thylene blue antihypertensive drugs clinical impact ritalin la may decrease the effectiveness of drugs used to treat hypertension [see warnings and precautions (5.3)] . intervention monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. examples potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ace) inhibitors, angiotensin ii receptor blockers (arbs), beta blockers, centrally acting alpha-2 receptor agonists halogenated anesthetics clinical impact concomitant use of halogenated anesthetics and ritalin la may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention avoid use of ritalin la in patients being treated with anesthetics on the day of surgery. examples halothane, isoflurane, enflurane, desflurane, sevoflurane risperidone clinical impact combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (eps) intervention monitor for signs of eps

onged penile erections, and priapism have been reported with methylphenidate products. immediate medical attention should be sought if signs or symptoms of 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 ritalin la, 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 ritalin la 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 beats per minute). individuals may have larger increases. monitor all patients for hypertension and tachycardia. 5.4 psychiatric adverse reactions exacerbation of preexisting psychosis cns stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. induction of a manic episode in patients with bipolar disorder 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 ritalin la. in a pooled analysis of multiple short-term, placebo-controlled studies of cns stimulants, psychotic or manic symptoms occurred in approximately 0.1% of cns stimulant-treated patients, compared to 0 in placebo-treated patients. 5.5 priapism prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 peripheral vasculopathy, including raynaud’s phenomenon cns stimulants, including ritalin la, 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 non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10-13 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 cns stimulants, including ritalin la. patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

of abuse and dependence while on therapy. maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for ritalin la use [see boxed warning, warnings and precautions (5.1), drug abuse and dependence (9.2, 9.3)] . 2.2 general dosing information the recommended starting dose for ritalin la is 20 mg once daily. increase dosage gradually, in increments of 10 mg weekly. daily dosage above 60 mg is not recommended. when a lower initial dose is appropriate, patients may begin treatment with 10 mg. administer ritalin la orally once daily in the morning. ritalin la may be swallowed as whole capsules or may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). ritalin la and/or their contents should not be crushed, chewed, or divided. the capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. the applesauce should not be warm because it could affect the modified release properties of this formulation. the mixture of drug and applesauce should be consumed immediately in its entirety. the drug and applesauce mixture should not be stored for future use. pharmacological treatment of adhd may be needed for extended periods. periodically reevaluate the long-term use of ritalin and ritalin-sr, and adjust dosage as needed. 2.3 patients currently using ritalin or ritalin-sr the recommended dose of ritalin la for patients currently taking ritalin twice daily or ritalin extended-release (sr) is provided below. table 1: recommended dose conversion from ritalin or ritalin-sr previous ritalin or ritalin-sr dose recommended ritalin la dose 5 mg ritalin twice daily 10 mg once daily 10 mg ritalin twice daily or 20 mg ritalin-sr 20 mg once daily 15 mg ritalin twice daily 30 mg once daily 20 mg ritalin twice daily or 40 mg ritalin-sr 40 mg once daily 30 mg ritalin twice daily or 60 mg ritalin-sr 60 mg once daily 2.4 switching from other methylphenidate products if switching from other methylphenidate products, discontinue that treatment, and titrate with ritalin la using the titration schedule. do not substitute for other methylphenidate products on a milligram-per-milligram basis, because different methylphenidate base compositions and differing pharmacokinetic profiles [see description (11), clinical pharmacology (12.3)] . clinical judgment should be used when selecting the starting dose. daily dosage above 60 mg is not recommended. 2.5 dose reduction and discontinuation if paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue ritalin la. if improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

te, and anorexia. ( 6 ) to report suspected adverse reactions, contact novartis pharmaceuticals corporation at 1-888-669-6682 or fda at 1-800-fda-1088 or www.fda.gov/medwatch . 6.1 clinical trials experience because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the clinical program for ritalin la consisted of 6 studies: 2 controlled clinical studies conducted in children with adhd aged 6 to 12 years and 4 clinical pharmacology studies conducted in healthy adult volunteers. these studies included a total of 256 subjects; 195 children with adhd and 61 healthy adult volunteers. the subjects received ritalin la in doses of 10 to 40 mg per day. safety of ritalin la was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. a placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of ritalin la in children with adhd aged 6 to 12 years. all subjects received ritalin la for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. in the 2-week double-blind treatment phase of this study, patients received either placebo or ritalin la at their individually-titrated dose (range, 10 to 40 mg). adverse reactions with an incidence greater than 5% during the initial 4-week single-blind ritalin la titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia. adverse reactions with an incidence greater than 2% among ritalin la-treated subjects, during the 2-week double-blind phase of the clinical study, are shown in table 2. table 2: adverse reactions in greater than 2% ritalin la-treated subjects in the 2-week double-blind phase preferred term ritalin la n = 65 n (%) placebo n = 71 n (%) anorexia 2 (3.1) 0 (0.0) insomnia 2 (3.1) 0 (0.0) adverse events associated with discontinuation of treatment in the 2-week double-blind treatment phase of a placebo-controlled parallel-group study in children with adhd, one ritalin la-treated subject (1/65, 1.5%) discontinued due to an adverse event (depressed mood). in the single-blind titration period of this study, subjects received ritalin la for up to 4 weeks. during this period a total of 6 subjects (6/161, 3.7%) discontinued due to adverse events. the adverse events leading to discontinuation were anger (2 patients), hypomania, anxiety, depressed mood, fatigue, migraine, and lethargy. 6.2 postmarketing experience the following adverse reactions have been identified during the post approval use of methylphenidate products. because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. adverse reactions reported with ritalin, ritalin-sr, and ritalin la infections and infestations: nasopharyngitis blood and the lymphatic system disorders: leukopenia, thrombocytopenia, anemia immune system disorders: hypersensitivity reactions, including angioedema and anaphylaxis metabolism and nutrition disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in children psychiatric disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood nervous system disorders: headache, dizziness, tremor, dyskinesia, including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs eye disorders: blurred vision, difficulties in visual accommodation cardiac disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris respiratory, thoracic, and mediastinal disorders: cough gastrointestinal disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, rhabdomyolysis investigations: weight loss (adult adhd patients) adverse reactions reported with other methylphenidate-containing products the list below shows adverse reactions not listed with ritalin, ritalin-sr, or ritalin la formulations that have been reported with other methylphenidate-containing products. blood and lymphatic disorders: pancytopenia immune system disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas psychiatric disorders: affect lability, mania, disorientation, libido changes nervous system disorders: migraine eye disorders: diplopia, mydriasis cardiac disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole vascular disorders: peripheral coldness, raynaud's phenomenon respiratory, thoracic, and mediastinal disorders: pharyngolaryngeal pain, dyspnea gastrointestinal disorders: diarrhea, constipation skin and subcutaneous tissue disorders: angioneurotic edema, erythema, fixed drug eruption musculoskeletal, connective tissue, and bone disorders: myalgia, muscle twitching renal and urinary disorders: hematuria reproductive system and breast disorders: gynecomastia general disorders: fatigue, hyperpyrexia urogenital disorders: priapism

thylene blue antihypertensive drugs clinical impact ritalin la may decrease the effectiveness of drugs used to treat hypertension [see warnings and precautions (5.3)] . intervention monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. examples potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ace) inhibitors, angiotensin ii receptor blockers (arbs), beta blockers, centrally acting alpha-2 receptor agonists halogenated anesthetics clinical impact concomitant use of halogenated anesthetics and ritalin la may increase the risk of sudden blood pressure and heart rate increase during surgery. intervention avoid use of ritalin la in patients being treated with anesthetics on the day of surgery. examples halothane, isoflurane, enflurane, desflurane, sevoflurane risperidone clinical impact combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (eps) intervention monitor for signs of eps

mum recommended human dose (mrhd) of 60 mg/day given to adolescents on a mg/m 2 basis. however, spina bifida was observed in rabbits at a dose 52 times the mrhd given to adolescents. a decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the mrhd given to adolescents (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions cns stimulants, such as ritalin la, can cause vasoconstriction and thereby decrease placental perfusion. no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. data animal data in embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the mrhd of 60 mg/day given to adolescents on a mg/m 2 basis. the no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the mrhd given to adolescents on a mg/m 2 basis). there was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the mrhd of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. the no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the mrhd on a mg/m 2 basis). when methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the mrhd of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. the no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the mrhd given to adolescents on a mg/m 2 basis). 8.2 lactation risk summary limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. there are no reports of adverse effects on the breastfed infant and no effects on milk production. long-term neurodevelopmental effects on infants from stimulant exposure are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ritalin la and any potential adverse effects on the breastfed infant from ritalin la 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 ritalin la for the treatment of adhd have been established in pediatric patients 6 to 12 years. the safety and effectiveness of ritalin la in pediatric patients less than 6 years have not been established. the long-term efficacy of ritalin la in pediatric patients has not been established. long-term suppression of growth growth should be monitored during treatment with stimulants, including ritalin la. pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see warnings and precautions (5.7)] . juvenile animal toxicity data rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. a deficit in acquisition of a specific learning task was observed in females only. the doses at which these findings were observed are at least 4 times the mrhd of 60 mg/day given to children on a mg/m 2 basis. in a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). when these animals were tested as adults (postnatal weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the mrhd of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the mrhd given to children on a mg/m 2 basis). the no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the mrhd given to children on a mg/m 2 basis). the clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 geriatric use ritalin la has not been studied in the geriatric population.

hd) of 60 mg/day given to adolescents on a mg/m 2 basis. however, spina bifida was observed in rabbits at a dose 52 times the mrhd given to adolescents. a decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the mrhd given to adolescents (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions cns stimulants, such as ritalin la, can cause vasoconstriction and thereby decrease placental perfusion. no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. data animal data in embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the mrhd of 60 mg/day given to adolescents on a mg/m 2 basis. the no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the mrhd given to adolescents on a mg/m 2 basis). there was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the mrhd of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. the no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the mrhd on a mg/m 2 basis). when methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the mrhd of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. the no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the mrhd given to adolescents on a mg/m 2 basis).

/m 2 basis. in a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). when these animals were tested as adults (postnatal weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the mrhd of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the mrhd given to children on a mg/m 2 basis). the no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the mrhd given to children on a mg/m 2 basis). the clinical significance of the long-term behavioral effects observed in rats is unknown.

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 ritalin la produces a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when administered orally to children diagnosed with adhd and healthy adults. no accumulation of methylphenidate is expected following multiple once daily oral dosing with ritalin la, however, there is a slight upward trend in the methylphenidate area under the curve and peak plasma concentrations (c max1 and c max2 ) after oral administration of ritalin la 20 mg and 40 mg capsules to adults. absorption the absolute oral bioavailability of methylphenidate in children was 22 ± 8% for d-methylphenidate and 5 ± 3% for l-methylphenidate. the relative bioavailability of ritalin la given once daily is comparable to the same total dose of ritalin tablets given in 2 doses 4 hours apart in both children and adults. the initial rate of absorption for ritalin la is similar to that of ritalin tablets as shown by the similar rate parameters between the 2 formulations, i.e., initial lag time (t lag ), first peak concentration (c max1 ), and time to the first peak (t max1 ), which is reached in 1 to 3 hours. the mean time to the interpeak minimum (t minip ), and time to the second peak (t max2 ) are also similar for ritalin la given once daily and ritalin tablets given in 2 doses 4 hours apart (see figure 1 and table 1), although the ranges observed are greater for ritalin la. ritalin la given once daily exhibits a lower second peak concentration (c max2 ), higher interpeak minimum concentrations (c minip ), and less peak and trough fluctuations than ritalin tablets given in 2 doses given 4 hours apart. this is due to an earlier onset and more prolonged absorption from the delayed-release beads (see figure 1 and table 4). figure 1: mean plasma concentration time-profile of methylphenidate after a single dose of ritalin la 40 mg and ritalin 20 mg given in two doses 4 hours apart table 4: mean ± sd and range of pharmacokinetic parameters of methylphenidate after a single dose of ritalin la and ritalin given in two doses 4 hours apart a n = 15. population children adult males formulation dose ritalin 10 mg & 10 mg ritalin la 20 mg ritalin 10 mg & 10 mg ritalin la 20 mg n 21 18 9 8 t lag (h) 0.24 ± 0.44 0.28 ± 0.46 1.0 ± 0.5 0.7 ± 0.2 0 - 1 0 - 1 0.7 - 1.3 0.3 - 1.0 t max1 (h) 1.8 ± 0.6 2.0 ± 0.8 1.9 ± 0.4 2.0 ± 0.9 1 - 3 1 - 3 1.3 - 2.7 1.3 - 4.0 c max1 (ng/ml) 10.2 ± 4.2 10.3 ± 5.1 4.3 ± 2.3 5.3 ± 0.9 4.2 - 20.2 5.5 - 26.6 1.8 - 7.5 3.8 - 6.9 t minip (h) 4.0 ± 0.2 4.5 ± 1.2 3.8 ± 0.4 3.6 ± 0.6 4 - 5 2 - 6 3.3 - 4.3 2.7 - 4.3 c minip (ng/ml) 5.8 ± 2.7 6.1 ± 4.1 1.2 ± 1.4 3.0 ± 0.8 3.1 - 14.4 2.9 - 21.0 0.0 - 3.7 1.7 - 4.0 t max2 (h) 5.6 ± 0.7 6.6 ± 1.5 5.9 ± 0.5 5.5 ± 0.8 5 - 8 5 - 11 5.0 - 6.5 4.3 - 6.5 c max2 (ng/ml) 15.3 ± 7.0 10.2 ± 5.9 5.3 ± 1.4 6.2 ± 1.6 6.2 - 32.8 4.5 - 31.1 3.6 - 7.2 3.9 - 8.3 auc (0-∞) 102.4 ± 54.6 86.6 ± 64.0 a 37.8 ± 21.9 45.8 ± 10.0 (ng/ml x h-1) 40.5 - 261.6 43.3 - 301.44 14.3 - 85.3 34.0 - 61.6 t 1/2 (h) 2.5 ± 0.8 2.4 ± 0.7 a 3.5 ± 1.9 3.3 ± 0.4 1.8 - 5.3 1.5 - 4.0 1.3 - 7.7 3.0 - 4.2 effect of food administration times relative to meals and meal composition may need to be individually titrated. when ritalin la was administered with a high fat breakfast to adults, ritalin la had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. the first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. the effect of a high fat lunch was not examined. there were no differences in the pharmacokinetics of ritalin la when administered with applesauce, compared to administration in the fasting condition. there is no evidence of dose dumping in the presence or absence of food. effect of alcohol an in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the ritalin la 40 mg capsule dosage form. at an alcohol concentration of 40% there was a 98% release of methylphenidate in the first hour. the results with the 40 mg capsule are considered to be representative of the other available capsule strengths. distribution binding to plasma proteins is low (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 systemic clearance is 0.40 ± 0.12 l/h/kg for d-methylphenidate and 0.73 ± 0.28 l/h/kg for l-methylphenidate. in studies with ritalin la and ritalin tablets in adults, methylphenidate from ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range, 1.3 to 7.7 hours). in children the average half-life is about 2.5 hours, with a range of about 1.5 to 5.0 hours. the rapid half-life in both children and adults may result in un-measurable concentrations between the morning and mid-day doses with ritalin tablets. no accumulation of methylphenidate is expected following multiple once a day oral dosing with ritalin la. the half-life of ritalinic acid is about 3 to 4 hours. metabolism the absolute oral bioavailability of methylphenidate in children was 22 ± 8% for d-methylphenidate and 5 ± 3% for l-methylphenidate, suggesting pronounced presystemic metabolism. biotransformation of methylphenidate by the carboxylesterase ces1a1 is rapid and extensive leading to the main, de-esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. therapeutic activity is principally due to the parent compound. excretion after oral administration of an immediate release formulation of methylphenidate, 78% to 97% of the dose is excreted in the urine and 1% to 3% in the feces in the form of metabolites within 48 to 96 hours. only small quantities (less than 1%) of unchanged methylphenidate appear in the urine. most of the dose is excreted in the urine as ritalinic acid (60% to 86%), the remainder being accounted for by minor metabolite. studies in specific populations male and female patients there were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered ritalin la. racial or ethnic groups there is insufficient experience with the use of ritalin la to detect ethnic variations in pharmacokinetics. pediatric patients the pharmacokinetics of ritalin la was examined in 18 children with adhd between 7 and 12 years of age. fifteen of these children were between 10 and 12 years of age. the time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. after a 20-mg dose of ritalin la, concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. this higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age. patients with renal impairment ritalin la has not been studied in renally-impaired patients. renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. patients with hepatic impairment ritalin la has not been studied in patients with hepatic impairment. hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. figure 1: mean plasma concentration time-profile of methylphenidate after a single dose of ritalin la 40 mg and ritalin 20 mg given in two doses 4 hours apart)

ormulations, i.e., initial lag time (t lag ), first peak concentration (c max1 ), and time to the first peak (t max1 ), which is reached in 1 to 3 hours. the mean time to the interpeak minimum (t minip ), and time to the second peak (t max2 ) are also similar for ritalin la given once daily and ritalin tablets given in 2 doses 4 hours apart (see figure 1 and table 1), although the ranges observed are greater for ritalin la. ritalin la given once daily exhibits a lower second peak concentration (c max2 ), higher interpeak minimum concentrations (c minip ), and less peak and trough fluctuations than ritalin tablets given in 2 doses given 4 hours apart. this is due to an earlier onset and more prolonged absorption from the delayed-release beads (see figure 1 and table 4). figure 1: mean plasma concentration time-profile of methylphenidate after a single dose of ritalin la 40 mg and ritalin 20 mg given in two doses 4 hours apart table 4: mean ± sd and range of pharmacokinetic parameters of methylphenidate after a single dose of ritalin la and ritalin given in two doses 4 hours apart a n = 15. population children adult males formulation dose ritalin 10 mg & 10 mg ritalin la 20 mg ritalin 10 mg & 10 mg ritalin la 20 mg n 21 18 9 8 t lag (h) 0.24 ± 0.44 0.28 ± 0.46 1.0 ± 0.5 0.7 ± 0.2 0 - 1 0 - 1 0.7 - 1.3 0.3 - 1.0 t max1 (h) 1.8 ± 0.6 2.0 ± 0.8 1.9 ± 0.4 2.0 ± 0.9 1 - 3 1 - 3 1.3 - 2.7 1.3 - 4.0 c max1 (ng/ml) 10.2 ± 4.2 10.3 ± 5.1 4.3 ± 2.3 5.3 ± 0.9 4.2 - 20.2 5.5 - 26.6 1.8 - 7.5 3.8 - 6.9 t minip (h) 4.0 ± 0.2 4.5 ± 1.2 3.8 ± 0.4 3.6 ± 0.6 4 - 5 2 - 6 3.3 - 4.3 2.7 - 4.3 c minip (ng/ml) 5.8 ± 2.7 6.1 ± 4.1 1.2 ± 1.4 3.0 ± 0.8 3.1 - 14.4 2.9 - 21.0 0.0 - 3.7 1.7 - 4.0 t max2 (h) 5.6 ± 0.7 6.6 ± 1.5 5.9 ± 0.5 5.5 ± 0.8 5 - 8 5 - 11 5.0 - 6.5 4.3 - 6.5 c max2 (ng/ml) 15.3 ± 7.0 10.2 ± 5.9 5.3 ± 1.4 6.2 ± 1.6 6.2 - 32.8 4.5 - 31.1 3.6 - 7.2 3.9 - 8.3 auc (0-∞) 102.4 ± 54.6 86.6 ± 64.0 a 37.8 ± 21.9 45.8 ± 10.0 (ng/ml x h-1) 40.5 - 261.6 43.3 - 301.44 14.3 - 85.3 34.0 - 61.6 t 1/2 (h) 2.5 ± 0.8 2.4 ± 0.7 a 3.5 ± 1.9 3.3 ± 0.4 1.8 - 5.3 1.5 - 4.0 1.3 - 7.7 3.0 - 4.2 effect of food administration times relative to meals and meal composition may need to be individually titrated. when ritalin la was administered with a high fat breakfast to adults, ritalin la had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. the first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. the effect of a high fat lunch was not examined. there were no differences in the pharmacokinetics of ritalin la when administered with applesauce, compared to administration in the fasting condition. there is no evidence of dose dumping in the presence or absence of food. effect of alcohol an in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the ritalin la 40 mg capsule dosage form. at an alcohol concentration of 40% there was a 98% release of methylphenidate in the first hour. the results with the 40 mg capsule are considered to be representative of the other available capsule strengths. distribution binding to plasma proteins is low (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 systemic clearance is 0.40 ± 0.12 l/h/kg for d-methylphenidate and 0.73 ± 0.28 l/h/kg for l-methylphenidate. in studies with ritalin la and ritalin tablets in adults, methylphenidate from ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range, 1.3 to 7.7 hours). in children the average half-life is about 2.5 hours, with a range of about 1.5 to 5.0 hours. the rapid half-life in both children and adults may result in un-measurable concentrations between the morning and mid-day doses with ritalin tablets. no accumulation of methylphenidate is expected following multiple once a day oral dosing with ritalin la. the half-life of ritalinic acid is about 3 to 4 hours. metabolism the absolute oral bioavailability of methylphenidate in children was 22 ± 8% for d-methylphenidate and 5 ± 3% for l-methylphenidate, suggesting pronounced presystemic metabolism. biotransformation of methylphenidate by the carboxylesterase ces1a1 is rapid and extensive leading to the main, de-esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. therapeutic activity is principally due to the parent compound. excretion after oral administration of an immediate release formulation of methylphenidate, 78% to 97% of the dose is excreted in the urine and 1% to 3% in the feces in the form of metabolites within 48 to 96 hours. only small quantities (less than 1%) of unchanged methylphenidate appear in the urine. most of the dose is excreted in the urine as ritalinic acid (60% to 86%), the remainder being accounted for by minor metabolite. studies in specific populations male and female patients there were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered ritalin la. racial or ethnic groups there is insufficient experience with the use of ritalin la to detect ethnic variations in pharmacokinetics. pediatric patients the pharmacokinetics of ritalin la was examined in 18 children with adhd between 7 and 12 years of age. fifteen of these children were between 10 and 12 years of age. the time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. after a 20-mg dose of ritalin la, concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. this higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age. patients with renal impairment ritalin la has not been studied in renally-impaired patients. renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. patients with hepatic impairment ritalin la has not been studied in patients with hepatic impairment. hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. figure 1: mean plasma concentration time-profile of methylphenidate after a single dose of ritalin la 40 mg and ritalin 20 mg given in two doses 4 hours apart)

nsitive 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 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 10 times the maximum recommended dose of 60 mg/day given to adolescents on a mg/m 2 basis.

nogens, 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 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 10 times the maximum recommended dose of 60 mg/day given to adolescents on a mg/m 2 basis.

patients treated with ritalin la showed a statistically significant improvement in symptom scores from baseline [mean (final score - baseline) = -10.7 points] over patients who received placebo [mean (final score - baseline) = +2.8 points]. the lower the final score on the cads-t scale from baseline, the less severe the disease is. this demonstrates that a single morning dose of ritalin la exerts a treatment effect in adhd. figure 2: cads-t total subscale - mean change from baseline*

orized collector is available, mix ritalin la 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 ritalin la in the household trash.

hcare 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 ritalin la can cause elevations of their blood pressure and pulse rate [see warnings and precautions (5.3)] . psychiatric risks advise patients that ritalin la, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see warnings and precautions (5.4)] . priapism advise patients of the possibility of painful or prolonged penile erections (priapism). instruct them to seek immediate medical attention in the event of priapism [see warnings and precautions (5.5)] . circulation problems in fingers and toes [peripheral vasculopathy, including raynaud’s phenomenon] instruct patients beginning treatment with ritalin la 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 ritalin la. 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 ritalin la may cause slowing of growth and weight loss [see warnings and precautions (5.7)] . alcohol effect advise patients to avoid alcohol while taking ritalin la. consumption of alcohol while taking ritalin la may result in a more rapid release of the dose of methylphenidate [see clinical pharmacology (12.3)] . pregnancy registry advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ritalin la during pregnancy [see use in specific populations (8.1)] . distributed by: novartis pharmaceuticals corporation east hanover, new jersey 07936 t2021-89