DEXMETHYLPHENIDATE ER 20 MG CP | WHITE IX 685 IMPAX GENERICS 0115992101

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, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing dexmethylphenidate hydrochloride extended-release (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 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-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 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, 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).

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 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 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/day 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 dexmethylphenidate hydrochloride 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 dexmethylphenidate hydrochloride extended-release doses of 5 mg/day to 30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extended-release and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release 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 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 up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride extended-release 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 10 mg/day N=64 Dexmethylphenidate Hydrochloride Extended-Release 20 mg/day N=60 Dexmethylphenidate Hydrochloride Extended-Release 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% Abbreviation: ADHD, attention deficit hyperactivity disorder. Adverse Reactions in Studies with Dexmethylphenidate Hydrochloride Extended-Release 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 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 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 doses of 20 mg/day, 30 mg/day, or 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a dexmethylphenidate hydrochloride extended-release dose group and for which the incidences in patients treated with dexmethylphenidate hydrochloride extended-release 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 20 mg N=57 Dexmethylphenidate Hydrochloride Extended-Release 30 mg N=54 Dexmethylphenidate Hydrochloride Extended-Release 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 dexmethylphenidate hydrochloride extended-release 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 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 20 mg (N=57) Dexmethylphenidate Hydrochloride Extended-Release 30 mg (N=54) Dexmethylphenidate Hydrochloride Extended-Release 40 mg (N=54) Placebo (N=53) Pulse (bpm) 3.1 11.1 4.3 11.7 6.0 10.1 -1.4 9.3 Diastolic BP (mmHg) -0.2 8.2 1.2 8.9 2.1 8.0 0.3 7.8 Weight (kg) -1.4 2.0 -1.2 1.9 -1.7 2.3 -0.1 3.9

The following additional adverse reactions have been identified during post approval 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 Methylphenidate Hydrochloride and Dexmethylphenidate Hydrochloride Formulations The following adverse reactions associated with the use of all methylphenidate hydrochloride and dexmethylphenidate hydrochloride 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 methylphenidate hydrochloride and dexmethylphenidate hydrochloride 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

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, 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 mg/kg/day 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.

The safety and effectiveness of dexmethylphenidate hydrochloride extended-release 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)]. The safety and effectiveness of dexmethylphenidate hydrochloride extended-release in pediatric patients aged less than 6 years have not been established. The long-term efficacy of dexmethylphenidate hydrochloride extended-release in pediatric patients has not been established. Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including dexmethylphenidate hydrochloride extended-release. 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/m2 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/m2 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/m2 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/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

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 dexmethylphenidate hydrochloride tablets as shown by the similar rate parameters between the 2 formulations, i.e., first peak concentration (Cmax1), and time to the first peak (tmax1), which is reached in 1.5 hours (typical range 1 to 4 hours). The mean time to the interpeak minimum (tminip) is slightly shorter, and time to the second peak (tmax2) is slightly longer for dexmethylphenidate hydrochloride extended-release capsules given once daily (about 6.5 hours; range, 4.5 to 7 hours) compared to dexmethylphenidate hydrochloride 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 (Cmax2), higher interpeak minimum concentrations (Cminip), and fewer peak and trough fluctuations than dexmethylphenidate hydrochloride 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 Cmax after administration of dexmethylphenidate hydrochloride extended-release capsules given once daily are 1.02 and 0.86 respectively, to the same total dose of dexmethylphenidate hydrochloride tablets given in 2 doses 4 hours apart. The variability in Cmax, Cmin, and AUC is similar between dexmethylphenidate hydrochloride extended-release capsules and dexmethylphenidate hydrochloride immediate-release 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 (n = 24) Capsules and 2 x 10 mg Dexmethylphenidate Hydrochloride Immediate-Release Tablets (n = 25) After single dose administration, dexmethylphenidate hydrochloride extended-release 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- -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 (d,l-) methylphenidate was d,l-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 capsule, the first peak, (Cmax1) 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 to detect ethnic variations in pharmacokinetics. Pediatric Patients The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride extended-release capsule 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 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. Patients with Hepatic Impairment There is no experience with the use of dexmethylphenidate hydrochloride extended-release 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 co-administration did not increase plasma concentrations of the CYP2D6 substrate desipramine.

Carcinogenesis Lifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In a lifetime carcinogenicity study carried out in B6C3F1 mice, racemic methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas was seen at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day of racemic methylphenidate given to children on a mg/m2-basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Racemic methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) of 60 mg/day of racemic methylphenidate in children on a mg/m2 basis. In a 24-week carcinogenicity study with racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60 mg/kg/day to 74 mg/kg/day of racemic methylphenidate. Mutagenesis Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vivo mouse bone marrow micronucleus test. In an in vitro assay using cultured Chinese Hamster Ovary cells treated with racemic methylphenidate, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Fertility studies have not been conducted with dexmethylphenidate. Racemic methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 10 times the maximum recommended human dose of 60 mg/day of racemic methylphenidate given to adolescents on a mg/m2 basis.

A randomized, double-blind, placebo-controlled, parallel-group study (Study 1) was conducted in 103 pediatric patients (ages 6 to 12, n = 86; ages 13 to 17, n = 17) who met DSM-IV criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes (Study 1). Patients were randomized to receive either a flexible-dose of dexmethylphenidate hydrochloride extended-release (5 mg/day to 30 mg/day) or placebo once daily for 7 weeks. During the first 5 weeks of treatment, patients were titrated to their optimal dose and remained on this optimal dose for the last 2 weeks of the study without dose changes or interruption. Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline to endpoint for dexmethylphenidate hydrochloride extended-release and placebo-treated patients using an intent-to-treat analysis of the primary efficacy outcome measure, the DSM-IV total subscale score of the Conners ADHD/DSM-IV Scales for teachers (CADS-T). The CADS-T includes the ADHD Index (12 items) and the DSM-IV total subscale (18 items, total score range: 0 to 54); the latter is divided into inattentive (9 items) and hyperactive-impulsive (9 items) subscales. Teachers assessed behavior observed during the school day by completing the CADS-T weekly. A decrease in the CADS-T DSM-IV total subscale score from baseline indicates improvement. The CADS-T total scores showed a statistically significant treatment effect in favor of dexmethylphenidate hydrochloride extended-release than placebo (Table 6). There were insufficient adolescents enrolled in this study to assess the efficacy for dexmethylphenidate hydrochloride extended-release in the adolescent population. However, pharmacokinetic considerations and evidence of effectiveness of immediate-release dexmethylphenidate hydrochloride in adolescents support the effectiveness of dexmethylphenidate hydrochloride extended-release in this population. Table 6: Summary of Efficacy Results from ADHD Study in Pediatric Patients (6 to 17 years) (Study 1) Study number Treatment group Primary efficacy measure: CADS-T total score Mean baseline score (SD) LS mean change from baseline (SE) Placebo-subtracted differencea (95% CI) Study 1 Dexmethylphenidate hydrochloride extended-release capsule 5 mg/day to 30 mg/day (n = 52) 33.3 (9.18) 16.41 (1.8) 10.64 (5.38, 15.91) Placebo (n = 45) 34.9 (10.03) 5.77 (1.93) -- Abbreviations: ADHD, attention deficit hyperactivity disorder; SD, standard deviation; SE, standard error; LS Mean, least-squares mean; CI, confidence interval, not adjusted for multiple comparisons. aDifference (drug minus placebo) in least-squares mean change from baseline. In 2 additional cross-over studies (Studies 2 and 3) in pediatric patients ages 6 to 12 years, who received 20 mg dexmethylphenidate hydrochloride extended-release or placebo, dexmethylphenidate hydrochloride extended-release was found to have a statistically significant treatment effect versus placebo on the Swanson, Kotkin, Agler, M-Flynn & Pelham (SKAMP) rating scale total scores at all-time points after dosing in each study (0.5, 1, 3, 4, 5, 7, 9, 10, 11, and 12 hours in Study 2 and 1, 2, 4, 6, 8, 9, 10, 11, and 12 hours in the study 3). SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting. A treatment effect was also observed 0.5 hours after administration of dexmethylphenidate hydrochloride extended-release 20 mg in an additional study of ADHD patients ages 6 to 12 years.

A randomized, double-blind, placebo-controlled, parallel-group (Study 4) was conducted in 221 adult patients ages 18 to 60 years who met DSM-IV criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes (Study 4). Patients were randomized to receive either a fixed dose of dexmethylphenidate hydrochloride extended-release (20 mg/day, 30 mg/day, or 40 mg/day) or placebo once daily for 5 weeks. Patients randomized to dexmethylphenidate hydrochloride extended-release were initiated on a 10 mg/day starting dose and titrated in increments of 10 mg/week to the randomly assigned fixed dose. Patients were maintained on their fixed dose (20 mg/day, 30 mg/day, or 40 mg/day) for a minimum of 2 weeks. Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline to endpoint for dexmethylphenidate hydrochloride extended-release and placebo-treated patients using an intent-to-treat analysis of the primary efficacy outcome measure, the investigator-administered DSM-IV Attention-Deficit/Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS). The DSM-IV ADHD-RS is an 18-item questionnaire with a score range of 0 to 54 points that measures the core symptoms of ADHD and includes both hyperactive/impulsive and inattentive subscales. All 3 dexmethylphenidate hydrochloride extended-release doses (20 mg/day, 30 mg/day, and 40 mg/day) showed a statistically significant treatment effect compared to placebo. There was no obvious increase in effectiveness with increasing the dose. Table 7: Summary of Efficacy Results from ADHD Study in Adults (Study 4) Study number Treatment group Primary efficacy Measure: ADHD-RS total score Mean baseline score (SD) LS mean change from baseline (SE) Placebo-subtracted differencea (95% CI) Study 4 Dexmethylphenidate hydrochloride extended-release capsule 20 mg/day (n = 57) 36.8 (7.2) 13.27 (1.44) 5.71 (1.64, 9.78) Dexmethylphenidate hydrochloride extended-release capsule 30 mg/day (n = 54) 36.9 (8.07) 12.86 (1.48) 5.31 (1.18, 9.44) Dexmethylphenidate hydrochloride extended-release capsule 40 mg/day (n = 54) 36.9 (8.25) 16.51 (1.48) 8.96 (4.83, 13.08) Placebo (n = 53) 37.5 (7.82) 7.55 (1.49) -- Abbreviations: ADHD, attention deficit hyperactivity disorder; SD, standard deviation; SE, standard error; LS Mean, least-squares mean; CI, confidence interval, not adjusted for multiple comparisons. aDifference (drug minus placebo) in least-squares mean change from baseline.

Advise patients to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of dexmethylphenidate hydrochloride extended-release, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), Overdosage (10)]. Advise patients to store dexmethylphenidate hydrochloride extended-release in a safe place, preferably locked, and instruct patients to not give dexmethylphenidate hydrochloride extended-release to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with dexmethylphenidate hydrochloride extended-release use. Instruct patients to contact a healthcare provider immediately if they develop symptoms, such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)]. Increased Blood Pressure and Heart Rate Instruct patients that dexmethylphenidate hydrochloride extended-release can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)]. Psychiatric Adverse Reactions Advise patients that dexmethylphenidate hydrochloride extended-release, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5)]. Circulation Problems in Fingers and Toes (Peripheral Vasculopathy, Including Raynaud s Phenomenon) Instruct patients beginning treatment with dexmethylphenidate hydrochloride extended-release capsules about the risk of peripheral vasculopathy, including Raynaud s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking dexmethylphenidate hydrochloride extended-release. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)]. Long-Term Suppression of Growth in Pediatric Patients Advise patients that dexmethylphenidate hydrochloride extended-release may cause slowing of growth and weight loss [see Warnings and Precautions (5.7)]. Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with dexmethylphenidate hydrochloride extended-release [see Warnings and Precautions (5.9)]. Motor and Verbal Tics, and Worsening of Tourette s Syndrome Advise patients that motor and verbal tics and worsening of Tourette s Syndrome may occur during treatment with dexmethylphenidate hydrochloride extended-release. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette s syndrome occurs [see Warnings and Precautions (5.10)]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including dexmethylphenidate hydrochloride extended-release, during pregnancy [see Use in Specific Populations (8.1)]. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 11-2023-05 Dispense with Medication Guide available at: documents.amneal.com/mg/dexmethylphenidate-hcl-er-30-cap.pdf

Dexmethylphenidate Hydrochloride (dex" meth il fen' i date hye" droe klor' ide) Extended-Release Capsules for oral use, CII What is the most important information I should know about Dexmethylphenidate Hydrochloride Extended-Release Capsules? Dexmethylphenidate hydrochloride extended-release capsules may cause serious side effects, including: Abuse, misuse, and addiction. Dexmethylphenidate hydrochloride extended-release capsules have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of dexmethylphenidate hydrochloride extended-release capsules, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of dexmethylphenidate hydrochloride extended-release capsules or when it is used in ways that are not approved, such as snorting or injection. Your healthcare provider should check you or your child s risk for abuse, misuse, and addiction before starting treatment with dexmethylphenidate hydrochloride extended-release capsules and will monitor you or your child during treatment. Dexmethylphenidate hydrochloride extended-release capsules may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give dexmethylphenidate hydrochloride extended-release capsules to anyone else. See What is dexmethylphenidate hydrochloride extended-release capsules ? for more information. Keep dexmethylphenidate hydrochloride extended-release capsules in a safe place and properly dispose of any unused medicine. See How should I store dexmethylphenidate hydrochloride extended-release capsules ? for more information. Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting dexmethylphenidate hydrochloride extended-release capsules. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking dexmethylphenidate hydrochloride extended-release capsules. Increased blood pressure and heart rate. Your healthcare provider should check you or your child s blood pressure and heart rate regularly during treatment with dexmethylphenidate hydrochloride extended-release capsules. Mental (psychiatric) problems: All Patients new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking dexmethylphenidate hydrochloride extended-release capsules, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What are Dexmethylphenidate Hydrochloride Extended-Release Capsules? Dexmethylphenidate hydrochloride extended-release capsules are a central nervous system stimulant (CNS) prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Dexmethylphenidate hydrochloride extended-release capsules may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Dexmethylphenidate hydrochloride extended-release capsules should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Dexmethylphenidate hydrochloride extended-release capsules are a federally controlled substance (CII) because it contains dexmethylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep dexmethylphenidate hydrochloride extended-release capsules in a safe place to protect it from theft. Never give your dexmethylphenidate hydrochloride extended-release capsules to anyone else because it may cause death or harm them. Selling or giving away dexmethylphenidate hydrochloride extended-release capsules may harm others and is against the law. Who should not take Dexmethylphenidate Hydrochloride Extended-Release Capsules? Dexmethylphenidate hydrochloride extended-release capsules should not be taken if you or your child: are allergic to methylphenidate hydrochloride, or any of the ingredients in dexmethylphenidate hydrochloride extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in dexmethylphenidate hydrochloride extended-release capsules. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor (MAOI). Dexmethylphenidate hydrochloride extended-release capsules may not be right for you or your child. Before starting dexmethylphenidate hydrochloride extended-release capsules, tell your or your child s healthcare provider about all health conditions (or a family history of), including: heart problems, heart disease, heart defects, or high blood pressure mental problems, including psychosis, mania, bipolar illness, or depression circulation problems in fingers or toes have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette s syndrome, or have a family history of tics or Tourette s syndrome. if you are pregnant or plan to become pregnant. It is not known if dexmethylphenidate hydrochloride extended-release capsules will harm your unborn baby. There is a pregnancy registry for females who are exposed to ADHD medications, including dexmethylphenidate hydrochloride extended-release capsules, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to dexmethylphenidate hydrochloride extended-release capsules and their baby. If you or your child becomes pregnant during treatment with dexmethylphenidate hydrochloride extended-release capsules, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD medications at 1-866 -961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. if you are breastfeeding or plan to breastfeed. Dexmethylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with dexmethylphenidate hydrochloride extended-release capsules. Tell your healthcare provider about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Dexmethylphenidate hydrochloride extended-release capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking dexmethylphenidate hydrochloride extended-release capsules. Your healthcare provider will decide whether dexmethylphenidate hydrochloride extended-release capsules can be taken with other medicines. Especially tell your healthcare provider if you or your child takes: anti-depression medicines, including MAOIs blood pressure medicines (anti-hypertensive) Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist. You should not take dexmethylphenidate hydrochloride extended-release capsules on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation. Do not start any new medicine while taking dexmethylphenidate hydrochloride extended-release capsules without talking to your healthcare provider first. How should Dexmethylphenidate Hydrochloride Extended-Release Capsules be taken? Take dexmethylphenidate hydrochloride extended-release capsules exactly as prescribed. Your healthcare provider may adjust the dose until it is right for you or your child. Take dexmethylphenidate hydrochloride extended-release capsules once each day in the morning. Dexmethylphenidate hydrochloride extended-release capsules are an extended-release capsule. Dexmethylphenidate hydrochloride extended-release capsules can be taken with or without food. Taking dexmethylphenidate hydrochloride extended-release capsules with food may slow the time it takes for the medicine to start working. Swallow dexmethylphenidate hydrochloride extended-release capsules whole with water or other liquids. Do not chew, crush, or divide the capsules or the beads in the capsule. If you or your child cannot swallow the capsule, open it and sprinkle the small beads of medicine over a spoonful of applesauce and swallow it right away without chewing. Your healthcare provider may do regular checks of the blood, heart, and blood pressure while taking dexmethylphenidate hydrochloride extended-release capsules. Children should have their height and weight checked often while taking dexmethylphenidate hydrochloride extended-release capsules. Dexmethylphenidate hydrochloride extended-release capsules treatment may be stopped if a problem is found during these check-ups. If you or your child take too many dexmethylphenidate hydrochloride extended-release capsules, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of Dexmethylphenidate Hydrochloride Extended-Release Capsules? Dexmethylphenidate hydrochloride extended-release capsules may cause serious side effects, including: see What is the most important information I should know about Dexmethylphenidate Hydrochloride Extended-Release Capsules? for information on reported heart and mental problems. painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately. circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud s phenomenon): fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have, numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking dexmethylphenidate hydrochloride extended-release capsules. Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with dexmethylphenidate hydrochloride extended-release capsules. Dexmethylphenidate hydrochloride extended-release capsules treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette s syndrome during treatment with dexmethylphenidate hydrochloride extended-release capsules. Common side effects include: Children (6 to 17 years) dyspepsia decreased appetite headache anxiety Adults dry mouth dyspepsia headache anxiety pharyngolaryngeal pain Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Dexmethylphenidate Hydrochloride Extended-Release Capsules? Store dexmethylphenidate hydrochloride extended-release capsules in a safe place and in a tightly closed container at room temperature between 68 to 77 F (20 to 25 C). Dispose of remaining, unused, or expired dexmethylphenidate hydrochloride extended-release capsules by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix dexmethylphenidate hydrochloride extended-release capsules with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away dexmethylphenidate hydrochloride extended-release capsules in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicine. Keep dexmethylphenidate hydrochloride extended-release capsules and all medicines out of the reach of children. General information about the safe and effective use of Dexmethylphenidate Hydrochloride Extended-Release Capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about dexmethylphenidate hydrochloride extended-release capsules that is written for healthcare professionals. Do not use dexmethylphenidate hydrochloride extended-release capsules for a condition for which it was not prescribed. Do not give dexmethylphenidate hydrochloride extended-release capsules to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. What are the ingredients in Dexmethylphenidate Hydrochloride Extended-Release Capsules? Active ingredient: dexmethylphenidate hydrochloride Inactive ingredients: Acetyltributyl citrate, ethylcellulose, gelatin, hypromellose, hypromellose acetate succinate, sugar spheres (which contain sucrose and starch [maize]), talc, and titanium dioxide. The 5 mg capsule also contains FD&C Red #3 and FD&C Blue #1. The 10 mg capsule also contains acid red 27 and FD&C Blue #1. The 15 mg capsule also contains D&C Red #28 and FD&C Blue #1. The 20 mg capsule also contains D&C Red #28, D&C Red #33, and FD&C Blue #1. Black printing ink SW-9008/SW-9009 contains black iron oxide, potassium hydroxide, propylene glycol, and shellac. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 For more information, call 1-877-835-5472. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. 11-2023-05 Dispense with Medication Guide available at: documents.amneal.com/mg/dexmethylphenidate-hcl-er-30-cap.pdf

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