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. halogenated anesthetics clinical impact concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention avoid use of methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery. 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.

ressive behavior. ( 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. ( 5.4 ) 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. ( 5.5 ) long-term suppression of growth: monitor height and weight at appropriate intervals in pediatric patients. ( 5.6 ) gastrointestinal obstruction: avoid use with preexisting gi narrowing. ( 5.8 ) 5.1 potential for abuse and dependence cns stimulants, including methylphenidate hydrochloride extended-release tablets, other methylphenidate‑containing products, and amphetamines, have a high potential for abuse and dependence. assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see 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 hydrochloride extended-release tablets treatment. 5.3 blood pressure and heart rate increases cns stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mm hg) and heart rate (mean increase approximately 3 to 6 bpm) [see adverse reactions ( 6.1 )]. individuals may have larger increases. monitor all patients for hypertension and tachycardia. 5.4 psychiatric adverse reactions exacerbation of 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 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 a family history of suicide, bipolar disorder, and 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 extended-release tablets. in a pooled analysis of multiple short-term, placebo-controlled studies of cns stimulants, psychotic or manic, symptoms occurred in approximately 0.1% of cns stimulant-treated patients compared to 0% in placebo-treated patients. 5.5 priapism prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products, including another formulation of methylphenidate hydrochloride extended-release tablets, in both pediatric and adult patients [see adverse reactions ( 6.2 )] . 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, such as methylphenidate hydrochloride extended-release tablets, used to treat adhd are associated with peripheral vasculopathy, including raynaud’s phenomenon. signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. effects of peripheral vasculopathy, including raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. signs and symptoms generally improve after reduction in dose or discontinuation of drug. careful observation for digital changes is necessary during treatment with adhd stimulants. further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. 5.7 long-term suppression of growth cns stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated pediatric 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 stimulants, including methylphenidate hydrochloride extended-release tablets. patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 potential for gastrointestinal obstruction because the methylphenidate hydrochloride extended-release tablet is nondeformable and does not appreciably change in shape in the gi tract, methylphenidate hydrochloride extended-release tablets should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or meckel's diverticulum). there have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations. due to the extended-release design of the tablet, methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the tablet whole [see patient counseling information ( 17 )] .

sk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy. maintain careful prescription records, educate patients about abuse, and periodically re-evaluate the need for methylphenidate hydrochloride extended-release tablets use [see boxed warning, warning and precautions ( 5.1 ), drug abuse and dependence ( 9 )]. 2.2 general administration information administer methylphenidate hydrochloride extended-release tablets orally once daily in the morning with or without food. swallow methylphenidate hydrochloride extended-release tablets whole with liquid. do not chew, divide, or crush [see warnings and precautions ( 5.8 )] . 2.3 dosage recommendations for patients new to methylphenidate table 1 includes the starting dosage and dosage recommendations for methylphenidate hydrochloride extended-release tablets in pediatric patients 6 to 17 years and adults who are not currently taking methylphenidate or other stimulants. table 1: dosage recommendations for methylphenidate hydrochloride extended-release tablets in pediatric patients 6 to 17 years and adults patient population methylphenidate hydrochloride extended-release tablets recommended starting dosage methylphenidate hydrochloride extended-release tablets dosage range pediatric patients 6 to 12 years 18 mg once daily 18 mg to 54 mg once daily 13 to 17 years 18 mg once daily 18 mg to 72 mg once daily (not to exceed 2 mg/kg/day) adults 18 (up to 65 years) 18 mg or 36 mg once daily 18 mg to 72 mg once daily pharmacological treatment of adhd may be needed for extended periods. periodically reevaluate the long-term use of methylphenidate hydrochloride extended-release tablets and adjust dosage as needed. 2.4 dosage recommendations for patients currently using methylphenidate the recommended starting dosage of methylphenidate hydrochloride extended-release tablets for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 mg to 60 mg daily is provided in table 2. table 2. recommended starting dosage when converting from methylphenidate regimens to methylphenidate hydrochloride extended-release tablets current methylphenidate daily dosage recommended starting dosage of methylphenidate hydrochloride extended-release tablets 5 mg methylphenidate twice daily or three times daily 18 mg once daily in the morning 10 mg methylphenidate twice daily or three times daily 36 mg once daily in the morning 15 mg methylphenidate twice daily or three times daily 54 mg once daily in the morning 20 mg methylphenidate twice daily or three times daily 72 mg once daily in the morning 2.5 dose titration doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved clinical response at a lower dose. daily dosages above 54 mg in pediatric patients 6 to 12 years and above 72 mg in pediatric patients 13 to 17 years have not been studied and are not recommended. daily dosages above 72 mg are not recommended in adults. dosage strengths of 27 mg, 45 mg, and 63 mg are available for additional titration options based on clinical response. 2.6 dose reduction and discontinuation if paradoxical aggravation of symptoms or other adverse effects occur, reduce the dosage, or, if necessary, discontinue methylphenidate hydrochloride extended-release tablets. if improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate hydrochloride extended-release tablets.

ns (>5%) were: pediatric patients 6 to 17 years: abdominal pain upper ( 6.1 ) adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis ( 6.1 ) to report suspected adverse reactions, contact trigen laboratories, llc at 1-800-444-5164 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. the safety of methylphenidate hydrochloride extended-release tablets for the treatment of adhd is based on adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets. below is a display of adverse reactions from those adequate and well-controlled studies in adhd. adults and pediatric patients 6 to 17 years with adhd were evaluated in six controlled clinical studies and eleven open-label clinical studies (see table 3). safety was assessed by collecting adverse reactions, vital signs, weights, and electrocardiograms (ecgs), and by performing physical examinations and laboratory analyses. a total of 3,906 patients participated in the clinical trials. table 3. exposure in double-blind and open-label clinical studies of another formulation of methylphenidate hydrochloride extended-release tablets patient population n dosage range pediatric patients 6 to 12 years 2216 18 mg to 54 mg once daily pediatric patients 13 to 17 years 502 18 mg to 72 mg once daily adults 1188 18 mg to 108 mg* once daily * 108 mg is 1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets. the most common adverse reactions in double-blind clinical trials (>5%) were: pediatric patients 6 to 17 years: abdominal pain upper (see table 4). adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis (see table 5). the most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased . adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. pediatric patients 6 to 17 years table 4 lists the adverse reactions reported in 1% or more of another formulation of methylphenidate hydrochloride extended-release tablet-treated pediatric patients (6 to 17 years) in four placebo-controlled, double-blind clinical trials. table 4. adverse reactions reported by ≥1% of pediatric patients (6 to 17 years) treated with another formulation of methylphenidate hydrochloride extended-release tablets in four placebo-controlled, double-blind clinical trials system/organ class adverse reaction another formulation of methylphenidate hydrochloride extended-release tablets (n=321) % placebo (n=318) % gastrointestinal disorders abdominal pain upper 6.2 3.8 vomiting 2.8 1.6 general disorders and administration site conditions pyrexia 2.2 0.9 infections and infestations nasopharyngitis 2.8 2.2 nervous system disorders dizziness 1.9 0 psychiatric disorders insomnia * 2.8 0.3 respiratory, thoracic and mediastinal disorders cough 1.9 0.9 oropharyngeal pain 1.2 0.9 * terms of initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) are combined into insomnia. adults table 5 lists the adverse reactions reported in 1% or more of adults treated with another formulation of methylphenidate hydrochloride extended-release tablets in two placebo-controlled, double-blind clinical trials. table 5. adverse reactions reported by ≥1% of adults treated with another formulation of methylphenidate hydrochloride extended-release tablets in two placebo-controlled, double-blind clinical trials * system/organ class adverse reaction another formulation of methylphenidate hydrochloride extended-release tablets (n=415) % placebo (n=212) % cardiac disorders tachycardia 4.8 0 palpitations 3.1 0.9 ear and labyrinth disorders vertigo 1.7 0 eye disorders vision blurred 1.7 0.5 gastrointestinal disorders dry mouth 14.0 3.8 nausea 12.8 3.3 dyspepsia 2.2 0.9 vomiting 1.7 0.5 constipation 1.4 0.9 general disorders and administration site conditions irritability 5.8 1.4 infections and infestations upper respiratory tract infection 2.2 0.9 investigations weight decreased 6.5 3.3 metabolism and nutrition disorders decreased appetite 25.3 6.6 anorexia 1.7 0 musculoskeletal and connective tissue disorders muscle tightness 1.9 0 nervous system disorders headache 22.2 15.6 dizziness 6.7 5.2 tremor 2.7 0.5 paresthesia 1.2 0 sedation 1.2 0 tension headache 1.2 0.5 psychiatric disorders insomnia 12.3 6.1 anxiety 8.2 2.4 initial insomnia 4.3 2.8 depressed mood 3.9 1.4 nervousness 3.1 0.5 restlessness 3.1 0 agitation 2.2 0.5 aggression 1.7 0.5 bruxism 1.7 0.5 depression 1.7 0.9 libido decreased 1.7 0.5 affect lability 1.4 0.9 confusional state 1.2 0.5 tension 1.2 0.5 respiratory, thoracic and mediastinal disorders oropharyngeal pain 1.7 1.4 skin and subcutaneous tissue disorders hyperhidrosis 5.1 0.9 * included doses up to 108 mg (1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets). adverse reactions observed in clinical trials with another formulation of methylphenidate hydrochloride extended-release tablets this section includes adverse reactions reported with use of another formulation of methylphenidate hydrochloride extended-release tablets in double-blind trials that do not meet the criteria specified for table 4 or table 5 and all adverse reactions reported by the other formulation of methylphenidate hydrochloride extended-release tablets-treated patients who participated in open-label and postmarketing clinical trials. blood and lymphatic system disorders: leukopenia eye disorders: accommodation disorder, dry eye vascular disorders: hot flush gastrointestinal disorders: abdominal discomfort, abdominal pain, diarrhea general disorders and administrative site conditions: asthenia, fatigue, feeling jittery, thirst infections and infestations: sinusitis investigations: alanine aminotransferase increased, blood pressure increased, cardiac murmur, heart rate increased musculoskeletal and connective tissue disorders: muscle spasms nervous system disorders: lethargy, psychomotor hyperactivity, somnolence psychiatric disorders: anger, hypervigilance, mood altered, mood swings, panic attack, sleep disorder, tearfulness, tic reproductive system and breast disorders: erectile dysfunction respiratory, thoracic and mediastinal disorders: dyspnea skin and subcutaneous tissue disorders: rash, rash macular vascular disorders: hypertension discontinuation due to adverse reactions adverse reactions in the four placebo-controlled studies of pediatric patients (6 to 17 years) leading to discontinuation occurred in 2 patients (0.6%) treated with another formulation of methylphenidate hydrochloride extended-release tablets including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%). in the two placebo-controlled studies of adults, 25 patients (6.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets and 6 placebo patients (2.8%) discontinued due to an adverse reaction. incidence of >0.5% in patients treated with another formulation of methylphenidate hydrochloride extended-release tablets included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). in placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%). in the eleven open-label studies of pediatric patients and adults, 266 patients (7.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets discontinued due to an adverse reaction. incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). tics in a long-term uncontrolled study (n=432 pediatric patients 6 to 12 years), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with another formulation of methylphenidate hydrochloride extended-release tablets. in a second uncontrolled study (n=682 pediatric patients 6 to 12 years) the cumulative incidence of new-onset tics was 1% (9/682). the treatment period was up to 9 months with mean treatment duration of 7.2 months. blood pressure and heart rate increases in the laboratory classroom clinical trials in pediatric patients 6 to 12 years (studies 1 and 2), both another formulation of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm hg during the day, relative to placebo. in the placebo-controlled trial in pediatric patients 13 to 17 years (study 4), mean increases from baseline in resting pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). mean increases from baseline in blood pressure at the end of the double-blind phase for another formulation of methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm hg (systolic) and 2.6 and 1.4 mm hg (diastolic), respectively. in one placebo-controlled study in adults (study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm hg (systolic) and -0.7 to 2.2 mm hg (diastolic) for another formulation of methylphenidate hydrochloride extended-release tablets and was 1.1 mm hg (systolic) and -1.8 mm hg (diastolic) for placebo. in a second placebo-controlled study in adults (study 5), mean changes from baseline in resting pulse rate were observed for another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively). mean changes from baseline in blood pressure at the end of the double–blind treatment for another formulation of methylphenidate hydrochloride extended-release tablets and placebo-treated patients were –1.2 and –0.5 mm hg (systolic) and 1.1 and 0.4 mm hg (diastolic), respectively [see warnings and precautions ( 5.3 )] . 6.2 postmarketing experience the following additional adverse reactions have been identified during post-approval use of another formulation of methylphenidate hydrochloride extended-release tablets. 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. blood and lymphatic system disorders: pancytopenia, thrombocytopenia, thrombocytopenic purpura cardiac disorders: angina pectoris, bradycardia, extrasystoles, supraventricular tachycardia, ventricular extrasystoles eye disorders: diplopia, mydriasis, visual impairment general disorders: chest pain, chest discomfort, drug effect decreased, hyperpyrexia, therapeutic response decreased hepatobiliary disorders: hepatocellular injury, acute hepatic failure immune system disorders: hypersensitivity reactions such as angioedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticarias, pruritus nec, rashes, eruptions, and exanthemas nec investigations: blood alkaline phosphatase increased, blood bilirubin increased, hepatic enzyme increased, platelet count decreased, white blood cell count abnormal musculoskeletal, connective tissue and bone disorders: arthralgia, myalgia, muscle twitching, rhabdomyolysis nervous system disorders: convulsion, grand mal convulsion, dyskinesia, serotonin syndrome in combination with serotonergic drugs psychiatric disorders: disorientation, hallucination, hallucination auditory, hallucination visual, mania, logorrhea, libido changes reproductive system and breast disorders: priapism skin and subcutaneous tissue disorders: alopecia, erythema vascular disorders: raynaud's phenomenon

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. halogenated anesthetics clinical impact concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention avoid use of methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery. 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.

n a mg/m 2 basis. however, malformations were observed in rabbits at a dose 54 times the mrhd given to adults. 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 extended-release tablets, can cause vasoconstriction and thereby decrease placental perfusion. no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine‑dependent mothers. data animal data in development studies conducted in rats and rabbits, methylphenidate was administered at doses up to 30 and 200 mg/kg/day, respectively. methylphenidate has been shown to cause malformations in rabbits when given in doses of 200 mg/kg/day, which is approximately 54 times the mrhd on a mg/m2 basis, respectively. a reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 4-fold the mrhd on a mg/m2 basis. 8.2 lactation risk summary limited published literature, based on breast milk sampling from five 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. however, long‑term neurodevelopmental effects on infants from cns stimulant exposure are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride extended-release tablets and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition. clinical considerations monitor breastfeeding infants for adverse reactions, such as agitation, anorexia, and reduced weight gain. 8.4 pediatric use the safety and effectiveness of methylphenidate hydrochloride extended-release tablets for the treatment of adhd have been established in pediatric patients 6 to 17 years. the safety and effectiveness of methylphenidate hydrochloride extended-release tablets in pediatric patients less than 6 years have not been established. the long-term efficacy of methylphenidate in pediatric patients have not been established. long term suppression of growth growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride extended-release 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 ) and adverse reactions ( 6.1 )] . juvenile animal toxicity data in the 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 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the mrhd of 54 mg/day given to children on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (9 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 (equal to 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 methylphenidate hydrochloride extended-release tablets have not been studied in patients greater than 65 years of age.

formations were observed in rabbits at a dose 54 times the mrhd given to adults. 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 extended-release tablets, can cause vasoconstriction and thereby decrease placental perfusion. no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine‑dependent mothers. data animal data in development studies conducted in rats and rabbits, methylphenidate was administered at doses up to 30 and 200 mg/kg/day, respectively. methylphenidate has been shown to cause malformations in rabbits when given in doses of 200 mg/kg/day, which is approximately 54 times the mrhd on a mg/m2 basis, respectively. a reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 4-fold the mrhd on a mg/m2 basis.

ing 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 4 times the mrhd of 54 mg/day given to children on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (9 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 (equal to the mrhd given to children on a mg/m2 basis). the clinical significance of the long-term behavioral effects observed in rats is unknown.

oncentration-time curve (auc 0-inf ) of 72 mg methylphenidate hydrochloride extended-release tablets and 72 mg (2 x 36 mg) methylphenidate extended-release tablets is 206.1 ng∙h/ml and 200.9 ng∙h/ml, respectively. absorption methylphenidate is readily absorbed. following oral administration of methylphenidate hydrochloride extended-release tablets plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1.5 hour, followed by gradual ascending concentrations over the next 5 to 6 hours, after which a gradual decrease begins. mean time to reach peak plasma concentrations of methylphenidate hydrochloride extended-release tablets occurs at 5.5 hours. methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. figure 1 displays mean plasma exposures of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily (administered every 4 hours) in adults. figure 1. mean methylphenidate plasma concentration-time profiles the mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of methylphenidate hydrochloride extended-release tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in table 7. table 7. methylphenidate pharmacokinetic parameters (mean ± sd) after single dose in healthy adults parameters methylphenidate hydrochloride extended-release tablets (18 mg once daily) (n=36) methylphenidate (5 mg three times daily) (n=35) c max (ng/ml) 3.7 ± 1.0 4.2 ± 1.0 t max (h) 6.8 ± 1.8 6.5 ± 1.8 auc inf (ng∙h/ml) 41.8 ± 13.9 38.0 ± 11.0 t ½ (h) 3.5 ± 0.4 3.0 ± 0.5 the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg per day (2 times the maximum recommended daily dosage of methylphenidate hydrochloride extended-release tablets). the mean half-life was about 3.6 hours. no differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. the auc and t 1/2 following repeated once-daily dosing are similar to those following the first dose of methylphenidate hydrochloride extended-release tablets in a dose range of 18 mg to 144 mg. effect of food there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. there is no evidence of dose dumping in the presence or absence of food. effect of alcohol in-vitr o studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate from methylphenidate hydrochloride extended-release tablets. at alcohol concentrations up to 40%, there was no increased release of methylphenidate in the first two hours. dose proportionality following administration methylphenidate hydrochloride extended-release tablets in single doses of 18 mg, 36 mg, and 54 mg per day to healthy adults, c max and auc (0–inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate c max and auc (0–inf) increased disproportionately with respect to dose. following administration of methylphenidate hydrochloride extended-release tablets, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer. in healthy adults, single and multiple dosing of once-daily methylphenidate hydrochloride extended-release tablets doses from 54 mg to 144 mg per day resulted in linear and dose-proportional increases in c max and auc inf for total methylphenidate (mph) and its major metabolite, α-phenyl-piperidine acetic acid (ppaa). there was no time dependency in the pharmacokinetics of methylphenidate. the ratio of metabolite (ppaa) to parent drug (mph) was constant across doses from 54 mg to 144 mg per day, both after single dose and upon multiple dosing. in a multiple-dose study in adhd with pediatric patients 13 to 16 years administered their prescribed dose (18 mg to 72 mg per day) of methylphenidate hydrochloride extended-release tablets, mean c max and auc tau of d- and total methylphenidate increased proportionally with respect to dose. distribution plasma methylphenidate concentrations in adults and pediatric patients 13 to 17 years decline biexponentially following oral administration. the half-life of methylphenidate in adults and adolescents following oral administration of methylphenidate hydrochloride extended-release tablets was approximately 3.5 hours. elimination metabolism in humans, methylphenidate is metabolized primarily by de-esterification to ppaa, which has little or no pharmacologic activity. in adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to ppaa is similar to that of methylphenidate three times daily. the metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets is similar. excretion after oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. the main urinary metabolite was ppaa, accounting for approximately 80% of the dose. speci fic populations male and female patients in healthy adults, the mean dose-adjusted auc (0–inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng∙h/ml in men and 37.1 ng∙h/ml in women, with no differences noted between the two groups. racial or ethnic groups in adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted auc (0–inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics. pediatric patients increase in age resulted in increased apparent oral clearance (cl/f) (58% increase in pediatric patients 13 to 17 years compared to pediatric patients 6 to 12 years). some of these differences could be explained by body-weight differences among these populations. this suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses. the pharmacokinetics of methylphenidate hydrochloride extended-release tablets have not been studied in pediatric patients less than 6 years of age. patients with renal impairment there is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with renal insufficiency. after oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ppaa. since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride extended-release tablets. patients with hepatic impairment there is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic insufficiency. figure 1

ions over the next 5 to 6 hours, after which a gradual decrease begins. mean time to reach peak plasma concentrations of methylphenidate hydrochloride extended-release tablets occurs at 5.5 hours. methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. figure 1 displays mean plasma exposures of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily (administered every 4 hours) in adults. figure 1. mean methylphenidate plasma concentration-time profiles the mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of methylphenidate hydrochloride extended-release tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in table 7. table 7. methylphenidate pharmacokinetic parameters (mean ± sd) after single dose in healthy adults parameters methylphenidate hydrochloride extended-release tablets (18 mg once daily) (n=36) methylphenidate (5 mg three times daily) (n=35) c max (ng/ml) 3.7 ± 1.0 4.2 ± 1.0 t max (h) 6.8 ± 1.8 6.5 ± 1.8 auc inf (ng∙h/ml) 41.8 ± 13.9 38.0 ± 11.0 t ½ (h) 3.5 ± 0.4 3.0 ± 0.5 the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg per day (2 times the maximum recommended daily dosage of methylphenidate hydrochloride extended-release tablets). the mean half-life was about 3.6 hours. no differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. the auc and t 1/2 following repeated once-daily dosing are similar to those following the first dose of methylphenidate hydrochloride extended-release tablets in a dose range of 18 mg to 144 mg. effect of food there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. there is no evidence of dose dumping in the presence or absence of food. effect of alcohol in-vitr o studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate from methylphenidate hydrochloride extended-release tablets. at alcohol concentrations up to 40%, there was no increased release of methylphenidate in the first two hours. dose proportionality following administration methylphenidate hydrochloride extended-release tablets in single doses of 18 mg, 36 mg, and 54 mg per day to healthy adults, c max and auc (0–inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate c max and auc (0–inf) increased disproportionately with respect to dose. following administration of methylphenidate hydrochloride extended-release tablets, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer. in healthy adults, single and multiple dosing of once-daily methylphenidate hydrochloride extended-release tablets doses from 54 mg to 144 mg per day resulted in linear and dose-proportional increases in c max and auc inf for total methylphenidate (mph) and its major metabolite, α-phenyl-piperidine acetic acid (ppaa). there was no time dependency in the pharmacokinetics of methylphenidate. the ratio of metabolite (ppaa) to parent drug (mph) was constant across doses from 54 mg to 144 mg per day, both after single dose and upon multiple dosing. in a multiple-dose study in adhd with pediatric patients 13 to 16 years administered their prescribed dose (18 mg to 72 mg per day) of methylphenidate hydrochloride extended-release tablets, mean c max and auc tau of d- and total methylphenidate increased proportionally with respect to dose. distribution plasma methylphenidate concentrations in adults and pediatric patients 13 to 17 years decline biexponentially following oral administration. the half-life of methylphenidate in adults and adolescents following oral administration of methylphenidate hydrochloride extended-release tablets was approximately 3.5 hours. elimination metabolism in humans, methylphenidate is metabolized primarily by de-esterification to ppaa, which has little or no pharmacologic activity. in adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to ppaa is similar to that of methylphenidate three times daily. the metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets is similar. excretion after oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. the main urinary metabolite was ppaa, accounting for approximately 80% of the dose. speci fic populations male and female patients in healthy adults, the mean dose-adjusted auc (0–inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng∙h/ml in men and 37.1 ng∙h/ml in women, with no differences noted between the two groups. racial or ethnic groups in adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted auc (0–inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics. pediatric patients increase in age resulted in increased apparent oral clearance (cl/f) (58% increase in pediatric patients 13 to 17 years compared to pediatric patients 6 to 12 years). some of these differences could be explained by body-weight differences among these populations. this suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses. the pharmacokinetics of methylphenidate hydrochloride extended-release tablets have not been studied in pediatric patients less than 6 years of age. patients with renal impairment there is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with renal insufficiency. after oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ppaa. since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride extended-release tablets. patients with hepatic impairment there is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic insufficiency. figure 1

is, respectively. in a 24-week carcinogenicity study 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 concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. mutagenesis methylphenidate was not mutagenic in the in vitro ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. 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/day, approximately 11-fold the mrhd of methylphenidate hydrochloride extended-release tablets on a mg/m 2 basis, respectively.

week carcinogenicity study 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 concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. mutagenesis methylphenidate was not mutagenic in the in vitro ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. 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/day, approximately 11-fold the mrhd of methylphenidate hydrochloride extended-release tablets on a mg/m 2 basis, respectively.

cebo-controlled studies were conducted in 416 pediatric patients 6 to 12 years. the controlled studies compared methylphenidate hydrochloride extended-release tablets given once daily (18 mg, 36 mg, or 54 mg), methylphenidate given three times daily over 12 hours (15 mg, 30 mg, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (study 3). the primary comparison of interest in all three trials was methylphenidate hydrochloride extended-release tablets versus placebo. symptoms of adhd were evaluated by community schoolteachers using the inattention/overactivity with aggression (iowa) conners scale. statistically significant reduction in the inattention/overactivity subscale versus placebo was shown consistently across all three controlled studies for methylphenidate hydrochloride extended-release tablets. studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. study 3 involved 4 weeks of parallel-group treatments with a last observation carried forward analysis at week 4. the scores for methylphenidate hydrochloride extended-release tablets and placebo for the three studies are presented in figure 2. error bars represent the mean plus standard error of the mean. figure 2: mean community school teacher iowa conners inattention/overactivity scores with methylphenidate hydrochloride extended-release tablets once daily (18 mg, 36 mg, or 54 mg) and placebo (studies 1, 2, and 3) in studies 1 and 2, symptoms of adhd were evaluated by laboratory schoolteachers using the swanson, kotkin, agler, m-fynn, and pelham (skamp) laboratory school rating scale. the combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with methylphenidate hydrochloride extended-release tablets versus placebo that were maintained through 12 hours after dosing. figure 3 presents the laboratory schoolteacher skamp ratings for methylphenidate hydrochloride extended-release tablets and placebo. figure 3: laboratory school teacher skamp ratings: mean (sem) of combined attention (studies 1 and 2) pediatric patients 13 to 17 years in a randomized, double-blind, multicenter, placebo-controlled trial (study 4) involving 177 patients, methylphenidate hydrochloride extended-release tablets was demonstrated to be effective in the treatment of adhd in pediatric patients aged 13 to 18 years at doses up to 72 mg once daily (1.4 mg/kg/day). of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg once daily) based on meeting specific improvement criteria on the adhd rating scale and the global assessment of effectiveness with acceptable tolerability. patients who met these criteria were then randomized to receive either their individualized dose of methylphenidate hydrochloride extended-release tablets (18 mg to 72 mg once daily, n=87) or placebo (n=90) during a two-week double-blind phase. at the end of this phase, mean scores for the investigator rating on the adhd rating scale demonstrated that methylphenidate hydrochloride extended-release tablets was statistically significantly superior to placebo. adults two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. the controlled studies compared methylphenidate hydrochloride extended-release tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (study 5) (36 mg to 108 mg once daily) and in a multicenter, parallel-group, 5-week, fixed-dose study (study 6) (18 mg, 36 mg, and 72 mg once daily). study 5 demonstrated the effectiveness of methylphenidate hydrochloride extended-release tablets in the treatment of adhd in adults aged 18 to 65 years at doses from 36 mg once daily to 108 mg once daily based on the change from baseline to final study visit on the adult adhd investigator rating scale (aisrs). of 226 patients who entered the 7-week trial, 110 were randomized to methylphenidate hydrochloride extended-release tablets and 116 were randomized to placebo. treatment was initiated at 36 mg once daily and patients continued with incremental increases of 18 mg once daily (36 mg to 108 mg once daily) based on meeting specific improvement criteria with acceptable tolerability. at the final study visit, mean change scores (ls mean, sem) for the investigator rating on the aisrs demonstrated methylphenidate hydrochloride extended-release tablets was statistically significantly superior to placebo. study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18 mg, 36 mg, and 72 mg). patients were randomized to receive methylphenidate hydrochloride extended-release tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg once daily (n=102), or placebo (n=96). all three doses of methylphenidate hydrochloride extended-release tablets were statistically significantly more effective than placebo in improving caars (conners' adult adhd rating scale) total scores at double-blind end point in adult subjects with adhd. figure 2 figure 3

temperature]. protect from humidity. disposal comply with local laws and regulations on drug disposal of cns stimulants. dispose of remaining, unused, or expired methylphenidate hydrochloride extended-release tablets 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 hydrochloride extended-release tablets with an undesirable, nontoxic substance to make it less appealing to children and pets. place the mixture in a container such as a sealed plastic bag and discard methylphenidate hydrochloride extended-release tablets in the household trash.

e ( 9.2 , 9.3 ), how supplied/storage and handling ( 16 )] . administration instructions instruct patients to swallow methylphenidate hydrochloride extended-release tablets whole with the aid of liquids, and not to chew, divide, or crush the tablets. advise patients that the medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. the tablet shell, along with insoluble core components, is eliminated from the body; advise patients not to be concerned if they occasionally notice in their stool something that looks like a tablet [see dosage and administration ( 2.2 ), warnings and precautions ( 5.8 )] . serious cardiovascular risks advise patients, caregivers, and their family members that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, and stroke with methylphenidate hydrochloride extended-release 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 advise patients and their caregivers that methylphenidate hydrochloride extended-release tablets can cause elevations of their blood pressure and pulse rate [see warnings and precautions ( 5.3 )] . psychiatric risks advise patients and their caregivers that methylphenidate hydrochloride extended-release 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, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). instruct the patient 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] (see warnings and precautions ( 5.5 )] . instruct patients beginning treatment with methylphenidate hydrochloride extended-release tablets about the risk of peripheral vasculopathy, including raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. instruct patients to report to their healthcare provider 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 extended-release tablets. further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. suppression of growth advise patients, families and caregivers that methylphenidate hydrochloride extended-release tablets may cause slowing of growth and weight loss [see warnings and precautions ( 5.6 )] . pregnancy registry advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to methylphenidate hydrochloride extended-release tablets during pregnancy [see use in specific populations ( 8.1 )] . manufactured for: trigen laboratories, llc alpharetta, ga 30005 1-800-444-5164 www.trigenlab.com 200320-1 patent numbers: us 9,855,258 us 9,827,234 us 9,707,217 us 10,265,308 us 10,695,336 trigen logo