate hydrochloride extended-release capsules produce a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when orally administered to healthy adults. The initial rate of absorption for dexmethylphenidate hydrochloride extended-release capsules is similar to that of Focalin tablets as shown by the similar rate parameters between the 2 formulations, i.e., first peak concentration (C max1 ), and time to the first peak (t max1 ), which is reached in 1.5 hours (typical range 1 to 4 hours). The mean time to the interpeak minimum (t minip ) is slightly shorter, and time to the second peak (t max2 ) is slightly longer for dexmethylphenidate hydrochloride extended-release capsules given once daily (about 6.5 hours; range, 4.5 to 7 hours) compared to Focalin tablets given in 2 doses 4 hours apart (see Figure 1), although the ranges observed are greater for dexmethylphenidate hydrochloride extended-release capsules. Dexmethylphenidate hydrochloride extended-release capsules given once daily exhibits a lower second peak concentration (C max2 ), higher interpeak minimum concentrations (C minip ), and fewer peak and trough fluctuations than Focalin tablets given in 2 doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1). The ratio of geometric mean of AUC (0-inf) and C max after administration of dexmethylphenidate hydrochloride extended-release capsules given once daily are 1.02 and 0.86 respectively, to the same total dose of Focalin tablets given in 2 doses 4 hours apart. The variability in C max , C min , and AUC is similar between dexmethylphenidate hydrochloride extended-release capsules and Focalin tablets with approximately a 3-fold range in each. Approximately 90% of the dose is absorbed after oral administration of radiolabeled racemic methylphenidate. However, due to first pass metabolism the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%. Figure 1. Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration 1 x 20 mg Dexmethylphenidate Hydrochloride Extended-Release Capsules (n = 24) and 2 x 10 mg Focalin Tablets (n = 25) After single dose administration, dexmethylphenidate hydrochloride extended-release capsules demonstrated dose proportional pharmacokinetics (PK) in the range of 5 mg to 40 mg. For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered [see Dosage and Administration ( 2 )] . Distribution The plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12% to 15%, independent of concentration. Dexmethylphenidate shows a volume of distribution of 2.65 ± 1.11 L/kg. Elimination Plasma dexmethylphenidate concentrations decline monophasically following oral administration of dexmethylphenidate hydrochloride extended-release capsules. The mean terminal elimination half-life of dexmethylphenidate was about 3 hours in healthy adults. Pediatric patients tend to have slightly shorter half-lives with means of 2 to 3 hours. Dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 L/hr/kg after intravenous administration. Metabolism In humans, dexmethylphenidate is metabolized primarily via de-esterification to d-α -phenyl-piperidine acetic acid (also known as d -ritalinic acid). This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo -enantiomer. Excretion After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic dl -methylphenidate was dl -ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose. Studies in Specific Populations Male and Female Patients After administration of dexmethylphenidate hydrochloride extended-release capsules, the first peak, (C max1 ) was on average 45% higher in women. The interpeak minimum and the second peak also tended to be slightly higher in women although the difference was not statistically significant, and these patterns remained even after weight normalization. Racial or Ethnic Groups There is insufficient experience with the use of dexmethylphenidate hydrochloride extended-release capsules to detect ethnic variations in pharmacokinetics. Pediatric Patients The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride extended-release capsules administration have not been studied in pediatrics less than 18 years of age. When a similar formulation of racemic methylphenidate was examined in 15 patients between 10 and 12 years of age, and 3 patients with ADHD between 7 and 9 years of age, the time to the first peak was similar, although the time until the between peak minimum, and the time until the second peak were delayed and more variable in pediatric patients compared to adults. After administration of the same dose to pediatric patients and adults, concentrations in pediatric patients were approximately twice the concentrations observed in adults. This higher exposure is almost completely due to smaller body size as no relevant age-related differences in dexmethylphenidate pharmacokinetic parameters (i.e., clearance and volume of distribution) are observed after normalization to dose and weight. Patients with Renal Impairment There is no experience with the use of dexmethylphenidate hydrochloride extended-release capsules in patients with renal impairment. Since renal clearance is not an important route of methylphenidate elimination, renal impairment is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride extended-release capsules. Patients with Hepatic Impairment There is no experience with the use of dexmethylphenidate hydrochloride extended-release capsules in patients with hepatic impairment. Drug Interaction Studies Methylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to a clinically relevant extent. Inducers or inhibitors of CYPs are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d - and l -enantiomers of methylphenidate did not relevantly inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A. Clinically, methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine. 1

Absorption Dexmethylphenidate hydrochloride extended-release capsules produce a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when orally administered to healthy adults. The initial rate of absorption for dexmethylphenidate hydrochloride extended-release capsules is similar to that of Focalin tablets as shown by the similar rate parameters between the 2 formulations, i.e., first peak concentration (C max1 ), and time to the first peak (t max1 ), which is reached in 1.5 hours (typical range 1 to 4 hours). The mean time to the interpeak minimum (t minip ) is slightly shorter, and time to the second peak (t max2 ) is slightly longer for dexmethylphenidate hydrochloride extended-release capsules given once daily (about 6.5 hours; range, 4.5 to 7 hours) compared to Focalin tablets given in 2 doses 4 hours apart (see Figure 1), although the ranges observed are greater for dexmethylphenidate hydrochloride extended-release capsules. Dexmethylphenidate hydrochloride extended-release capsules given once daily exhibits a lower second peak concentration (C max2 ), higher interpeak minimum concentrations (C minip ), and fewer peak and trough fluctuations than Focalin tablets given in 2 doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1). The ratio of geometric mean of AUC (0-inf) and C max after administration of dexmethylphenidate hydrochloride extended-release capsules given once daily are 1.02 and 0.86 respectively, to the same total dose of Focalin tablets given in 2 doses 4 hours apart. The variability in C max , C min , and AUC is similar between dexmethylphenidate hydrochloride extended-release capsules and Focalin tablets with approximately a 3-fold range in each. Approximately 90% of the dose is absorbed after oral administration of radiolabeled racemic methylphenidate. However, due to first pass metabolism the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%. Figure 1. Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration 1 x 20 mg Dexmethylphenidate Hydrochloride Extended-Release Capsules (n = 24) and 2 x 10 mg Focalin Tablets (n = 25) After single dose administration, dexmethylphenidate hydrochloride extended-release capsules demonstrated dose proportional pharmacokinetics (PK) in the range of 5 mg to 40 mg. For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered [see Dosage and Administration ( 2 )] . Distribution The plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12% to 15%, independent of concentration. Dexmethylphenidate shows a volume of distribution of 2.65 ± 1.11 L/kg. Elimination Plasma dexmethylphenidate concentrations decline monophasically following oral administration of dexmethylphenidate hydrochloride extended-release capsules. The mean terminal elimination half-life of dexmethylphenidate was about 3 hours in healthy adults. Pediatric patients tend to have slightly shorter half-lives with means of 2 to 3 hours. Dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 L/hr/kg after intravenous administration. Metabolism In humans, dexmethylphenidate is metabolized primarily via de-esterification to d-α -phenyl-piperidine acetic acid (also known as d -ritalinic acid). This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo -enantiomer. Excretion After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic dl -methylphenidate was dl -ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose. Studies in Specific Populations Male and Female Patients After administration of dexmethylphenidate hydrochloride extended-release capsules, the first peak, (C max1 ) was on average 45% higher in women. The interpeak minimum and the second peak also tended to be slightly higher in women although the difference was not statistically significant, and these patterns remained even after weight normalization. Racial or Ethnic Groups There is insufficient experience with the use of dexmethylphenidate hydrochloride extended-release capsules to detect ethnic variations in pharmacokinetics. Pediatric Patients The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride extended-release capsules administration have not been studied in pediatrics less than 18 years of age. When a similar formulation of racemic methylphenidate was examined in 15 patients between 10 and 12 years of age, and 3 patients with ADHD between 7 and 9 years of age, the time to the first peak was similar, although the time until the between peak minimum, and the time until the second peak were delayed and more variable in pediatric patients compared to adults. After administration of the same dose to pediatric patients and adults, concentrations in pediatric patients were approximately twice the concentrations observed in adults. This higher exposure is almost completely due to smaller body size as no relevant age-related differences in dexmethylphenidate pharmacokinetic parameters (i.e., clearance and volume of distribution) are observed after normalization to dose and weight. Patients with Renal Impairment There is no experience with the use of dexmethylphenidate hydrochloride extended-release capsules in patients with renal impairment. Since renal clearance is not an important route of methylphenidate elimination, renal impairment is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride extended-release capsules. Patients with Hepatic Impairment There is no experience with the use of dexmethylphenidate hydrochloride extended-release capsules in patients with hepatic impairment. Drug Interaction Studies Methylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to a clinically relevant extent. Inducers or inhibitors of CYPs are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d - and l -enantiomers of methylphenidate did not relevantly inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A. Clinically, methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine. 1