(e.g., phenobarbital, phenytoin, primidone) and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. it may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate. 7.4 risperidone 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). monitor for signs of eps.

avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. for the hyperactive-impulsive type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn; intrusive. the combined type requires both inattentive and hyperactive-impulsive criteria to be met. methylphenidate hcl extended-release tablets are a cns stimulant indicated for the treatment of attention deficit hyperactivity disorder (adhd) in children 6 years of age and older, adolescents and adults up to the age of 65. (1) 1.1 special diagnostic considerations specific etiology of this syndrome is unknown, and there is no single diagnostic test. adequate diagnosis requires the use of medical and special psychological, educational and social resources. learning may or may not be impaired. the diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of dsm-iv characteristics. 1.2 need for comprehensive treatment program methylphenidate hydrochloride (hcl) extended-release tablets are indicated as an integral part of a total treatment program for adhd that may include other measures (psychological, educational, social). drug treatment may not be indicated for all patients with adhd. stimulants are not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. appropriate educational placement is essential and psychosocial intervention is often helpful. when remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the patient’s symptoms.

ic illness. clinical evaluation for bipolar disorder is recommended prior to stimulant use. monitor for aggressive behavior. (5.2) seizures: stimulants may lower the convulsive threshold. discontinue in the presence of seizures. (5.3) 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) visual disturbance: difficulties with accommodation and blurring of vision have been reported with stimulant treatment. (5.7) long-term suppression of growth: monitor height and weight at appropriate intervals in pediatric patients. (5.6) gastrointestinal obstruction with preexisting gi narrowing. (5.8) hematologic monitoring: periodic cbc, differential and platelet counts are advised during prolonged therapy. (5.9) 5.1 serious cardiovascular events sudden death and preexisting structural cardiac abnormalities or other serious heart problems children and adolescents sudden death has been reported in association with cns stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. adults sudden deaths, stroke and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for adhd. although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. adults with such abnormalities should also generally not be treated with stimulant drugs. hypertension and other cardiovascular conditions stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mm hg) and average heart rate (about 3 to 6 bpm) [see adverse reactions (6.5) ] , and individuals may have larger increases. while the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. assessing cardiovascular status in patients being treated with stimulant medications children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. 5.2 psychiatric adverse events preexisting psychosis administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. bipolar illness particular care should be taken in using stimulants to treat adhd in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. emergence of new psychotic or manic symptoms treatment-emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. if such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. in a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. aggression aggressive behavior or hostility is often observed in patients with adhd, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of adhd. although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for adhd should be monitored for the appearance of or worsening of aggressive behavior or hostility. 5.3 seizures there is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior eeg abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior eeg evidence of seizures. in the presence of seizures, the drug should be discontinued. 5.4 priapism prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products, including methylphenidate hcl extended-release tablets, in both pediatric and adult patients [see adverse reactions (6.6) ] . 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. 5.5 peripheral vasculopathy, including raynaud’s phenomenon stimulants, including methylphenidate hcl 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. 5.6 long-term suppression of growth careful follow-up of weight and height in children 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 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. published data are inadequate to determine whether chronic use of amphetamines may cause similar suppression of growth; however, it is anticipated that they likely have this effect as well. therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.7 visual disturbance difficulties with accommodation and blurring of vision have been reported with stimulant treatment. 5.8 potential for gastrointestinal obstruction because the methylphenidate hcl extended-release tablet is nondeformable and does not appreciably change in shape in the gi tract, methylphenidate hcl 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 controlled-release design of the tablet, methylphenidate hcl extended-release tablets should be used only in patients who are able to swallow the tablet whole [see patient counseling information (17) ] . 5.9 hematologic monitoring periodic cbc, differential and platelet counts are advised during prolonged therapy.

n the morning with or without food. methylphenidate hcl extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed [see patient counseling information (17) ] . 2.2 patients new to methylphenidate the recommended starting dose of methylphenidate hcl extended-release tablets for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (see table 1). table 1. methylphenidate hcl extended-release tablets recommended starting doses and dose ranges patient age recommended starting dose dose range children 6 to 12 years of age 18 mg/day 18 mg to 54 mg/day adolescents 13 to 17 years of age 18 mg/day 18 mg to 72 mg/day not to exceed 2 mg/kg/day adults 18 to 65 years of age 18 or 36 mg/day 18 mg to 72 mg/day 2.3 patients currently using methylphenidate the recommended dose of methylphenidate hcl extended-release tablets for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in table 2. dosing recommendations are based on current dose regimen and clinical judgment. conversion dosage should not exceed 72 mg daily. table 2. recommended dose conversion from methylphenidate regimens to methylphenidate hcl extended-release tablets recommended methylphenidate hcl extended-release tablets previous methylphenidate daily dose starting dose 5 mg methylphenidate twice daily or three times daily 18 mg every morning 10 mg methylphenidate twice daily or three times daily 36 mg every morning 15 mg methylphenidate twice daily or three times daily 54 mg every morning 20 mg methylphenidate twice daily or three times daily 72 mg every morning other methylphenidate regimens: clinical judgment should be used when selecting the starting dose. 2.4 dose titration doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved an optimal response at a lower dose. daily dosages above 54 mg in children and 72 mg in adolescents have not been studied and are not recommended. daily dosages above 72 mg in adults are not recommended. a 27 mg dosage strength is available for physicians who wish to prescribe between the 18 mg and 36 mg dosages. 2.5 maintenance/extended treatment there is no body of evidence available from controlled trials to indicate how long the patient with adhd should be treated with methylphenidate hcl extended-release tablets. it is generally agreed, however, that pharmacological treatment of adhd may be needed for extended periods. the effectiveness of methylphenidate hcl extended-release tablets for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. the physician who elects to use methylphenidate hcl extended-release tablets for extended periods in patients with adhd should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy. improvement may be sustained when the drug is either temporarily or permanently discontinued. 2.6 dose reduction and discontinuation if paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued. if improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

ren and adolescents) was abdominal pain upper. the most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability and hyperhidrosis [see adverse reactions (6.1) ] . the most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia and blood pressure increased [see adverse reactions (6.3) ] . the development program for methylphenidate hcl extended-release tablets included exposures in a total of 3,906 participants in clinical trials. children, adolescents and adults with adhd were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see table 3). safety was assessed by collecting adverse events, vital signs, weights and ecgs, and by performing physical examinations and laboratory analyses. table 3. methylphenidate hcl extended-release tablets exposure in double-blind and open-label clinical studies patient population n dose range children 2,216 18 to 54 mg once daily adolescents 502 18 to 72 mg once daily adults 1,188 18 to 108 mg once daily adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using their own terminology. consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using meddra terminology. the stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. an event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. throughout this section, adverse reactions are reported. adverse reactions are adverse events that were considered to be reasonably associated with the use of methylphenidate hcl extended-release tablets based on the comprehensive assessment of the available adverse event information. a causal association for methylphenidate hcl extended-release tablets often cannot be reliably established in individual cases. further, 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 majority of adverse reactions were mild to moderate in severity. the most common adverse reaction in double-blind clinical trials (>5%) in children and adolescents was abdominal pain upper. the most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability and hyperhidrosis. (6.1 and 6.2) the most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia and blood pressure increased. (6.3) to report suspected adverse reactions, contact amneal pharmaceuticals at 1-877-835-5472 or fda at 1-800-fda-1088 or www.fda.gov/medwatch . 6.1 commonly observed adverse reactions in double-blind, placebo-controlled clinical trials adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. children and adolescents table 4 lists the adverse reactions reported in 1% or more of methylphenidate hcl extended-release tablets-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials. table 4. adverse reactions reported by ≥1% of methylphenidate hcl extended-release tablets-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials of methylphenidate hcl extended-release tablets system/organ class adverse reaction methylphenidate hcl 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 hcl extended-release tablets=0.6%) and insomnia (methylphenidate hcl extended-release tablets=2.2%) are combined into insomnia. the majority of adverse reactions were mild to moderate in severity. adults table 5 lists the adverse reactions reported in 1% or more of methylphenidate hcl extended-release tablets-treated adults in 2 placebo-controlled, double-blind clinical trials. table 5. adverse reactions reported by ≥1% of methylphenidate hcl extended-release tablets-treated adult subjects in 2 placebo-controlled, double-blind clinical trials* system/organ class adverse reaction methylphenidate hcl 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 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. the majority of adrs were mild to moderate in severity. 6.2 other adverse reactions observed in methylphenidate hcl extended-release tablets clinical trials this section includes adverse reactions reported by methylphenidate hcl extended-release tablets-treated subjects in double-blind trials that do not meet the criteria specified for table 4 or table 5 and all adverse reactions reported by methylphenidate hcl extended-release tablets-treated subjects 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 6.3 discontinuation due to adverse reactions adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 methylphenidate hcl extended-release tablets patients (0.6%) 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 2 placebo-controlled studies of adults, 25 methylphenidate hcl extended-release tablets patients (6%) and 6 placebo patients (2.8%) discontinued due to an adverse reaction. those events with an incidence of >0.5% in the methylphenidate hcl extended-release tablets patients included anxiety (1.7%), irritability (1.4%), blood pressure increased (1%) and nervousness (0.7%). in placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%). in the 11 open-label studies of children, adolescents and adults, 266 methylphenidate hcl extended-release tablets patients (7%) discontinued due to an adverse reaction. those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%) and tic (0.6%). 6.4 tics in a long-term uncontrolled study (n=432 children), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with methylphenidate hcl extended-release tablets. in a second uncontrolled study (n=682 children) the cumulative incidence of new-onset tics was 1% (9/682 children). the treatment period was up to 9 months with mean treatment duration of 7.2 months. 6.5 blood pressure and heart rate increases in the laboratory classroom clinical trials in children (studies 1 and 2), both methylphenidate hcl 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 adolescent trial (study 4), mean increases from baseline in resting pulse rate were observed with methylphenidate hcl 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 methylphenidate hcl 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 methylphenidate hcl 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 methylphenidate hcl 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 methylphenidate hcl 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 methylphenidate hcl 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 (5.1) ] . 6.6 post-marketing experience the following additional adverse reactions have been identified during postapproval use of methylphenidate hcl 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: 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

(e.g., phenobarbital, phenytoin, primidone) and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. it may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate. 7.4 risperidone 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). monitor for signs of eps.

d-release tablets based on the auc. the safety of methylphenidate for use during human pregnancy has not been established. there are no adequate and well-controlled studies in pregnant women. methylphenidate hcl extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.2 labor and delivery the effect of methylphenidate hcl extended-release tablets on labor and delivery in humans is unknown. 8.3 nursing mothers it is not known whether methylphenidate is excreted in human milk. because many drugs are excreted in human milk, caution should be exercised if methylphenidate hcl extended-release tablets are administered to a nursing woman. in lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma. 8.4 pediatric use methylphenidate hcl extended-release tablets should not be used in children under six years, since safety and efficacy in this age group have not been established. long-term effects of methylphenidate in children have not been well established. 8.5 geriatric use methylphenidate hcl extended-release tablets have not been studied in patients greater than 65 years of age.

be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

l extended-release tablets occurred between 6 and 10 hours. methylphenidate hcl extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily (see figure 1). the relative bioavailability of methylphenidate hcl extended-release tablets once daily and methylphenidate three times daily in adults is comparable. figure 1. mean methylphenidate plasma concentrations in 36 adults, following a single dose of methylphenidate hcl extended-release tablets 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours. the mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of methylphenidate hcl extended-release tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in table 6. table 6. pharmacokinetic parameters (mean ± sd) after single dose in healthy adults parameters methylphenidate hcl extended-release tablets (18 mg once daily) (n=36) methylphenidate (5 mg three times daily) (n=35) c max (ng/ml) 3.7 ± 1 4.2 ± 1 t max (h) 6.8 ± 1.8 6.5 ± 1.8 auc inf (ng•h/ml) 41.8 ± 13.9 38 ± 11 t ½ (h) 3.5 ± 0.4 3 ± 0.5 the pharmacokinetics of methylphenidate hcl extended-release tablets were evaluated in healthy adults following single-and multiple-dose administration (steady-state) of doses up to 144 mg/day. the mean half-life was about 3.6 hours. no differences in the pharmacokinetics of methylphenidate hcl 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 hcl extended-release tablets in a dose range of 18 to 144 mg. dose proportionality following administration of methylphenidate hcl extended-release tablets in single doses of 18, 36 and 54 mg/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 hcl 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 hcl extended-release tablets doses from 54 to 144 mg/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 to 144 mg/day, both after single dose and upon multiple dosing. in a multiple-dose study in adolescent adhd patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of methylphenidate hcl 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 adolescents decline biexponentially following oral administration. the half-life of methylphenidate in adults and adolescents following oral administration of methylphenidate hcl extended-release tablets was approximately 3.5 hours. metabolism and excretion in humans, methylphenidate is metabolized primarily by de-esterification to ppaa, which has little or no pharmacologic activity. in adults the metabolism of methylphenidate hcl 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 hcl extended-release tablets is similar. 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. food effects in patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hcl extended-release tablets when administered after a high-fat breakfast. there is no evidence of dose dumping in the presence or absence of food. alcohol effect an in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hcl 18 mg extended-release tablet dosage form. at an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. the results with the 18 mg tablet strength are considered representative of the other available tablet strengths. special populations gender in healthy adults, the mean dose-adjusted auc (0-inf) values for methylphenidate hcl 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. race in adults receiving methylphenidate hcl 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. age increase in age resulted in increased apparent oral clearance (cl/f) (58% increase in adolescents compared to children). 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 hcl extended-release tablets have not been studied in children less than 6 years of age. renal insufficiency there is no experience with the use of methylphenidate hcl 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 hcl extended-release tablets. hepatic insufficiency there is no experience with the use of methylphenidate hcl extended-release tablets in patients with hepatic insufficiency. figure 1

ts 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours. the mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of methylphenidate hcl extended-release tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in table 6. table 6. pharmacokinetic parameters (mean ± sd) after single dose in healthy adults parameters methylphenidate hcl extended-release tablets (18 mg once daily) (n=36) methylphenidate (5 mg three times daily) (n=35) c max (ng/ml) 3.7 ± 1 4.2 ± 1 t max (h) 6.8 ± 1.8 6.5 ± 1.8 auc inf (ng•h/ml) 41.8 ± 13.9 38 ± 11 t ½ (h) 3.5 ± 0.4 3 ± 0.5 the pharmacokinetics of methylphenidate hcl extended-release tablets were evaluated in healthy adults following single-and multiple-dose administration (steady-state) of doses up to 144 mg/day. the mean half-life was about 3.6 hours. no differences in the pharmacokinetics of methylphenidate hcl 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 hcl extended-release tablets in a dose range of 18 to 144 mg. dose proportionality following administration of methylphenidate hcl extended-release tablets in single doses of 18, 36 and 54 mg/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 hcl 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 hcl extended-release tablets doses from 54 to 144 mg/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 to 144 mg/day, both after single dose and upon multiple dosing. in a multiple-dose study in adolescent adhd patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of methylphenidate hcl 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 adolescents decline biexponentially following oral administration. the half-life of methylphenidate in adults and adolescents following oral administration of methylphenidate hcl extended-release tablets was approximately 3.5 hours. metabolism and excretion in humans, methylphenidate is metabolized primarily by de-esterification to ppaa, which has little or no pharmacologic activity. in adults the metabolism of methylphenidate hcl 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 hcl extended-release tablets is similar. 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. food effects in patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hcl extended-release tablets when administered after a high-fat breakfast. there is no evidence of dose dumping in the presence or absence of food. alcohol effect an in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hcl 18 mg extended-release tablet dosage form. at an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. the results with the 18 mg tablet strength are considered representative of the other available tablet strengths. special populations gender in healthy adults, the mean dose-adjusted auc (0-inf) values for methylphenidate hcl 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. race in adults receiving methylphenidate hcl 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. age increase in age resulted in increased apparent oral clearance (cl/f) (58% increase in adolescents compared to children). 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 hcl extended-release tablets have not been studied in children less than 6 years of age. renal insufficiency there is no experience with the use of methylphenidate hcl 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 hcl extended-release tablets. hepatic insufficiency there is no experience with the use of methylphenidate hcl extended-release tablets in patients with hepatic insufficiency. figure 1

of methylphenidate hcl extended-release tablets on a mg/kg and mg/m 2 basis, 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 80-fold and 8-fold the highest recommended human dose of methylphenidate hcl extended-release tablets on a mg/kg and mg/m 2 basis, respectively.

tended-release tablets on a mg/kg and mg/m 2 basis, 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 80-fold and 8-fold the highest recommended human dose of methylphenidate hcl extended-release tablets on a mg/kg and mg/m 2 basis, respectively.

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 hcl extended-release tablets. the scores for methylphenidate hcl extended-release tablets and placebo for the three studies are presented in figure 2. figure 2. mean community school teacher iowa conners inattention/overactivity scores with methylphenidate hcl extended-release tablets once daily (18, 36, or 54 mg) and placebo. 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. error bars represent the mean plus standard error of the mean. in studies 1 and 2, symptoms of adhd were evaluated by laboratory schoolteachers using the 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 hcl extended-release tablets versus placebo that were maintained through 12 hours after dosing. figure 3 presents the laboratory schoolteacher skamp ratings for methylphenidate hcl extended-release tablets and placebo. *swanson, kotkin, agler, m-fynn and pelham figure 3. laboratory school teacher skamp ratings: mean (sem) of combined attention (studies 1 and 2) figure 2 figure 3 14.2 adolescents in a randomized, double-blind, multicenter, placebo-controlled trial (study 4) involving 177 patients, methylphenidate hcl extended-release tablets were demonstrated to be effective in the treatment of adhd in adolescents aged 13 to 18 years at doses up to 72 mg/day (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/day) 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 hcl extended-release tablets (18 to 72 mg/day, 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 hcl extended-release tablets were statistically significantly superior to placebo. 14.3 adults two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. the controlled studies compared methylphenidate hcl extended-release tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (study 6) (18, 36 and 72 mg/day). study 5 demonstrated the effectiveness of methylphenidate hcl extended-release tablets in the treatment of adhd in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day 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 hcl extended-release tablets and 116 were randomized to placebo. treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) 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 that methylphenidate hcl extended-release tablets were 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, 36 and 72 mg). patients were randomized to receive methylphenidate hcl extended-release tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). all three doses of methylphenidate hcl 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.

œ54” on one side and plain on the other side. they are supplied as follows: bottles of 30: ndc 65162-237-03 bottles of 90: ndc 65162-237-09 storage and handling store at 20° to 25°c (68° to 77°f); excursions permitted between 15° to 30°c (59° to 86°f) [see usp controlled room temperature]. protect from humidity.

l extended-release tablets. further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. general considerations prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. a patient medication guide is available for methylphenidate hcl extended-release tablets. the prescriber or health professional should instruct patients, their families and their caregivers to read the medication guide and should assist them in understanding its contents. patients should be given the opportunity to discuss the contents of the medication guide and to obtain answers to any questions they may have. the complete text of the medication guide is reprinted at the end of this document. administration instructions patients should be informed that methylphenidate hcl extended-release tablets should be swallowed whole with the aid of liquids. tablets should not be chewed, divided, or crushed. 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; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. driving or operating heavy machinery stimulants may impair the ability of the patient to operate potentially hazardous machinery or vehicles. patients should be cautioned accordingly until they are reasonably certain that methylphenidate hcl extended-release tablets do not adversely affect their ability to engage in such activities. for more information call 1-877-835-5472. manufactured by: amneal pharmaceuticals of ny llc brookhaven, ny 11719 rev. 07-2021-01