ve drugs clinical impact: methylphenidate hydrochloride oral solution may decrease the effectiveness of drugs used to treat hypertension [see warnings and precautions (5.3)]. intervention: monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. 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.

ylphenidate hydrochloride oral solution use. (5.4) • priapism: cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. immediate medical attention should be sought if signs or symptoms of painful or prolonged penile erections or priapism are observed. (5.5) • peripheral vasculopathy, including raynaud’s phenomenon: stimulants used to treat adhd are associated with peripheral vasculopathy, including raynaud’s phenomenon. careful observation for digital changes is necessary during treatment with adhd stimulants. (5.6) • long-term suppression of growth: monitor height and weight at appropriate intervals in pediatric patients. (5.7) 5.1 potential for abuse and dependence cns stimulants, including methylphenidate hydrochloride oral solution, 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 boxed warning, drug abuse and dependence (9.2, 9.3)]. 5.2 serious cardiovascular reactions sudden death, stroke and myocardial infarction have been reported in adults with cns 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 oral solution treatment. 5.3 blood pressure and heart rate increases cns stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmhg) and heart rate (mean increase approximately 3 to 6 bpm). individuals may have larger increases. monitor all patients for hypertension and tachycardia. 5.4 psychiatric adverse reactions exacerbation of pre-existing psychosis cns stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. induction of a manic episode in patients with bipolar illness cns stimulants may induce a manic or mixed mood episode in patients. prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). new psychotic or manic symptoms cns stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. if such symptoms occur, consider discontinuing methylphenidate hydrochloride oral solution. in a pooled analysis of multiple short- term, placebo-controlled studies of cns stimulants, psychotic or manic symptoms occurred in approximately 0.1% of cns stimulant-treated patients, compared to 0 in placebo-treated patients. 5.5 priapism prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 peripheral vasculopathy, including raynaud’s phenomenon stimulants used to treat adhd, including methylphenidate hydrochloride oral solution, are associated with peripheral vasculopathy, including raynaud’s phenomenon. signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. effects of peripheral vasculopathy, including raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. signs and symptoms generally improve after reduction in dose or discontinuation of drug. careful observation for digital changes is necessary during treatment with adhd stimulants. further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. 5.7 long-term suppression of growth cns stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. closely monitor growth (weight and height) in pediatric patients treated with stimulants, including methylphenidate hydrochloride oral solution. patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. the safety and effectiveness of methylphenidate hydrochloride oral solution have not been established in pediatric patient less than 6 years of age.

nidate hydrochloride oral solution use [see boxed warning, warnings and precautions (5.1), drug abuse and dependence (9)]. 2.2 general dosing information pediatric patients 6 years of age and older the recommended starting dosage is 5 mg orally twice daily before breakfast and lunch (preferably 30 to 45 minutes before meals). increase the dosage gradually, in increments of 5 mg to 10 mg weekly. daily dosage above 60 mg is not recommended. adults administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. the maximum recommended daily dose is 60 mg. the average dosage is 20 to 30 mg daily. for adult patients who are unable to sleep if medication is taken late in the day, administer the last dose before 6 p.m. pharmacological treatment of adhd may be needed for extended periods. periodically re-evaluate the long-term use of methylphenidate hydrochloride oral solution, and adjust the dosage as needed. 2.3 dosage reduction and discontinuation if paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage, or, if necessary, discontinue methylphenidate hydrochloride oral solution. methylphenidate hydrochloride oral solution should be periodically discontinued to assess the pediatric patient’s condition. if improvement is not observed after appropriate dosage adjustment over a one- month period, discontinue methylphenidate hydrochloride oral solution.

associated with the use of methylphenidate containing products were identified in clinical studies, postmarketing reports, or literature. because some of these reactions were 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. infections and infestations: nasopharyngitis blood and the lymphatic system disorders: leukopenia, thrombocytopenia, anemia, pancytopenia immune system disorders: hypersensitivity reactions, including angioedema and anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients psychiatric disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, affect lability, mania, disorientation, libido changes nervous system disorders: headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebral arteritis and/or occlusion, serotonin syndrome in combination with serotonergic drugs, migraine eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis cardiac disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris, sudden cardiac death, myocardial infarction, bradycardia, extrasystole respiratory, thoracic and mediastinal disorders: cough, pharyngolaryngeal pain, dyspnea gastrointestinal disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia, diarrhea general disorders: fatigue, hyperpyrexia hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura angioneurotic edema, erythema, fixed drug eruption musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, rhabdomyolysis, myalgia, muscle twitching renal and urinary disorders: hematuria reproductive system and breast disorders: gynecomastia urogenital disorders: priapism vascular disorders: peripheral coldness, raynaud’s phenomenon investigations: weight loss common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain. (6) to report suspected adverse reactions, contact wes pharma inc at 1-888-212-6921 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

ve drugs clinical impact: methylphenidate hydrochloride oral solution may decrease the effectiveness of drugs used to treat hypertension [see warnings and precautions (5.3)]. intervention: monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. 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.

(mrhd) of 60 mg/day given to adults on a mg/m 2 basis. however, spina bifida was observed in rabbits at a dose 65 times the mrhd given to adults. a decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 7 times the mrhd given to adults (see data). the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions cns stimulants, such as methylphenidate hydrochloride oral solution, can cause vasoconstriction and thereby decrease placental perfusion. no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. data animal data in embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 65 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis. the no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (19 times the mrhd given to adults on a mg/m 2 basis). there was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (12 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. the no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the mrhd on a mg/m 2 basis). when methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. the no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the mrhd given to adults on a mg/m 2 basis). 8.2 lactation risk summary limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight- adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. there are no reports of adverse effects on the breastfed infant and no effects on milk production. long-term neurodevelopmental effects on infants from stimulant exposure are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride oral solution and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride oral solution or from the underlying maternal condition. clinical considerations monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 pediatric use the safety and effectiveness of methylphenidate hydrochloride oral solution for the treatment of adhd have been established in pediatric patients six years of age and older. the safety and effectiveness of methylphenidate hydrochloride oral solution in pediatric patients under six years of age have not been established. the long-term efficacy of methylphenidate in pediatric patients has not been established. long-term suppression of growth growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride oral solution. pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see warnings and precautions (5.6)]. juvenile animal toxicity data in a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). when these animals were tested as adults (postnatal weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the mrhd of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the mrhd given to children on a mg/m 2 basis). the no effect level for juvenile neurobehavioral development in rats (5 mg/kg/day) is less than the mrhd given to children on a mg/m 2 basis. the clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 geriatric use methylphenidate hydrochloride oral solution has not been studied in the geriatric population.

adults on a mg/m 2 basis. however, spina bifida was observed in rabbits at a dose 65 times the mrhd given to adults. a decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 7 times the mrhd given to adults (see data). the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions cns stimulants, such as methylphenidate hydrochloride oral solution, can cause vasoconstriction and thereby decrease placental perfusion. no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. data animal data in embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 65 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis. the no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (19 times the mrhd given to adults on a mg/m 2 basis). there was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (12 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. the no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the mrhd on a mg/m 2 basis). when methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the mrhd of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. the no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the mrhd given to adults on a mg/m 2 basis).

en 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 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the mrhd given to children on a mg/m 2 basis). the no effect level for juvenile neurobehavioral development in rats (5 mg/kg/day) is less than the mrhd given to children on a mg/m 2 basis. the clinical significance of the long-term behavioral effects observed in rats is unknown.

75 healthy volunteers. electrocardiograms were collected up to 12 hours postdose. frederica’s method for heart rate correction was employed to derive the corrected qt interval (qtcf). the maximum mean prolongation of qtcf intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. this was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 pharmacokinetics absorption following a single dose administration of 20 mg methylphenidate hydrochloride oral solution and 20 mg tablet of methylphenidate hydrochloride in healthy volunteers under fasted conditions, time to peak plasma concentration (t max ) of methylphenidate was at 1 to 2 hours after dosing, and: • the mean peak plasma concentration (c max ) of methylphenidate was 9.1 ng/ml and 9.8 ng/ml, respectively. • the mean area under concentration curve (auc) of methylphenidate was 46.7 hour*ng/ml and 50.0 hour*ng/ml, respectively. effect of food ingestion of a high-fat meal with methylphenidate hydrochloride oral solution increased methylphenidate mean c max and auc by about 13% and 25%, respectively. time to c max (t max ) was delayed by approximately 1 hour. distribution plasma protein binding is 10% to 33%. the volume of distribution was 2.65 ± 1.11 l/kg for d-methylphenidate and 1.80 ± 0.91 l/kg for l-methylphenidate. elimination the mean terminal half-life (t½) of methylphenidate was 2.7 hours following administration of 20 mg methylphenidate hydrochloride oral solution. the systemic clearance is 0.40 ± 0.12 l/h/kg for d-methylphenidate and 0.73 ± 0.28 l/h/kg for l-methylphenidate. metabolism methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. excretion after oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. the main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. specific populations male and female patients, racial groups, and age the effect of gender, race, and age on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride oral solution administration have not been studied. patients with renal impairment methylphenidate hydrochloride oral solution has not been studied in in patients with renal impairment. since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride oral solution. patients with hepatic impairment methylphenidate hydrochloride oral solution has not been studied in patients with hepatic impairment. since methylphenidate is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body, hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate hydrochloride oral solution.

lf-life (t½) of methylphenidate was 2.7 hours following administration of 20 mg methylphenidate hydrochloride oral solution. the systemic clearance is 0.40 ± 0.12 l/h/kg for d-methylphenidate and 0.73 ± 0.28 l/h/kg for l-methylphenidate. metabolism methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. excretion after oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. the main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. specific populations male and female patients, racial groups, and age the effect of gender, race, and age on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride oral solution administration have not been studied. patients with renal impairment methylphenidate hydrochloride oral solution has not been studied in in patients with renal impairment. since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride oral solution. patients with hepatic impairment methylphenidate hydrochloride oral solution has not been studied in patients with hepatic impairment. since methylphenidate is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body, hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate hydrochloride oral solution.

train 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, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured chinese hamster ovary (cho) cells. methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. impairment of fertility no human data on the effect of methylphenidate on fertility are available. methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. the study was conducted at doses up to 160 mg/kg/day, approximately 13 times the maximum recommended human dose of 60 mg/day given to adults on a mg/m 2 basis.

sitive 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, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured chinese hamster ovary (cho) cells. methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. impairment of fertility no human data on the effect of methylphenidate on fertility are available. methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. the study was conducted at doses up to 160 mg/kg/day, approximately 13 times the maximum recommended human dose of 60 mg/day given to adults on a mg/m 2 basis.

pets. place the mixture in a container such as a sealed plastic bag and discard methylphenidate hydrochloride oral solution in the household trash.

tential serious cardiovascular risk including sudden death, myocardial infarction, and stroke with methylphenidate hydrochloride oral solution. instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see warnings and precautions (5.2)]. blood pressure and heart rate increases instruct patients that methylphenidate hydrochloride oral solution can elevate blood pressure and heart rate [see warnings and precautions (5.3)]. psychiatric risks advise patients that methylphenidate hydrochloride oral solution, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see warnings and precautions (5.4)]. priapism advise patients of the possibility of painful or prolonged penile erections (priapism). instruct 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) instruct patients about the risk of peripheral vasculopathy, including raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride oral solution. further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see warnings and precautions (5.6)]. suppression of growth advise patients that methylphenidate hydrochloride oral solution may cause slowing of growth and weight loss in pediatric patients [see warnings and precautions (5.7)]. pregnancy exposure registry inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to methylphenidate hydrochloride oral solution during pregnancy [see use in specific populations (8.1)]. distributed by: eywa pharma inc. 2 research way, floor 3 princeton, nj 08540 manufactured by: wes pharma inc westminster, md 21157 revised: 08/2021