is contraindicated. examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue antihypertensive drugs clinical impact methylphenidate hydrochloride may decrease the effectiveness of drugs used to treat hypertension [see warnings and precautions( 5.3 )] . intervention monitor blood pressure and 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 methylphenidate hydrochloride may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention avoid use of methylphenidate hydrochloride 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

olonged penile erections, and priapism have been reported with methylphenidateproducts.immediatemedical attention should be sought if signs or symptoms of prolonged penile erections or priapism areobserved( 5.5 ). peripheral vasculopathy, i ncluding raynaud’s phenomenon :stimulants used to treat adhd are associated with peripheralvasculopathy,includingraynaud’sphenomenon.carefulobservation for digital changes is necessaryduringtreatment with adhd stimulants( 5.6 ). long-term suppression of growth : monitor height and weight at appropriateintervals in pediatric patients ( 5.7 ). 5.1 potential for abuse and dependence cns stimulants,including methylphenidate hydrochloride tablets, other methylphenidate-containingproducts, 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 [seeboxed 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 stimulanttreatment 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 methylphenidate hydrochloride treatment. 5.3 blood pressure and heart rate increases cns stimulants cause an increase in blood pressure (mean increaseapproximately 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 psychoticdisorder. induction of a manic episode in patients with bipolar disorder cns stimulants may induce a manic or mixedmood 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 hydrochloride. in a pooled analysis of multipleshort-term, placebo-controlled studies of cns stimulants,psychotic or manicsymptoms occurred in approximately 0.1% of cnsstimulant-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 sometime on the drug, often subsequent to an increase in dose. priapism has also appeared during a period of drug withdrawal (drug holidays or duringdiscontinuation).patients who developabnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 peripheral vasculopathy, including raynaud’s phenomenon cns stimulants, including methylphenidate hydrochloride, used to treat adhd are associated with peripheral vasculopathy, including raynaud’s phenomenon. signs and symptoms are usuallyintermittent 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 throughoutthe course of treatment. signs and symptomsgenerallyimprove 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 pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughoutthe 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 reboundduringthis period of development. closely monitor growth (weight and height) in pediatric patients treated with cns stimulants, including methylphenidate hydrochloride. patients who are not growing or gainingheight or weight as expected may need to have their treatment interrupted.

eedformethylphenidate hydrochloride tablets use [seeboxedwarning,warningsandprecautions( 5.1 ),drugabuseanddependence( 9 .2, 9.3)]. 2.2 general dosing information methylphenidate hydrochloride tablets pediatric patients 6 years and older: start with 5 mg orally twice daily (before breakfast and lunch). increase dosage gradually, in increments of 5- to 10-mgweekly.daily dosage above 60 mg is not recommended. adults: average dosage is 20 to 30 mg daily. administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. maximum total daily dosage is 60 mg.patients who are unable to sleep if medication is taken late in the dayshould take the last dose before 6 p.m. pharmacological treatment of adhd may be needed for extended periods. periodically reevaluate the long-term use of methylphenidate hydrochloride tablets, and adjust dosage as needed. 2.3 dose reduction and discontinuation if paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage,or, if necessary,discontinue methylphenidate hydrochloride tablets.ifimprovement is notobservedafterappropriatedosageadjustmentover a one-monthperiod, the drugshouldbediscontinued.

and othermethylphenidate products 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. adverse reactions reported with methylphenidate hydrochloride infections andinfestations: nasopharyngitis blood and the lymphatic system disorders : leukopenia, thrombocytopenia,anemia immune system disorders: hypersensitivity reactions, includingangioedema, and anaphylaxis metabolism and nutrition disorders: decreased appetite, reduced weight gain, and suppression of growth during prolongeduse 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 andsubcutaneoustissue disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythemamultiforme 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-containingproducts the list below shows adverse reactions not listed for methylphenidate hydrochloride tablets that have been reported with other methylphenidate-containingproducts. blood and lymphatic disorders: pancytopenia immune system disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas psychiatric disorders: affect lability, mania,disorientation, and libido changes nervous system disorders: migraine eye disorders: diplopia, mydriasis cardiac disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole vascular disorders: peripheral coldness, raynaud'sphenomenon respiratory, thoracic, and mediastinal disorders: pharyngolaryngeal pain, dyspnea gastrointestinal disorders: diarrhea, constipation skin andsubcutaneoustissue disorders: angioneuroticedema,erythema, fixed drug eruption musculoskeletal, connective tissue, and bone disorders: myalgia,muscle twitching renal and urinary disorders: hematuria reproductive system and breast disorders: gynecomastia general disorders: fatigue, hyperpyrexia urogenital disorders : priapism commonadverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain ( 6 ). to report suspected adverse reactions, contact ascend laboratories, llc at 1-877-asc-rx01 (877-272-7901) or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

is contraindicated. examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue antihypertensive drugs clinical impact methylphenidate hydrochloride may decrease the effectiveness of drugs used to treat hypertension [see warnings and precautions( 5.3 )] . intervention monitor blood pressure and 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 methylphenidate hydrochloride may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention avoid use of methylphenidate hydrochloride 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

pectively, the maximum recommended human dose (mrhd) of 60 mg/day given to adolescents on a mg/m 2 basis. however, spina bifida was observed in rabbits at a dose 52 times the mrhd given to adolescents. a decrease in pup body weight was observed in a pre- and post-natal 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 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, 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 (15times 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 adolescents 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 adolescents 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 hydrochloride and any potential adverse effects on the breastfed infant from methylphenidate 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 methylphenidate hydrochloride for the treatment of adhd have been established in pediatric patients 6 to 17 years. the safety and effectiveness of methylphenidate hydrochloride in pediatric patients less than 6 years have not been established. the long-term efficacy of methylphenidate hydrochloride in pediatric patients has not been established. long-term suppression of growth growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride. 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 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 4 times the mrhd of 60 mg/day given to children on a mg/m 2 basis. 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 4 times the mrhd of 60 mg/day 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 methylphenidate hydrochloride has not been studied in the geriatricpopulation.

nded human dose (mrhd) of 60 mg/day given to adolescents on a mg/m 2 basis. however, spina bifida was observed in rabbits at a dose 52 times the mrhd given to adolescents. a decrease in pup body weight was observed in a pre- and post-natal 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 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, 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 (15times 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 adolescents 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 adolescents 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).

bserved are at least 4 times the mrhd of 60 mg/day given to children on a mg/m 2 basis. 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 4 times the mrhd of 60 mg/day 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.

12 hourspostdose. frederica’s method for heart rate correction was employed to derive the corrected qt interval (qtcf). the maximum mean prolongation of qtcf intervals was less than 5 ms, and the upperlimit of the 90% confidence interval was below 10 ms for all time-matchedcomparisons versus placebo. this was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 pharmacokinetics absorption methylphenidate in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. relative bioavailability of the extended-release tablet compared to the methylphenidate hydrochloride tablet, measured by the urinary excretion of methylphenidate major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. the time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride tablets and 4.7 hours(1.3 to 8.2hours) for the methylphenidate hydrochloride extended-release tablets. an average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults. effect of food after a high-fat meal, both area under the curve (auc) (by 25 %) and cmax (by 27 %) are higher. time to cmax (tmax) is faster after a high-fat meal (median tmax: 2.5 hours) ascompared to without food (median tmax: 3 hours). distribution binding toplasma proteins is low (10% to 33%). the volume of distribution was 2.65 ± 1.11l/kg for d-methylphenidate and 1.80 ± 0.91l/kg for l- methylphenidate. elimination the systemic clearance is 0.40 ± 0.12 l/h/kg for d-methylphenidate and 0.73 ± 0.28l/h/kg for l-methylphenidate. metabolism methylphenidate is metabolizedprimarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. excretion after oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). the cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for methylphenidate hydrochloride extended-release tablets. studies in specificpopulations male and female patients in a clinical study involving adult subjects who received methylphenidate hydrochloride extended-release tablets, plasma concentrations of methylphenidate’s major metabolite appeared to be greater in females than in males. no gender differences were observed for methylphenidate plasma concentration in the same subjects. racial or ethnic groups there is insufficient experience with the use ofmethylphenidate to detectethnic variations in pharmacokinetics. patients with renal impairment methylphenidate has not been studied in renally-impaired patients. renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound,and the major metabolite (ritalinic acid), has little or no pharmacologic activity. patients with hepatic impairment methylphenidate has not been studied in patients with hepatic impairment.hepaticimpairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolizedprimarily to ritalinic acid by nonmicrosomalhydrolytic esterases that are widely distributedthroughoutthebody.

ion binding toplasma proteins is low (10% to 33%). the volume of distribution was 2.65 ± 1.11l/kg for d-methylphenidate and 1.80 ± 0.91l/kg for l- methylphenidate. elimination the systemic clearance is 0.40 ± 0.12 l/h/kg for d-methylphenidate and 0.73 ± 0.28l/h/kg for l-methylphenidate. metabolism methylphenidate is metabolizedprimarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. excretion after oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). the cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for methylphenidate hydrochloride extended-release tablets. studies in specificpopulations male and female patients in a clinical study involving adult subjects who received methylphenidate hydrochloride extended-release tablets, plasma concentrations of methylphenidate’s major metabolite appeared to be greater in females than in males. no gender differences were observed for methylphenidate plasma concentration in the same subjects. racial or ethnic groups there is insufficient experience with the use ofmethylphenidate to detectethnic variations in pharmacokinetics. patients with renal impairment methylphenidate has not been studied in renally-impaired patients. renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound,and the major metabolite (ritalinic acid), has little or no pharmacologic activity. patients with hepatic impairment methylphenidate has not been studied in patients with hepatic impairment.hepaticimpairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolizedprimarily to ritalinic acid by nonmicrosomalhydrolytic esterases that are widely distributedthroughoutthebody.

nogens, there was no evidence of carcinogenicity. male and femalemice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74mg/kg/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 invivo in males and females in the mouse bone marrow micronucleus assay. impairmentoffertility no human data on the effect of methylphenidate on fertility are available. 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/day,approximately 10 times the mrhd of 60mg/day given to adolescents on a mg/m2 basis.

nce of carcinogenicity. male and femalemice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74mg/kg/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 invivo in males and females in the mouse bone marrow micronucleus assay. impairmentoffertility no human data on the effect of methylphenidate on fertility are available. 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/day,approximately 10 times the mrhd of 60mg/day given to adolescents on a mg/m2 basis.

idate hydrochloride tablets in the householdtrash.

den death, myocardial infarction, stroke, and hypertension with methylphenidate 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 methylphenidate hydrochloride tablets can cause elevations of their blood pressure and pulse rate [see warnings and precautions ( 5.3 )] . psychiatric risks advise patients that methylphenidate 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 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 methylphenidate 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 methylphenidate 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 methylphenidate hydrochloride tablets , during pregnancy [see use in specific populations ( 8.1 )]. manufactured by: alkem laboratories 1733 gilsinn lane, fenton, mo 63026 distributed by: ascend laboratories, llc parsippany, nj 07054