vention: adjust the dosage of the antihypertensive drug as needed. 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. antihypertensive drugs: monitor blood pressure. adjust dosage of antihypertensive drug as needed ( 7 )

les 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 painful or 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 pediatric patients ( 5.7 ) 5.1 potential for abuse and dependence cns stimulants, including methylphenidate hcl extended-release capsules, 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 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 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 methylphenidate hcl extended-release capsules 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 bpm). individuals may have larger increases. monitor all patients for hypertension and tachycardia. 5.4 psychiatric adverse reactions exacerbation of pre-existing psychosis cns stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. induction of a manic episode in patients with bipolar disorder cns stimulants may induce a manic or mixed 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 methylphenidate hcl extended-release capsules. 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 methylphenidate hcl extended-release capsules, used to treat adhd are associated with peripheral vasculopathy, including raynaud’s phenomenon. signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. effects of peripheral vasculopathy, including raynaud’s phenomenon, were observed in postmarketing 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 children 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 children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (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 methylphenidate hcl extended-release capsules. patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

ylphenidate hcl extended-release capsules use [see boxed warning, warnings and precautions ( 5.1 ), drug abuse and dependence ( 9 )] . 2.2 dosage recommendations the recommended starting dose of methylphenidate hcl extended-release capsules is 20 mg once daily. dosage may be adjusted in weekly 10 mg to 20 mg increments to the maximum recommended dose of 60 mg per day. dosage should be individualized according to the needs and responses of the patient. pharmacological treatment of adhd may be needed for extended periods. periodically re-evaluate the long-term use of methylphenidate hcl extended-release capsules, and adjust the dosage as needed. 2.3 administration instructions administer methylphenidate hcl extended-release capsules orally once daily in the morning, before breakfast. swallow the capsule whole with the aid of liquids. alternatively, open the capsule and sprinkle the contents onto a small amount (tablespoon) of applesauce and administer immediately. do not store for future use. drink fluids following the intake of the sprinkled capsule contents with applesauce. the capsules and the capsule contents must not be crushed or chewed. 2.4 dose reduction and discontinuation if paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue methylphenidate hcl extended-release capsules. if improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate hcl extended-release capsules.

report suspected adverse reactions, contact mallinckrodt at 1-800-778-7898 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 practice. clinical trials experience with methylphenidate hcl extended-release capsules included 188 pediatric patients 6 to 15 years old with adhd exposed to methylphenidate hcl extended-release capsules. patients received methylphenidate hcl extended-release capsules 20 mg, 40 mg, and/or 60 mg per day. the 188 patients were evaluated in the following studies: study 1, a 3-week placebo-controlled clinical study consisting of a total of 314 pediatric patients (ages 6 to 15 years; methylphenidate hcl extended-release capsules n=155); study 2, a placebo-controlled, crossover clinical study consisting of 25 pediatric patients (ages 7 to 12 years); and study 3, an uncontrolled clinical study consisting of 8 pediatric patients (ages 6 to 10 years). adverse reactions leading to discontinuation of treatment in the 3-week placebo-controlled, parallel-group trial, two methylphenidate hcl extended-release capsules-treated patients (1%) and no placebo-treated patients discontinued due to an adverse reaction (rash and pruritus; and headache, abdominal pain, and dizziness, respectively). most common adverse reactions the most common adverse reactions that occurred in 5% or more of patients treated with methylphenidate hcl extended-release capsules in a pool of studies 1, 2 and 3 (ages 6 to 15 years) where the incidence in patients treated with methylphenidate hcl extended-release capsules was at least twice the incidence in placebo-treated patients were anorexia and insomnia. adverse reactions that occurred in ≥5% of patients treated with methylphenidate hcl extended-release capsules and greater than placebo in pooled studies 1, 2, and 3 are presented in table 2: table 2: adverse reactions (≥5% and greater than placebo) in pediatric patients ages 6 to 15 years receiving methylphenidate hcl extended-release capsules in pooled three to four week trials body system preferred term methylphenidate hcl extended-release capsules (n=188) % placebo (n=190) % general headache 12 8 abdominal pain (stomachache) 7 4 digestive system anorexia 9 2 nervous system insomnia 5 2 6.2 postmarketing experience the following adverse reactions have been identified during postmarketing use of methylphenidate hcl extended-release capsules and other methylphenidate hcl products. because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. adverse reactions with methylphenidate hcl extended-release capsules blood and the lymphatic system disorders: thrombocytopenia cardiac disorders: cardiac arrest, sudden death immune system disorders: angioedema musculoskeletal and connective tissue disorders: rhabdomyolysis psychiatric disorders: abnormal behavior, aggression, anxiety, irritability, obsessive-compulsive disorder, suicidal behavior (including completed suicide), libido changes, serotonin syndrome in combination with serotonergic drugs nervous system disorders : migraine, reversible ischemic neurological deficit, bruxism skin and subcutaneous tissue disorders: fixed drug eruption vascular disorders: peripheral coldness, raynaud’s phenomenon adverse reactions with other methylphenidate hcl products blood and the lymphatic system disorders: leukopenia, anemia, pancytopenia cardiac disorders: palpitations, increased blood pressure, tachycardia, angina pectoris, cardiac arrhythmia, myocardial infarction, bradycardia, extrasystole eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis gastrointestinal disorders: nausea, abdominal pain, dry mouth, vomiting, dyspepsia, diarrhea, constipation general disorders: fatigue, hyperpyrexia hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury immune system disorders : hypersensitivity, including anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas infections and infestations: nasopharyngitis metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, myalgia, muscle twitching nervous system disorders : nervousness, dizziness, headache, dyskinesia, including choreoatheetoid movements, drowsiness, tremor, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs psychiatric disorders: depressed mood, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), affect liability, mania, disorientation renal and urinary disorders: hematuria reproductive system and breast disorders: gynecomastia respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, dyspnea, cough skin and subcutaneous tissue disorders: scalp hair loss, hyperhidrosis, angioneurotic edema, erythema, exfoliative dermatitis, thrombocytopenic purpura, urticaria, erythema multiforme rash urogenital disorders: priapism vascular disorders: isolated cases of cerebral arteritis and/or occlusion

vention: adjust the dosage of the antihypertensive drug as needed. 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. antihypertensive drugs: monitor blood pressure. adjust dosage of antihypertensive drug as needed ( 7 )

n to adolescents on a mg/m 2 basis. however, spina bifida was observed in rabbits at a dose 53 times the mrhd given to adolescents. a decrease in pup body weight was observed in a pre- and postnatal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the mrhd given to 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 methylphenidate hcl extended-release capsules, can cause vasoconstriction and thereby decrease placental perfusion. no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. animal data in embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the mrhd of 60 mg/day given to adolescents on a mg/m 2 basis. the no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the mrhd given to adolescents on a mg/m 2 basis). there was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. the no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the mrhd on a mg/m 2 basis). when methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. the no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the mrhd given to adolescents on a mg/m 2 basis). 8.2 lactation risk summary 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 methylphenidate hcl extended-release capsules and any potential adverse effects on the breastfed infant from methylphenidate hcl extended-release capsules or from the underlying maternal condition. clinical considerations monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 pediatric use the safety and effectiveness of methylphenidate hcl extended-release capsules for the treatment of adhd have been established in pediatric patients 6 to 15 years of age. the safety and effectiveness of methylphenidate hcl extended-release capsules in pediatric patients younger than 6 years of age have not been established. long-term efficacy of methylphenidate hcl extended-release capsules in pediatric patients have not been established. long-term suppression of growth growth should be monitored during treatment with stimulants, including methylphenidate hcl extended-release capsules. pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see warnings and precautions ( 5.6 )] . juvenile animal toxicity data in a study conducted in young rats, 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 6 times the mrhd 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 (12 times the mrhd on a mg/m 2 basis). the no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the mrhd on a mg/m 2 basis). the clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 geriatric use methylphenidate hcl extended-release capsules have not been studied in patients over the age of 65 years.

asis. however, spina bifida was observed in rabbits at a dose 53 times the mrhd given to adolescents. a decrease in pup body weight was observed in a pre- and postnatal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the mrhd given to 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 methylphenidate hcl extended-release capsules, can cause vasoconstriction and thereby decrease placental perfusion. no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. animal data in embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the mrhd of 60 mg/day given to adolescents on a mg/m 2 basis. the no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the mrhd given to adolescents on a mg/m 2 basis). there was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. the no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the mrhd on a mg/m 2 basis). when methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. the no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the mrhd given to adolescents on a mg/m 2 basis).

al 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 6 times the mrhd 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 (12 times the mrhd on a mg/m 2 basis). the no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the mrhd on a mg/m 2 basis). the clinical significance of the long-term behavioral effects observed in rats is unknown.

phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet (median t max1 about 1.5 hours post dose), and a second rising portion approximately three hours later (median t max2 about 4.5 hours post dose)*, followed by a gradual decline (figure 1). the means for c max and area under the curve (auc) following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours. *25-30% of the subjects had only one observed peak (c max ) concentration of methylphenidate. figure 1: comparison of immediate release (ir) and methylphenidate hcl extended-release capsules formulations after repeated doses of methylphenidate hcl in pediatric patients 7 to 12 years of age with adhd effect of food ingestion of a high-fat meal with methylphenidate hcl extended-release capsules increased the mean c max and auc of methylphenidate by about 30% and 17%, respectively. the presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see dosage and administration ( 2.1 )] . the bioavailability (c max and auc) of methylphenidate was unaffected by sprinkling the methylphenidate hcl extended-release capsule contents on applesauce as compared to the intact capsule. effect of alcohol at an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. the results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see drug interactions ( 7 )] . distribution plasma protein binding is 10% to 33%. the volume of distribution was 2.65 ± 1.11 l/kg for d-methylphenidate and 1.80 ± 0.91 l/kg for l-methylphenidate. elimination the mean terminal half-life (t½) of methylphenidate following administration of methylphenidate hcl extended-release capsules (t½=6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½=3.4 hours) in healthy adult volunteers. metabolism in vitro studies showed that methylphenidate was not metabolized by cytochrome p450 isoenzymes. methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. excretion after oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. the main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. specific populations male and female patients the pharmacokinetics of methylphenidate after a single dose of methylphenidate hcl extended-release capsules were similar between adult men and women. racial or ethnic groups the influence of race on the pharmacokinetics of methylphenidate after methylphenidate hcl extended-release capsules administration has not been studied. pediatric patients the pharmacokinetics of methylphenidate after methylphenidate hcl extended-release capsules administration has not been studied in children less than 6 years of age. patients with renal impairment methylphenidate hcl extended-release capsules have not been studied in patients with renal insufficiency. since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate hcl extended-release capsules. patients with hepatic impairment methylphenidate hcl extended-release capsules have not been studied in patients with hepatic insufficiency. hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. drug interaction studies in vitro studies showed that methylphenidate did not inhibit cytochrome p450 isoenzymes at clinically observed plasma drug concentrations. figure 1

) concentration of methylphenidate. figure 1: comparison of immediate release (ir) and methylphenidate hcl extended-release capsules formulations after repeated doses of methylphenidate hcl in pediatric patients 7 to 12 years of age with adhd effect of food ingestion of a high-fat meal with methylphenidate hcl extended-release capsules increased the mean c max and auc of methylphenidate by about 30% and 17%, respectively. the presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see dosage and administration ( 2.1 )] . the bioavailability (c max and auc) of methylphenidate was unaffected by sprinkling the methylphenidate hcl extended-release capsule contents on applesauce as compared to the intact capsule. effect of alcohol at an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. the results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see drug interactions ( 7 )] . distribution plasma protein binding is 10% to 33%. the volume of distribution was 2.65 ± 1.11 l/kg for d-methylphenidate and 1.80 ± 0.91 l/kg for l-methylphenidate. elimination the mean terminal half-life (t½) of methylphenidate following administration of methylphenidate hcl extended-release capsules (t½=6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½=3.4 hours) in healthy adult volunteers. metabolism in vitro studies showed that methylphenidate was not metabolized by cytochrome p450 isoenzymes. methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. excretion after oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. the main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. specific populations male and female patients the pharmacokinetics of methylphenidate after a single dose of methylphenidate hcl extended-release capsules were similar between adult men and women. racial or ethnic groups the influence of race on the pharmacokinetics of methylphenidate after methylphenidate hcl extended-release capsules administration has not been studied. pediatric patients the pharmacokinetics of methylphenidate after methylphenidate hcl extended-release capsules administration has not been studied in children less than 6 years of age. patients with renal impairment methylphenidate hcl extended-release capsules have not been studied in patients with renal insufficiency. since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate hcl extended-release capsules. patients with hepatic impairment methylphenidate hcl extended-release capsules have not been studied in patients with hepatic insufficiency. hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. drug interaction studies in vitro studies showed that methylphenidate did not inhibit cytochrome p450 isoenzymes at clinically observed plasma drug concentrations. figure 1

ic 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 concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg per day of methylphenidate. mutagenesis methylphenidate 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 vitro chromosomal aberration assay using human lymphocytes. sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured chinese hamster ovary cells. methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. impairment of fertility 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 up to 160 mg/kg per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m 2 basis.

ich is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg per day of methylphenidate. mutagenesis methylphenidate 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 vitro chromosomal aberration assay using human lymphocytes. sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured chinese hamster ovary cells. methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. impairment of fertility 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 up to 160 mg/kg per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m 2 basis.

each treatment week. the primary efficacy endpoint was determined by the average of the total scores for the 10-item tcgis completed by the classroom teacher in the morning and again in the afternoon on the three observation days during the last week of double-blind therapy. patients treated with methylphenidate hcl extended-release capsules showed a statistically significant improvement in symptom scores from baseline over patients who received placebo (see figure 2). separate analyses of tcgis scores in the morning and afternoon revealed superiority in improvement with methylphenidate hcl extended-release capsules over placebo during both time periods (see figure 3). figure 2: least squares mean change from baseline in tcgis total score in pediatric patients 6 to 15 years of age with adhd figure 3: least squares mean change from baseline in tcgis total score in pediatric patients 6 to 15 years of age with adhd: morning (am) and afternoon (pm) * figures 2 & 3 : last observation carried forward analysis at week 3. error bars represent the standard error of the mean. figure 2 figure 3

�œ1850” in white letters “50 mg” in black letters 100 ndc 0406-1850-01 60 mg white/white “m” in a box over “1860” in black letters “60 mg” in black letters 100 ndc 0406-1860-01 storage and handling store at 25°c (77°f); excursions permitted to 15° to 30°c (59° to 86°f) [see usp controlled room temperature]. disposal comply with local laws and regulations on drug disposal of cns stimulants. dispose of remaining, unused, or expired methylphenidate hcl extended-release capsules by a medicine take-back program or by an authorized collector registered with the drug enforcement administration. if no take-back program or authorized collector is available, mix methylphenidate hcl extended-release capsules 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 methylphenidate hcl extended-release capsules in the household trash.