tablets with maois or within 14 days after discontinuing maoi treatment is contraindicated. examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue antihypertensive drugs clinical impact dexmethylphenidate hydrochloride tablets may decrease the effectiveness of drugs used to treat hypertension [see warnings and precautions ( 5.3 )]. intervention adjust the dosage of the antihypertensive drug as needed. examples potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ace) inhibitors, angiotensin ii receptor blockers (arbs), beta blockers, centrally acting alpha-2 receptor agonists halogenated anesthetics clinical impact concomitant use of halogenated anesthetics and dexmethylphenidate hydrochloride tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention monitor blood pressure and avoid use of dexmethylphenidate hydrochloride tablets in patients being treated with anesthetics on the day of surgery. examples halothane, isoflurane, enflurane, desflurane, sevoflurane risperidone clinical impact combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (eps) intervention monitor for signs of eps

. priapism : cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed ( 5.5 ). peripheral vasculopathy, including raynaud’s phenomenon : stimulants used to treat adhd are associated with peripheral vasculopathy, including raynaud’s phenomenon. careful observation for digital changes is necessary during treatment with adhd stimulants ( 5.6 ). long-term suppression of growth: monitor height and weight at appropriate intervals in the pediatric population ( 5.7 ). 5.1 potential for abuse and dependence cns stimulants, including dexmethylphenidate hydrochloride tablets, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see boxed warning , drug abuse and dependence ( 9.2 , 9.3 )] . 5.2 serious cardiovascular reactions sudden death, stroke, and myocardial infarction have been reported in adults with cns stimulant treatment at recommended doses. sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking cns stimulants at recommended doses for adhd. avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during dexmethylphenidate hydrochloride tablets treatment. 5.3 blood pressure and heart rate increases 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). individuals may have larger increases. monitor all patients for hypertension and tachycardia. 5.4 psychiatric adverse reactions exacerbation of preexisting psychosis cns stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting 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 treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). new psychotic or manic symptoms cns stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. if such symptoms occur, consider discontinuing dexmethylphenidate hydrochloride tablets. 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 in placebo-treated patients. 5.5 priapism prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). 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 tablets, used to treat adhd are associated with peripheral vasculopathy, including raynaud’s phenomenon. signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. effects of peripheral vasculopathy, including raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. signs and symptoms generally improve after reduction in dose or discontinuation of drug. careful observation for digital changes is necessary during treatment with adhd stimulants. further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. 5.7 long-term suppression of growth cns stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. careful follow-up of weight and height in 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 consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have 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 period of development. closely monitor growth (weight and height) in pediatric patients treated with cns stimulants, including dexmethylphenidate hydrochloride tablets, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

ords, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for dexmethylphenidate hydrochloride tablets use [see boxed warning , warnings and precautions ( 5.1 ), drug abuse and dependence ( 9.2 , 9.3 )] . 2.2 pediatric patients with attention deficit hyperactivity disorder patients new to methylphenidate the recommended starting dose of dexmethylphenidate hydrochloride tablets for pediatric patients who are not currently taking racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg daily (2.5 mg twice daily) with or without food. patients currently on methylphenidate the recommended starting dose of dexmethylphenidate hydrochloride tablets for pediatric patients currently using methylphenidate is half (1/2) the total daily dose of racemic methylphenidate. titration schedule the dose may be titrated weekly in increments of 2.5 to 5 mg to a maximum of 20 mg daily (10 mg twice daily). the dose should be individualized according to the needs and response of the patient. maintenance/extended treatment pharmacological treatment of adhd may be needed for extended periods. periodically reevaluate the long-term use of dexmethylphenidate hydrochloride tablets and adjust dosage as needed. 2.3 administration instructions dexmethylphenidate hydrochloride tablets are administered orally twice daily, at least 4 hours apart. 2.4 dose reduction and discontinuation if paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue dexmethylphenidate hydrochloride tablets. if improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

te of placebo) in pediatric patients 6 to 17 years were abdominal pain, fever, nausea, and anorexia ( 6.1 ). to report suspected adverse reactions, contact tris pharma, inc. at 1-732-940-0358 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. clinical trials experience with dexmethylphenidate hydrochloride tablets in pediatric patients with adhd the safety data in this section is based on data related to dexmethylphenidate hydrochloride tablets exposure during the premarketing development program in a total of 696 participants in clinical trials (684 patients, 12 healthy adult subjects). these participants received dexmethylphenidate hydrochloride tablets 5, 10, or 20 mg/day. the 684 adhd patients (ages 6 to 17 years) were evaluated in 2 controlled clinical studies, 2 clinical pharmacology studies, and 2 open-label long-term safety studies. most common adverse reactions (incidence of greater than or equal to 5% and at least twice placebo): abdominal pain, fever, anorexia, and nausea adverse reactions leading to discontinuation: overall, 50 of 684 (7.3%) pediatric patients treated with dexmethylphenidate hydrochloride 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 two, placebo-controlled, parallel group studies in pediatric patients with adhd taking dexmethylphenidate hydrochloride tablets doses of 5, 10, and 20 mg/day. the table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride tablets for which the incidence was at least 5% and twice the incidence among placebo-treated patients. table 1: common adverse reactions in pediatric patients (6 to 17 years of age) with adhd system organ class adverse reactions dexmethylphenidate hydrochloride tablets (n = 79) placebo (n = 82) body as a whole abdominal pain 15% 6% fever 5% 1% digestive system anorexia 6% 1% nausea 9% 1% abbreviation: adhd, attention deficit hyperactivity disorder. 6.2 postmarketing experience 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, such as angioedema, anaphylactic reactions adverse reactions reported with all methylphenidate hydrochloride and dexmethylphenidate hydrochloride tablets 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 nervous system disorders: headache, dizziness, tremor, dyskinesia, including choreoatheetoid 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, and bone disorders: arthralgia, muscle cramps, rhabdomyolysis investigations: weight loss (adult adhd patients) additional adverse reactions reported with other methylphenidate-containing 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 psychiatric disorders: affect lability, mania, disorientation, libido changes nervous system disorders: migraine eye disorders: diplopia, mydriasis cardiac disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole vascular disorders: peripheral coldness, raynaud's phenomenon 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 urogenital disorders: priapism

tablets with maois or within 14 days after discontinuing maoi treatment is contraindicated. examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue antihypertensive drugs clinical impact dexmethylphenidate hydrochloride tablets may decrease the effectiveness of drugs used to treat hypertension [see warnings and precautions ( 5.3 )]. intervention adjust the dosage of the antihypertensive drug as needed. examples potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ace) inhibitors, angiotensin ii receptor blockers (arbs), beta blockers, centrally acting alpha-2 receptor agonists halogenated anesthetics clinical impact concomitant use of halogenated anesthetics and dexmethylphenidate hydrochloride tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention monitor blood pressure and avoid use of dexmethylphenidate hydrochloride tablets in patients being treated with anesthetics on the day of surgery. examples halothane, isoflurane, enflurane, desflurane, sevoflurane risperidone clinical impact combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (eps) intervention monitor for signs of eps

man 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. plasma levels in adults were comparatively similar to plasma levels in adolescents (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 tablets, 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 the mrhd of 20 mg/day. 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 tablets and any potential adverse effects on the breastfed infant from dexmethylphenidate hydrochloride tablets 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 tablets have been established in pediatric patients ages 6 to 17 years in two adequate and well-controlled clinical trials [see clinical studies ( 14 )] . the safety and effectiveness of dexmethylphenidate hydrochloride tablets in pediatric patients less than 6 years have not been established. the long-term efficacy of dexmethylphenidate hydrochloride tablets in pediatric patients has not been established. long term suppression of growth growth should be monitored during treatment with stimulants, including dexmethylphenidate hydrochloride tablets. 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 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 tablets have not been studied in the geriatric population.

iven 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. plasma levels in adults were comparatively similar to plasma levels in adolescents (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 tablets, 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 the mrhd of 20 mg/day. 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.

it 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 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.

ations increase rapidly, reaching a maximum in the fasted state at about 1 to 1.5 hours postdose. no differences in the pharmacokinetics of dexmethylphenidate were noted following single and repeated twice daily dosing, thus indicating no significant drug accumulation in children with adhd. after single dose administration of dexmethylphenidate hydrochloride tablets to pediatric patients, dexmethylphenidate exposure (c max and auc 0-inf ) showed dose-proportional increase in the range of 2.5 mg to 10 mg. comparable plasma dexmethylphenidate levels were achieved following single dl-threo -methylphenidate hcl doses given as capsules in twice the total mg amount (equimolar with respect to dexmethylphenidate). 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%. effect of food high fat breakfast did not significantly affect c max or auc 0-inf of dexmethylphenidate when two 10 mg dexmethylphenidate hydrochloride tablets were administered, but delayed t max from 1.5 hours post dose to 2.9 hours post dose. 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 declined exponentially following oral administration of dexmethylphenidate hydrochloride tablets. intravenous dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 l/hr/kg. the mean terminal elimination half-life of dexmethylphenidate was approximately 2.2 hours. 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 little or 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 special populations male and female patients pharmacokinetic parameters were similar for boys and girls (mean age 10 years). in a single dose study conducted in adults, the mean dexmethylphenidate auc 0-inf values (adjusted for body weight) following single two 10 mg doses of dexmethylphenidate hydrochloride were 25% to 35% higher in adult female volunteers (n = 6) compared to male volunteers (n = 9). both t max and t 1/2 were comparable for males and females. racial or ethnic groups there is insufficient experience with the use of dexmethylphenidate hydrochloride to detect ethnic variations in pharmacokinetics. pediatric patients the pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride tablets administration have not been studied in children less than 6 years of age. when single doses of dexmethylphenidate hydrochloride tablets were given to children between the ages of 6 to 12 years and healthy adult volunteers, c max of dexmethylphenidate was similar, however, pediatric patients showed somewhat lower aucs compared to the adults. patients with renal impairment there is no experience with the use of dexmethylphenidate hydrochloride tablets in patients with renal impairment. since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride tablets. patients with hepatic impairment there is no experience with the use of dexmethylphenidate hydrochloride tablets 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.

n 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%. effect of food high fat breakfast did not significantly affect c max or auc 0-inf of dexmethylphenidate when two 10 mg dexmethylphenidate hydrochloride tablets were administered, but delayed t max from 1.5 hours post dose to 2.9 hours post dose. 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 declined exponentially following oral administration of dexmethylphenidate hydrochloride tablets. intravenous dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 l/hr/kg. the mean terminal elimination half-life of dexmethylphenidate was approximately 2.2 hours. 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 little or 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 special populations male and female patients pharmacokinetic parameters were similar for boys and girls (mean age 10 years). in a single dose study conducted in adults, the mean dexmethylphenidate auc 0-inf values (adjusted for body weight) following single two 10 mg doses of dexmethylphenidate hydrochloride were 25% to 35% higher in adult female volunteers (n = 6) compared to male volunteers (n = 9). both t max and t 1/2 were comparable for males and females. racial or ethnic groups there is insufficient experience with the use of dexmethylphenidate hydrochloride to detect ethnic variations in pharmacokinetics. pediatric patients the pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride tablets administration have not been studied in children less than 6 years of age. when single doses of dexmethylphenidate hydrochloride tablets were given to children between the ages of 6 to 12 years and healthy adult volunteers, c max of dexmethylphenidate was similar, however, pediatric patients showed somewhat lower aucs compared to the adults. patients with renal impairment there is no experience with the use of dexmethylphenidate hydrochloride tablets in patients with renal impairment. since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride tablets. patients with hepatic impairment there is no experience with the use of dexmethylphenidate hydrochloride tablets 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.

ly 4 times the mrhd (children) of 60 mg/day of racemic methylphenidate on a mg/m 2 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 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 mrhd of 60 mg/day of racemic methylphenidate given adolescents on a mg/m 2 basis.

ren) of 60 mg/day of racemic methylphenidate on a mg/m 2 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 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 mrhd of 60 mg/day of racemic methylphenidate given adolescents on a mg/m 2 basis.

doubled at weekly intervals, depending on clinical response and tolerability, up to the maximum dose. the primary outcome was change from baseline to week 4 of the average score (an average of 2 ratings during the week) of the teacher’s version of the swanson, nolan and pelham (snap)-adhd rating scale. this 18 item scale measures adhd symptoms of inattention and hyperactivity/impulsivity, rated on a scale of 0 (not at all) to 3 (very much). patients treated with dexmethylphenidate hydrochloride tablets showed a statistically significant improvement in symptom scores from baseline over patients who received placebo (table 3). table 3: summary of efficacy results from adhd acute-phase study in pediatric patients (6 to 17 years) (study 1) abbreviations: adhd, attention deficit hyperactivity disorder; sd, standard deviation; snap; swanson, nolan and pelham; n, number of patients available at the assessment time point. a average of two ratings. b statistically significantly different from placebo. study number treatment group primary efficacy measure: teacher snap-adhd total score a mean baseline score (sd) mean change from baseline week 4 score (sd) study 1 dexmethylphenidate hydrochloride tablets 5-20 mg/day b (n = 44) 1.4 (0.7) (n = 42) - 0.7 (0.7) (n = 42) placebo (n = 42) 1.6 (0.7) (n = 41) - 0.2 (0.7) (n = 39) study 2 was a multicenter, placebo-controlled, double-blind, 2-week treatment withdrawal study in 75 children (ages 6 to 12 years) who were responders during a 6-week, open-label initial treatment period. children took study medication twice a day separated by a 3.5 to 5.5 hour interval. the primary outcome was proportion of treatment failures at the end of the 2-week withdrawal phase, where treatment failure was defined as a rating of 6 (much worse) or 7 (very much worse) on the investigator clinical global impression - improvement (cgi-i). patients continued on dexmethylphenidate hydrochloride tablets showed a statistically significant lower rate of failure over patients who received placebo (table 4). table 4: summary of efficacy results from adhd randomized withdrawal study in pediatric patients (6 to 17 years) (study 2) abbreviation: adhd, attention deficit hyperactivity disorder. a one patient did not have the value at visit 10 and hence not included in this analysis. b statistically significantly different from placebo. study number treatment group primary efficacy measure: proportion of treatment failure a number of treatment failures / number of randomized patients percentage study 2 dexmethylphenidate hydrochloride tablets 5-20 mg/day b 6/35 17.1% placebo 25/40 62.5%

pose of remaining, unused, or expired dexmethylphenidate hydrochloride tablets by a medicine takeback program or by an authorized collector registered with the drug enforcement administration. if no take-back program or authorized collector is available, mix dexmethylphenidate hydrochloride tablets with an undesirable, nontoxic substance to make it less appealing to children and pets. place the mixture in a container, such as a sealed plastic bag and discard dexmethylphenidate hydrochloride tablets in the household trash.

including sudden death, myocardial infarction, stroke, and hypertension with dexmethylphenidate hydrochloride tablets 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 )] . blood pressure and heart rate increases instruct patients that dexmethylphenidate hydrochloride tablets can cause elevations of their blood pressure and pulse rate [see warnings and precautions ( 5.3 )] . psychiatric risks advise patients that dexmethylphenidate hydrochloride tablets, 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 tablets 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 tablets. further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see warnings and precautions ( 5.6 )] . suppression of growth advise patients that dexmethylphenidate hydrochloride tablets may cause slowing of growth and weight loss [see warnings and precautions ( 5.7 )] . pregnancy registry advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to adhd medications, including dexmethylphenidate hydrochloride tablets, during pregnancy [see use in specific populations ( 8.1 )] . manufactured by: tris pharma, inc. monmouth junction, nj 08852 lb8408 rev 04 08/2021