ee 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 may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention monitor blood pressure and avoid use of dexmethylphenidate hydrochloride in patients being treated with anesthetics on the day of surgery. examples halothane, isoflurane, enflurane, desflurane, sevoflurane antihypertensive drugs: monitor blood pressure. adjust dosage of antihypertensive drug as needed(7.1). halogenated anesthetics: avoid use of dexmethylphenidate hydrochloride tablets on the day of surgeryif halogenated anesthetics will be used(7.1).

e, or arrhythmias during dexmethylphenidate hydrochloride treatment. 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 bpm). individuals may have larger increases. monitor all patients for hypertension and tachycardia. 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 tablet. 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. 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. peripheral vasculopathy, including raynaud’s phenomenon cns stimulants, including dexmethylphenidate hydrochloride tablet, 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. 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 tablet, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. serious cardiovascular events: sudden death has been reported in association with cns-stimulant treatment at usual doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. in adults, sudden death, stroke, and myocardial infarction have been reported. avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, arrhythmias, or coronary artery disease (5.2). • blood pressure and heart rate increases: monitor blood pressure and pulse. consider the benefits and risk in patients for whom an increase in blood pressure or heart rate would be problematic (5.3). • psychotic adverse reactions: use of stimulants may cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychiatric illness. evaluate for pre- existing psychotic or bipolar disorder prior to dexmethylphenidate hydrochloride tablets use (5.4). • 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).

s 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 tablet for pediatric patients currently using methylphenidate is half 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 and adjust dosage as needed. 2.3 administration instructions dexmethylphenidate hydrochloride tablet is 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 tablet. if improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. administer orally twice daily, 4 hours apart with or without food(2) for patients new to methylphenidate: recommend starting dose of 5mg once daily (2.5 mg twice daily)(2.2). for patients currently taking methylphenidate: initiate dexmethylphenidate hydrochloride therapy with half (1/2) the current total daily dose of methylphenidate(2.3). titrate weekly in increments of 2.5 to 5 mg to a maximum of 20 mg/day (10 mg twice daily)(2.2).

se 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 in pediatric patients with adhd the safety data in this section is based on data related to dexmethylphenidate hydrochloride 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 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 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 tablet doses of 5, 10, and 20 mg/day. the table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride tablet 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 tablet (n = 79) placebo (n = 82) body as a whole abdominal pain 15% 6% fever 5% 1% digestive system anorexia 6% 1% 9% 1% * adhd: attention deficit hyperactivity disorder 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 ritalin and dexmethylphenidate hydrochloride formulations the following adverse reactions associated with the use of all ritalin 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 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 ritalin and dexmethylphenidate hydrochloride formulations [see adverse reactions (6.2)] 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 the most common adverse reactions (greater than or equal to 5% and twice the rate of placebo) in pediatric patients 6 to 17 years were abdominal pain, fever, nausea, and anorexia, ( 6.1) to report suspected adverse reactions, contact lupin pharmaceuticals, inc. at 908-603-6000 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

ee 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 may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention monitor blood pressure and avoid use of dexmethylphenidate hydrochloride in patients being treated with anesthetics on the day of surgery. examples halothane, isoflurane, enflurane, desflurane, sevoflurane antihypertensive drugs: monitor blood pressure. adjust dosage of antihypertensive drug as needed(7.1). halogenated anesthetics: avoid use of dexmethylphenidate hydrochloride tablets on the day of surgeryif halogenated anesthetics will be used(7.1).

en 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, 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 (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 and any potential adverse effects on the breastfed infant from dexmethylphenidate hydrochloride 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 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 in pediatric patients less than 6 years have not been established. the long-term efficacy of dexmethylphenidate hydrochloride 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/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 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. 8.5 geriatric use dexmethylphenidate hydrochloride has not been studied in the geriatric population.

sis. adequate and well-controlled studies in pregnant women have not been conducted. dexmethylphenidate hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. nursing mothers it is not known whether dexmethylphenidate is excreted in human milk. because many drugs are excreted in human milk, caution should be exercised if dexmethylphenidate hydrochloride is administered to a nursing woman. pediatric use the safety and efficacy of dexmethylphenidate hydrochloride in children under 6 years old have not been established. long-term effects of dexmethylphenidate hydrochloride in children have not been well established (see warnings ). 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 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [mrhd] of racemic methylphenidate 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 (12 times the racemic mrhd on a mg/m2 basis). the no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the racemic mrhd on a mg/m2 basis). the clinical significance of the long-term behavioral effects observed in rats is unknown.

s with adhd, plasma dexmethylphenidate concentrations increase rapidly, reaching a maximum in the fasted state at about 1 to 1.5 hours postdose. no differences in the pharmacokinetics of dexmethylphenidate hydrochloride 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 tablet to pediatric patients, dexmethylphenidate exposure (cmax and auc0-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 hydrochloride tablet). 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 cmax or auc0-inf of dexmethylphenidate when two 10 mg dexmethylphenidate hydrochloride tablets were administered, but delayed tmax 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 auc0-inf values (adjusted for body weight) following single two 10 mg doses of dexmethylphenidate hydrochloride tablets were 25% to 35% higher in adult female volunteers (n = 6) compared to male volunteers (n = 9). both tmax and t1/2 were comparable for males and females. racial or ethnic groups there is insufficient experience with the use of dexmethylphenidate hydrochloride tablets 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 tablet were given to children between the ages of 6 to 12 years and healthy adult volunteers, cmax 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 tablet 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 tablet. patients with hepatic impairment there is no experience with the use of dexmethylphenidate hydrochloride tablet 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. pharmacodynamics dexmethylphenidate hydrochloride is a central nervous system stimulant. dexmethylphenidate hydrochloride, the more pharmacologically active enantiomer of the d- and l-enantiomers, is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. the mode of therapeutic action in attention deficit hyperactivity disorder (adhd) is not known. effects on qt interval the effect of dexmethylphenidate hydrochloride extended-release capsules on the qt interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate hydrochloride extended-release capsules, 40mg in 75 healthy volunteers. ecgs were collected up to 12 hours postdose. frederica's method for heart rate correction was employed to derive the corrected qt interval (qtcf). the maximum mean prolongation of qtcf intervals was <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. this was below the threshold of clinical concern and there was no evident-exposure response relationship. pharmacokinetics absorption dexmethylphenidate hydrochloride is readily absorbed following oral administration of dexmethylphenidate hydrochloride tablets. in patients with adhd, plasma dexmethylphenidate concentrations increase rapidly, reaching a maximum in the fasted state at about 1 to 1.5 hours postdose. no differences in the pharmacokinetics of dexmethylphenidate hydrochloride were noted following single and repeated twice daily dosing, thus indicating no significant drug accumulation in children with adhd. when given to children as capsules in single doses of 2.5 mg, 5 mg, and 10 mg, c max and auc 0-inf of dexmethylphenidate were proportional to dose. in the same study, plasma dexmethylphenidate levels were comparable to those achieved following single dl-threo- methylphenidate hcl doses given as capsules in twice the total mg amount (equimolar with respect to dexmethylphenidate hydrochloride). food effects in a single dose study conducted in adults, coadministration of 2 x 10 mg dexmethylphenidate hydrochloride with a high fat breakfast resulted in a dexmethylphenidate t max of 2.9 hours postdose as compared to 1.5 hours postdose when given in a fasting state. c max and auc 0-inf were comparable in both the fasted and non-fasted states. distribution plasma dexmethylphenidate concentrations in children decline exponentially following oral administration of dexmethylphenidate hydrochloride. metabolism and excretion in humans, dexmethylphenidate is metabolized primarily to d- α-phenyl-piperidine acetic acid (also known as d- ritalinic acid) by de-esterification. this metabolite has little or no pharmacological activity. there is little or no in vivo interconversion to the l-threo -enantiomer, based on a finding of minute levels of l-threo -methylphenidate being detectable in a few samples in only 2 of 58 children and adults. after oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. the main urinary metabolite was ritalinic acid, accountable for approximately 80% of the dose. in vitro studies showed that dexmethylphenidate did not inhibit cytochrome p450 isoenzymes. the mean plasma elimination half-life of dexmethylphenidate is approximately 2.2 hours. special populations gender 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 2 x 10 mg doses of dexmethylphenidate hydrochloride were 25%-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. race there is insufficient experience with the use of dexmethylphenidate hydrochloride to detect ethnic variations in pharmacokinetics. age the pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride administration have not been studied in children less than 6 years of age. when single doses of dexmethylphenidate hydrochloride were given to children between the ages of 6 to 12 years and healthy adult volunteers, c max of dexmethylphenidate was similar, however, children showed somewhat lower aucs compared to the adults. renal insufficiency there is no experience with the use of dexmethylphenidate hydrochloride in patients with renal insufficiency. after oral administration of radiolabeled racemic methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid. since very little unchanged drug is excreted in the urine, renal insufficiency is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride. hepatic insufficiency there is no experience with the use of dexmethylphenidate hydrochloride in patients with hepatic insufficiency. (see precautions, drug interactions ). clinical studies dexmethylphenidate hydrochloride was evaluated in 2 double-blind, parallel-group, placebo-controlled trials in untreated or previously treated patients aged 6 to 17 years old with a dsm-iv diagnosis of attention deficit hyperactivity disorder (adhd). both studies included all three subtypes of adhd, i.e. , combined type, predominantly inattentive type, or predominantly hyperactive-impulsive type. while both children and adolescents were included, the sample was predominantly children, thus, the findings are most pertinent to this age group. in both studies, the primary comparison of interest was dexmethylphenidate hydrochloride versus placebo. dexmethylphenidate hydrochloride (5, 10, or 20 mg/day total dose), dl-threo -methylphenidate hcl (10, 20, or 40 mg/day total dose), and placebo were compared in a multicenter, 4-week, parallel group study in n=132 patients. patients took the study medication twice daily, 3.5 to 5.5 hours between doses. treatment was initiated with the lowest dose, and doses could be doubled at weekly intervals, depending on clinical response and tolerability, up to the maximum dose. the change from baseline to week 4 of the averaged score (an average of 2 ratings during the week) of the teacher's version of the snap-adhd rating scale, a scale for assessing adhd symptoms, was the primary outcome. patients treated with dexmethylphenidate hydrochloride showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. figure 1 mean change from baseline in teacher snap-adhd scores in a 4-week double-blind placebo-controlled study of dexmethylphenidate hydrochloride* *figure 1: error bars represent the standard error of the mean. the other study, involving n=75 patients, was a multicenter, placebo-controlled, double-blind, 2-week treatment withdrawal study in children 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 showed a statistically significant lower rate of failure over patients who received placebo. figure 2: percent of treatment failures following a 2 week double-blind placebo-controlled withdrawal of dexmethylphenidate hydrochloride c:\users\ldeepthi\desktop\dexmethyl\dex-fig1.jpg c:\users\ldeepthi\desktop\dexmethyl\dex-fig2.jpg

g dexmethylphenidate hydrochloride with a high fat breakfast resulted in a dexmethylphenidate t max of 2.9 hours postdose as compared to 1.5 hours postdose when given in a fasting state. c max and auc 0-inf were comparable in both the fasted and non-fasted states. distribution plasma dexmethylphenidate concentrations in children decline exponentially following oral administration of dexmethylphenidate hydrochloride. metabolism and excretion in humans, dexmethylphenidate is metabolized primarily to d- α-phenyl-piperidine acetic acid (also known as d- ritalinic acid) by de-esterification. this metabolite has little or no pharmacological activity. there is little or no in vivo interconversion to the l-threo -enantiomer, based on a finding of minute levels of l-threo -methylphenidate being detectable in a few samples in only 2 of 58 children and adults. after oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. the main urinary metabolite was ritalinic acid, accountable for approximately 80% of the dose. in vitro studies showed that dexmethylphenidate did not inhibit cytochrome p450 isoenzymes. the mean plasma elimination half-life of dexmethylphenidate is approximately 2.2 hours. special populations gender 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 2 x 10 mg doses of dexmethylphenidate hydrochloride were 25%-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. race there is insufficient experience with the use of dexmethylphenidate hydrochloride to detect ethnic variations in pharmacokinetics. age the pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride administration have not been studied in children less than 6 years of age. when single doses of dexmethylphenidate hydrochloride were given to children between the ages of 6 to 12 years and healthy adult volunteers, c max of dexmethylphenidate was similar, however, children showed somewhat lower aucs compared to the adults. renal insufficiency there is no experience with the use of dexmethylphenidate hydrochloride in patients with renal insufficiency. after oral administration of radiolabeled racemic methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid. since very little unchanged drug is excreted in the urine, renal insufficiency is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride. hepatic insufficiency there is no experience with the use of dexmethylphenidate hydrochloride in patients with hepatic insufficiency. (see precautions, drug interactions ). clinical studies dexmethylphenidate hydrochloride was evaluated in 2 double-blind, parallel-group, placebo-controlled trials in untreated or previously treated patients aged 6 to 17 years old with a dsm-iv diagnosis of attention deficit hyperactivity disorder (adhd). both studies included all three subtypes of adhd, i.e. , combined type, predominantly inattentive type, or predominantly hyperactive-impulsive type. while both children and adolescents were included, the sample was predominantly children, thus, the findings are most pertinent to this age group. in both studies, the primary comparison of interest was dexmethylphenidate hydrochloride versus placebo. dexmethylphenidate hydrochloride (5, 10, or 20 mg/day total dose), dl-threo -methylphenidate hcl (10, 20, or 40 mg/day total dose), and placebo were compared in a multicenter, 4-week, parallel group study in n=132 patients. patients took the study medication twice daily, 3.5 to 5.5 hours between doses. treatment was initiated with the lowest dose, and doses could be doubled at weekly intervals, depending on clinical response and tolerability, up to the maximum dose. the change from baseline to week 4 of the averaged score (an average of 2 ratings during the week) of the teacher's version of the snap-adhd rating scale, a scale for assessing adhd symptoms, was the primary outcome. patients treated with dexmethylphenidate hydrochloride showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. figure 1 mean change from baseline in teacher snap-adhd scores in a 4-week double-blind placebo-controlled study of dexmethylphenidate hydrochloride* *figure 1: error bars represent the standard error of the mean. the other study, involving n=75 patients, was a multicenter, placebo-controlled, double-blind, 2-week treatment withdrawal study in children 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 showed a statistically significant lower rate of failure over patients who received placebo. figure 2: percent of treatment failures following a 2 week double-blind placebo-controlled withdrawal of dexmethylphenidate hydrochloride c:\users\ldeepthi\desktop\dexmethyl\dex-fig1.jpg c:\users\ldeepthi\desktop\dexmethyl\dex-fig2.jpg

en) of 60 mg/day of racemic methylphenidate 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 60-74 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 (cho) 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 adolescents on a mg/m2 basis.

ose. 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 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 tablet 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 – 17 years) (study 1) study number treat group primary efficacy measure: teacher snap-adhd total score mean baseline score (sd) mean change from baseline week 4 score (sd) study 1 dexmethylphenidate hydrochloride tablets 5-20 mg/dayb (n = 44) placebo (n = 42) 1.4 (0.7) (n = 42) 1.6 (0.7) (n = 41) - 0.7 (0.7) (n = 42) - 0.2 (0.7) (n = 39) adhd: attention deficit hyperactivity disorder; sd: standard deviation; n = number of patients available at the assessment time point. a average of two ratings. b statistically significantly different from placebo 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 tablet 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 – 17 years) (study 2) study number treatment group primary efficacy measure: proportion of treatment failure a number of treatment failure/ number of randomized patients percentage study 2 dexmethylphenidate hydrochloride tablet 5-20 mg/day b placebo 6/35 25/40 17.1% 62.5% 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.

¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦.... ndc 43386-860-10 10 mg tablets: white, round, flat-faced, beveled-edge tablets, debossed with “861” on the one side and “n” on the other side. bottles of 30…………………………………………………. ndc 43386-861-03 bottles of 100........................................................................... ndc 43386-861-01 bottles of 1000………………………………………………. ndc 43386-861-10 store at 20°c to 25°c (68°f to 77°f), with excursions permitted between 15°c and 30°c (59°f to 86°f) [see usp controlled room temperature]. protect from light and moisture. dispense in tight, light-resistant container (usp), with a child-resistant closure. disposal comply with local laws and regulations on drug disposal of cns stimulants. dispose of remaining, unused, or expired dexmethylphenidate hydrochloride tablet 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 tablet 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 tablet in the household trash.