METHYLPHENIDATE LA (Generic for RITALIN LA)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Methylin chewable tablets: Administer 30 to 45 minutes before meals in divided doses 2 to 3 times daily. Chewable tablets should be taken with at least 8 ounces of fluid to avoid choking. Twice-daily dosages may be administered in the morning and around noon. Individualized timing of the midday dose is usually necessary, as determined by the loss of positive drug effect, which occurs 2 to 6 hours after the morning dose. Administer the last dose of the day prior to 6 PM.
-Immediate-release dosage forms (Ritalin, Methylin, Metadate, generic equivalents): Administer 30 to 45 minutes before meals in divided doses 2 to 3 times daily. Twice-daily dosages may be administered in the morning and around noon. Individualized timing of the midday dose is usually necessary, as determined by the loss of positive drug effect, which occurs 2 to 6 hours after the morning dose. Administer the last dose of the day prior to 6 PM.
-Extended-release tablets (Ritalin SR, Metadate ER, generic methylphenidate ER): May be administered without regard to meals. Administer whole; do not cut, crush, or chew. Extended-release tablets have a duration of action of approximately 8 hours. Administer the last dose of the day several hours before bedtime.
-Once-daily extended-release tablets (Concerta, Relexxii): Administer once daily in the morning with an adequate amount of fluid. May be administered without regard to meals. Administer whole; do not cut, crush, or chew. The biologically inert portion of this tablet may appear intact in the stool; this is normal.
-Once-daily extended-release capsules (Metadate CD, Ritalin LA, Aptensio XR): Administer once daily in the morning with an adequate amount of fluid. May be administered without regard to meals; however, the manufacturer of Aptensio XR recommends that patients establish a routine pattern with regard to meals. Do not cut, crush, or chew. If swallowing is difficult, the capsule may be opened and the contents gently sprinkled on a tablespoon of applesauce and swallowed immediately. The capsule contents (beads) should not be crushed or chewed. Instruct the patient to drink fluids (e.g., water, milk, or juice) after the intake of the beads with applesauce.-The Institute for Safe Medication Practices states the capsule contents of Metadate CD and Ritalin LA may be administered via a nasogastric tube as long as they are not crushed and an adequate amount of fluid is used to wash the full dose down the tube.

-Once-daily extended-release chewable tablets (Quillichew ER): Administer once daily in the morning with or without food.-The 10 mg and 15 mg doses can be achieved by breaking in half the scored 20 mg and 30 mg tablets, respectively.

-Once-daily extended-release orally disintegrating tablets (Cotempla XR-ODT): Administer once daily in the morning consistently either with or without food. Do not remove tablet from the blister pack until just prior to dosing; use dry hands when opening the blister pack. Remove the tablet by peeling back the foil; do not push the tablet through the foil. Place the whole tablet on the tongue and allow it to disintegrate without chewing or crushing. No liquid is needed to take the tablet.
-Once-daily extended-release capsules (Jornay PM): Administer once daily in the evening consistently either with or without food. Initiate dosing at 8:00 PM and adjust the timing of administration between 6:30 PM and 9:30 PM to optimize tolerability and efficacy the next morning and throughout the day. If a dose is missed, advise the patient to take it as soon as it's remembered that same evening. If a patient remembers the missed dose the next morning, skip the dose and do not give until the next scheduled evening administration. If swallowing is difficult, the capsule may be opened, and the contents gently sprinkled on applesauce and swallowed immediately. Do not crush or chew the capsule contents (beads).
-Once-daily extended-release capsules (Adhansia XR): Administer once daily in the morning consistently either with or without food. Do not cut, crush, or chew. If swallowing is difficult, the capsule may be opened, and the contents gently sprinkled on 1 tablespoon of applesauce or yogurt and swallowed immediately or within 10 minutes. If not consumed within 10 minutes after mixing, it should be discarded and not stored. The capsule contents (beads) should be taken in its entirety without chewing. The single dose capsules should not be divided.

Oral Liquid Formulations
Immediate-release Oral Solution (Methylin)
-Measure methylphenidate dosage with an oral syringe or calibrated measuring device.
-Administer 30 to 45 minutes before meals in divided doses 2 to 3 times daily. Twice-daily dosages may be administered in the morning and around noon. Individualized timing of the midday dose is usually necessary, as determined by the loss of positive drug effect, which occurs 2 to 6 hours after the morning dose. Administer the last dose of the day prior to 6 PM.

Once-daily Extended-release Oral Suspension (Quillivant XR)
Reconstitution
-Reconstitute prior to dispensing.
-Tap the bottle several times to loosen the powder.
-To prepare the suspension, add the specified amount of water to the bottle, fully insert the bottle adapter into the bottle neck, replace the cap, and vigorously shake the bottle for at least 10 seconds.
-Storage: Store reconstituted suspension at 77 degrees F; dispense in original packaging (bottle in carton). The reconstituted suspension is stable for 4 months from date of reconstitution.
Administration
-Vigorously shake the bottle of suspension for a minimum of 10 seconds before each use.
-Measure dosage with the calibrated oral dosing dispenser provided.
-Administer in the morning without regard to meals.



Topical Administration
Transdermal Patch Formulations
Transdermal Patch (Daytrana)
-Patch should be applied 2 hours before the effect is needed.
-Do not cut or trim patch.
-Apply patch immediately after opening the pouch and removing protective liner. Do not use if pouch seal is broken. Do not touch the adhesive side of the patch during application to avoid absorption of methylphenidate. Wash hands immediately if adhesive side of the patch is touched. Discard the patch if difficulty is encountered in separating the patch from the release liner, or if tearing or other damage occurs. Discard patch if adhesive containing medication has transferred to the liner during removal of the patch from the liner.
-Place on a dry, clean area of the hip and hold in place for 30 seconds with the palm of the hand. Do not apply to oily, damaged, or irritated skin. Do not apply topical preparations to the application site immediately prior to patch application. Avoid the waistline area where the patch could be rubbed by clothing.
-Applications sites should be alternated from one hip to the next each day, avoiding sites where a patch was recently placed, when possible.
-Instruct patient on proper application and disposal of patch. Adherence of the patch may be affected by showering, bathing, or swimming. The carton contains an administration chart that can help the patient monitor application and removal time, which the patient and/or caregiver should be encouraged to use. If a patch was removed without the caregiver's knowledge, or if a patch is missing from the tray, the caregiver should be encouraged to ask the child when and how the patch was removed.
-Avoid exposing the application site to hair dryers, heating pads, electric blankets, heated water beds, or other direct external heat sources. The rate and extent of absorption of methylphenidate are significantly increased during application of heat to the patch during use. Temperature-dependent increases in absorption may be greater than 2-fold, potentially resulting in overdose.
-Do not apply or re-apply the patch with dressings, tape, or adhesives. If the patch is not fully adhered to the skin during application or wear time, discard the patch according to disposal instructions and apply a new patch.
-The total daily wear time should not exceed 9 hours, regardless of patch replacement.
-Patches should be peeled off slowly. Patch removal may be aided by applying an oil-based product (i.e., petroleum jelly, mineral oil, olive oil) to the patch edges and gently working the oil underneath the edges of the patch.
-Disposal: Instruct patient and/or caregiver to fold used patches, so that the adhesive side of the patch adheres to itself, and then flush it down the toilet or dispose of in an appropriate lidded container. If the patient stops using the prescription, each unused patch should be removed from its pouch, separated from the protective liner, folded onto itself, and flushed down the toilet or disposed of in an appropriate lidded container. Do not flush pouch and protective liner down the toilet. Instead, dispose of them in an appropriate container with a lid.

Insomnia is one of the most common adverse reactions to methylphenidate. In clinical studies of evening-dosed methylphenidate extended-release capsules (Jornay PM) in pediatric patients 6 to 12 years, insomnia was the most frequently reported adverse reaction, occurring in 33% to 41% of patients. During clinical studies of the methylphenidate transdermal system (Daytrana), insomnia occurred in 13.3% of children and 6.2% of adolescents receiving active drug. For extended-release methylphenidate (Concerta or Relexxii), 2.8% of pediatric patients experienced insomnia. Initial insomnia was associated with the use of methylphenidate extended-release oral suspension (Quillivant XR) in 2% of children during clinical trials. Insomnia occurred in 6% of pediatric patients (12 to 17 years) taking methylphenidate extended-release capsules (Adhansia XR), with the highest incidence (13%) in those receiving 85 mg/day. Insomnia was reported in 10% of pediatric patients 6 to 12 years during an open-label treatment phase. Insomnia may be more frequent or severe during initial therapy, but will typically resolve as tolerance develops, provided the dosage is appropriate, and doses are not administered within 6 hours of bedtime. Avoidance of exercising late in the day, limiting caffeinated beverages, and setting regular bedtime schedules may limit sleep disruption. Continued interrupted sleep patterns may indicate a need for dosage reduction. Once-daily morning dosing of methylphenidate may be effective in some children and may also help to limit intolerable adverse reactions. If intolerable adverse reactions occur with the transdermal patch, either the dosage or wear time may be reduced. Individualization of wear time may help manage some of the adverse reactions caused by transdermal methylphenidate.

Centrally-mediated adverse reactions of methylphenidate are frequent but usually mild at normally prescribed dosages. These effects may be more frequent or severe during initial therapy, and will likely diminish within a few weeks of continued use. Nervousness is one of the most common adverse reactions of methylphenidate and may occur with all formulations; it has been reported in 2% or more of patients during placebo-controlled trials. Commonly reported (2% or more) adverse reactions occurring more often in pediatric patients receiving methylphenidate (various dosage forms) than those receiving placebo included vertigo (1.7%) and dizziness (1.9% to 6.7%) and paresthesias (1.2%). During a clinical trial of the methylphenidate transdermal system (Daytrana) in adolescents 13 to 17 years of age with ADHD, dizziness occurred in 5.5% of patients receiving Daytrana and more often than in patients receiving placebo; paresthesias were also reported. Motion sickness was reported in 2% of patients taking the extended-release suspension. Dizziness was reported in 3% of pediatric patients (12 to 17 years) receiving methylphenidate extended-release capsules (Adhansia XR) during clinical trials. Psychomotor hyperactivity occurred in 5% of children 6 to 12 years receiving methylphenidate extended-release capsules (Jornay PM) during open-label or placebo-controlled evaluations. Drowsiness, lethargy, fatigue, and thirst have also been reported with most methylphenidate dosage forms. Once-daily morning dosing of methylphenidate may be effective in some patients and may also help to limit intolerable adverse reactions. If intolerable adverse reactions occur with the transdermal patch, either the dosage or wear time may be reduced. Individualization of wear time may help manage some of the adverse reactions caused by transdermal methylphenidate. Asthenia, seizures, and a reversible ischemic neurological deficit have been reported during postmarketing use of some formulations of methylphenidate, although the frequency is unknown and causality to the drug has not been established.

Headache is a common neurologic effect of methylphenidate and occurs in approximately 2.4% to 19% of pediatric patients. Migraine headaches have been reported with postmarketing use; however, the frequency is unknown and causality to the drug has not been established. Headaches linked to methylphenidate use may respond to dose reduction.

Gastrointestinal (GI) reactions are some of the most common adverse reactions associated with methylphenidate use in pediatric patients. Anorexia (reported as loss or decrease of appetite) is a frequent adverse reaction of stimulant medications and occurs in approximately 2% to 35% of pediatric patients taking methylphenidate. Appetite changes may occur as early as the first days of therapy. Prolonged decreased appetite leads to weight loss in 2.4% to 12% of patients. Anorexia and weight loss appear to occur more frequently in children compared to adults, particularly during prolonged therapy. In a study of 4 and 5 year olds receiving extended-release methylphenidate (Aptensio XR), high rates of adverse reactions, most notably weight loss, were experienced. When weights were compared to those prior to initiations, 20 of 39 patients had lost enough weight to decrease 10 or more percentiles on the CDC growth chart for weight. Other adverse GI-related reactions associated with methylphenidate use include nausea (2.4% to 13%), vomiting (2% to 13%), abdominal pain (4% to 15%), xerostomia (3%), and teeth grinding (bruxism). Dyspepsia, constipation, and diarrhea have also been reported. For the following GI adverse reactions reported with the use of methylphenidate extended-release capsules (Adhensia XR) in pediatric patients (12 to 17 years), the reported incidence was greater patients who received the 70 mg or 85 mg doses vs. all doses: anorexia (26% and 28% for higher doses vs. 20%), nausea (7% and 8% for higher doses vs. 6%), xerostomia (4% and 5% for higher doses vs. 3%), vomiting (6% for higher doses vs. 3%), and weight loss (8% and 13% for higher dose vs. 7%). Eating small, frequent meals or snacks may help limit appetite problems. Once-daily morning dosing of methylphenidate may be effective in some children and may help limit undesirable adverse reactions. In some patients, side effects will improve within a few weeks of continued use; however, continued decreased appetite or weight loss may indicate a need for dosage reduction. If intolerable adverse reactions occur with the use of the methylphenidate transdermal patch, either the dosage or the wear time may be reduced. Monitor height and weight parameters relative to age at the initiation of treatment and periodically during therapy; interrupt treatment in patients who are not growing or gaining weight as expected. Clinicians should also be aware that while GI adverse reactions are relatively common with typical methylphenidate use, excessive symptoms (e.g., frequent vomiting) might represent excessive dosage and toxicity.

Data are inadequate to determine whether chronic use of stimulants, such as methylphenidate, causes long-term growth inhibition. Although data are limited, available studies do not indicate that stimulant use compromises the attainment of normal adult height and weight in most children. Practitioners should monitor height and weight parameters relative to age at treatment initiation and periodically thereafter (at minimum yearly). Patients who are not growing or gaining weight as expected may need to have their treatment interrupted. In a 24-month follow-up, the MultiModal Treatment Study showed a deceleration of growth of roughly 1 cm per year with stimulant use. In general, growth remained in the normal curve for most children, except those in the lowest percentiles of height for age. Data obtained on the effects of stimulants on growth suppression in children 7 to 10 years of age suggested that regularly medicated children (7 days/week throughout the year) had a temporary average slowing in growth of 2 cm in height and 2.7 kg in weight over 3 years. Reduction of annual growth rate was maximal in the first year, decreased in the second year, and absent in the third year of treatment; however, no compensatory growth rebound effects were found while on stimulant therapy. In clinical trials of methylphenidate, some degree of weight loss occurred in approximately 5% to 10% of pediatric patients. Proposed mechanisms of growth inhibition include the suppression of appetite or an alteration in growth hormone secretion. Some experts recommend the use of drug holidays to allow growth to 'catch-up'. However, drug holidays are typically reserved for children with well-controlled attention-deficit hyperactivity disorder (ADHD) symptoms and are of unproved value in limiting growth suppression.

Various psychiatric effects have been reported during treatment with stimulants such as methylphenidate. Nervousness, irritability (6% to 11%), and emotional lability (2.4% to 22%) were the most common psychiatric reactions reported during pediatric trials of methylphenidate; anxiety and depressed mood occurred less frequently. Irritability was associated with discontinuation of methylphenidate transdermal patch in adolescents. Once-daily morning dosing of methylphenidate may be effective in some children and may help to limit intolerable adverse reactions. If intolerable adverse reactions occur with the transdermal patch, either the dosage or the wear time may be reduced. Other commonly reported adverse reactions in adults with ADHD from placebo-controlled trials of methylphenidate include agitation (2% to 2.2%), aggression (1.7%), depression (1.7%), confusion (1.2%), and tension (1.2%). Other psychiatric reactions reported in methylphenidate clinical trials included anger, hypervigilance, mood alterations, tearfulness, and panic attacks. Nervousness is one of the most common adverse reactions of methylphenidate and may improve with a dosage reduction or omitting the afternoon dose for products that are dosed multiple times per day. Methylphenidate may aggravate pre-existing symptoms such as anxiety, tension, and agitation. Stimulants can cause new-onset psychotic or manic symptoms (i.e., hallucinations, psychosis, delusional thinking, or mania). These symptoms occurred in approximately 0.1% of patients treated with stimulants (methylphenidate or amphetamine at usual doses) in a pooled analysis of short-term, placebo-controlled studies. In a cohort study assessing 221,846 adolescents and young adults who received a prescription for a stimulant for ADHD, new-onset psychosis occurred in approximately 1 in 660 patients. The percentage of patients who had a psychotic episode was 0.1% in patients receiving methylphenidate compared to 0.21% in patients receiving amphetamine (hazard ratio with amphetamine use, 1.65; 95% CI 1.31 to 2.09). The median time from when the stimulant was dispensed to the psychotic episode was 128 days. Advise patients and their caregivers to promptly report any changes in mood or behavior. If suicide-related events emerge during treatment, consider dose reduction or drug discontinuation, especially if symptoms are severe, abrupt in onset, or were not part of the presenting symptoms of the patient. Patients with ADHD who become overly preoccupied with a task (overfocused or inflexible) or are described as 'zombie-like' are considered to exhibit supranormalization; these behaviors typically require dosage reduction. During postmarketing use of methylphenidate products, disorientation, auditory and visual hallucinations, logorrhea, mania, abnormal behavior, aggression, anxiety, nervousness, hostility, depression, obsessive-compulsive disorder, and suicidal ideation and behaviors (including completed suicide) have been reported. In addition, severe depression may occur during abrupt discontinuation after abusive use of methylphenidate; monitor patients carefully. While centrally-mediated effects are relatively common with both ADHD and typical methylphenidate use, excessive symptoms (agitation, confusion, and hallucinations) might represent excessive dosage and toxicity. Methylphenidate has been reported as a frequently suspected drug in serious adverse reactions in children, according to the Institute for Safe Medication Practices (ISMP). Of the serious adverse reactions reported to the FDA during a 5-year time span (2008 to 2012), sudden death and psychiatric effects (aggression, suicidal behaviors, psychotic episodes) were predominant for methylphenidate. Because reports submitted to the FDA likely represent only a portion of actual events and may be skewed, further investigation to determine frequency of occurrence and causality to the drug is warranted.

Dyskinesia has been reported during postmarketing use of CNS stimulants, including methylphenidate. The onset or exacerbation of motor and verbal tics has also been reported. Patients should be monitored for the emergence or worsening of dyskinesias, tics or Tourette's syndrome; consider dose reduction or discontinuation of treatment if clinically indicated.

Methylphenidate-induced increases in blood pressure and heart rate have been reported in 2% or more of patients during clinical trials for various methylphenidate products. 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). Selected individuals may have larger increases. Data from pediatric clinical trials indicate an average increase in systolic and diastolic blood pressure of 1 to 4 mmHg relative to placebo. Hypertension may occur in rare individuals. Monitor blood pressure and heart rate at baseline, after dosage increases, and periodically throughout methylphenidate therapy. Sinus tachycardia has been reported in 0.7% and 1% of adolescents and children, respectively, receiving transdermal therapy (Daytrana) and 2% to 8% of pediatric patients with various oral products. Cardiovascular events, including sudden death, have been associated with stimulant use in pediatric patients with structural cardiac abnormalities or other serious heart problems. Cardiovascular and cerebrovascular effects associated with methylphenidate use range in severity from mild to life-threatening and include cardiac murmur, palpitations, angina, chest pain (unspecified), cardiac arrhythmia (arrhythmia exacerbation) including supraventricular tachycardia (SVT), sinus tachycardia, bradycardia, extrasystole, myocardial infarction (reported in adults), stroke (reported in adults), and cerebral arteritis (vasculitis) or occlusion. The presence of any serious heart rate increases, blood pressure increase, or cardiovascular event requires evaluation and consideration of drug discontinuation. Pediatric patients who develop symptoms such as exertional chest pain (unspecified), unexplained syncope, or other symptoms suggestive of cardiac or cerebrovascular disease during methylphenidate treatment should undergo a prompt cardiac evaluation. Such cardiac adverse reactions may be associated with methylphenidate toxicity; evaluate patients carefully who present with cardiac symptoms for possible overdose. During a 5-year time span (2008 to 2012), 37 cases of sudden death associated with methylphenidate use in pediatric patients were reported to the FDA; however, causality to the drug has not been established. In a nationwide self-controlled case series (n = 1,224), use of methylphenidate in children and adolescents was associated with an increased risk of arrhythmia during the first 8 weeks of therapy (incidence rate ratio [IRR] 1.61; 95% CI 1.48 to 1.74), with the highest risk observed within the first 3 days of treatment (IRR 2.01; 95% CI 1.74 to 2.31) and in those with congenital heart disease (IRR 3.49; 95% CI 2.33 to 5.22). Overall, no significant risk of myocardial infarction was observed, but risk was elevated after the first week of treatment through week 8.

Hyperhidrosis (increased sweating) has been reported in at least 2% of pediatric patients receiving methylphenidate products in controlled clinical trials, and at rates at least twice the rate of the placebo group. Excessive sweating has been associated with methylphenidate toxicity; evaluate a patient who presents with complaints of increased sweating for other symptoms of possible toxicity or need for dose adjustment. Thirst has been reported during extended-release methylphenidate (Concerta) postmarketing use.

Hypersensitivity reactions to oral methylphenidate are infrequent and have included skin rash (unspecified) (2%), urticaria, arthralgia, exfoliative dermatitis, and erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura. Angioedema, anaphylactoid reactions, alopecia, urticaria, rash, rash (erythematous), macular rash, auricular swelling, bullous rash conditions, exfoliative dermatitis, eruptions, erythema, and exanthemas have been reported during postmarketing use of methylphenidate products. Some skin reactions may be accompanied by pruritus. Excoriation occurred in 4% of pediatric patients during clinical trials of methylphenidate extended-release oral solution. Contusion was reported in 3% of patients receiving Jornay PM and more frequently than in patients receiving placebo during clinical trials.

Dermatologic adverse reactions, ranging from mild temporary reactions to more severe permanent effects, can occur with methylphenidate transdermal patches. Chemical leukoderma, skin hypopigmentation due to repeated exposure to specific chemical compounds, may occur with use of the methylphenidate patch. This condition is not physically harmful, but is disfiguring and is thought to be irreversible, which may cause emotional distress. Advise patients and caregivers to monitor for new areas of skin discoloration, especially under the drug patch, and report any changes to their health care professional immediately. If chemical leukoderma occurs, discontinue the patch and consider alternative treatment options. Chemical leukoderma can mimic the appearance of vitiligo. Areas of skin color loss described have ranged up to 8 inches in diameter and were mostly limited to areas where the patch was rotated; however, a small number of patients have reported discoloration on parts of the body where the patch was never applied. Time to onset has ranged from 2 months to 4 years after patch initiation. More commonly, erythema and pruritus occur during use of transdermal methylphenidate. Use of transdermal methylphenidate may lead to a contact sensitization or skin irritation such as allergic contact dermatitis. Application site reactions resulted in patch discontinuance in roughly 6.7% of children and 1.9% of adolescents during long-term (up to 6 to 12 months) trials. In an open-label study designed to assess dermal reactions to the methylphenidate patch in children with ADHD (n = 305), 1 patient (0.3%) experienced allergic contact dermatitis consisting of erythema and edema at the patch application site with concurrent urticarial lesions on the abdomen and legs. During postmarketing use of transdermal methylphenidate, application site reactions have included bleeding, bruising (ecchymosis), burning, discharge, discoloration, discomfort, dryness (xerosis), eczema (atopic dermatitis), edema, skin erosion, excoriation, exfoliation, fissure, skin hyperpigmentation, skin hypopigmentation, induration, infected skin, inflammation, skin irritation, pain, papules, paresthesias, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth. Advise patients to alternate hip application sites each day to help prevent sensitization. If skin irritation develops, remove the patch. Erythema at the site of application is not always indicative of an allergic reaction; however, if contact sensitization is suspected (i.e., there is also edema, papules, or vesicles that do not significantly improve within 24 to 48 hours or spread beyond the patch site), discontinue the methylphenidate patch. Patients who develop contact dermatitis with transdermal methylphenidate may also be sensitized to oral methylphenidate and should be initiated on oral therapy under close supervision. Some patients who develop sensitization to the patch may not be able to use the oral products. Patients sensitized from use of transdermal methylphenidate, as evidenced by development of an allergic contact dermatitis, may develop systemic sensitization with subsequent use of oral methylphenidate. Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive patch test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, hyperpyrexia, malaise, arthralgia, diarrhea, or vomiting.

Stimulants used to treat ADHD, including methylphenidate, are associated with peripheral vasculopathy. Effects of peripheral vasoconstriction, 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 are usually intermittent and mild and generally improve after reduction in dose or discontinuation of drug. However, very rare sequelae include digital skin ulcer and/or soft tissue breakdown. Carefully monitor for digital changes during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Additionally, during postmarketing use of extended-release methylphenidate, peripheral coldness has been reported, although the frequency is unknown and causality to the drug has not been established.

During a 3-week placebo-controlled trial in pediatric patients 6 to 12 years (n = 81; mean dose 52 mg), back pain was reported in 3% of patients receiving Jornay PM and more frequently than in patients receiving placebo. Arthralgia, myalgia, muscle cramps, and muscle twitching have been reported during postmarketing use of methylphenidate products; however, the incidences are unknown, and causality to the drug has not been established.

Hematologic abnormalities including anemia, thrombocytopenia, leukopenia, and other blood dyscrasias have occurred rarely during treatment with methylphenidate; however, causality has not been established. Abnormal white blood cell count, leukopenia, pancytopenia, thrombocytopenia, and thrombocytopenic purpura have been reported during postmarketing use. Periodic blood counts and platelet counts may be advisable for those on chronic treatment with methylphenidate as a precaution.

In rare instances, elevated hepatic enzymes (e.g., elevated alanine aminotransferase), acute hepatic failure, and hepatocellular injury have occurred during treatment with methylphenidate; however, causality has not been established. Elevated alkaline phosphatase and hyperbilirubinemia have also been reported.

Ocular pain has been reported in 2% of pediatric patients during clinical trials of methylphenidate. Ocular reactions such as visual impairment, blurred vision, mydriasis, diplopia, dry eye, and accommodation disorder have been reported during postmarketing experience with various methylphenidate products. Blurred vision occurred in 1.7% of adult patients who received extended-release methylphenidate during clinical trials compared to 0.5% of patients who received placebo, and in 2% or more of patients during clinical trial experience with other methylphenidate products in children, adolescents, and adults. The sympathetic stimulation from stimulants may block aqueous outflow and may raise intraocular pressure, exacerbating ocular hypertension or glaucoma. Patients are encouraged to report any unusual changes in vision promptly for examination and evaluation.

Respiratory adverse reactions occurring in children and adolescents receiving methylphenidate include naso-pharyngitis (2.8% to 3%), streptococcal pharyngitis (3%), cough (1.9%), upper respiratory tract infection (17%), and oropharyngeal pain (1.2%). Sinusitis and dyspnea have been reported during postmarketing use of methylphenidate; however, the frequencies are unknown.

Frequent or prolonged erections and priapism have been reported during use of stimulant and non-stimulant medications for ADHD. Reported cases of priapism have occurred after a period of time on stimulant therapy and often subsequent to a dose increase. Priapism has also been reported during periods of drug withdrawal (e.g., drug holidays or discontinuation). Prolonged erections in male patients should be promptly reported, as immediate diagnosis and treatment are essential to avoid tissue damage. Priapism can occur in males of any age; younger males, particularly those who have not reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs. In a review of methylphenidate products by the FDA, the median age of patients who experienced priapism was 12.5 years (range: 8 to 33 years). Caution should be used when considering changing male patients from stimulant to non-stimulant medications; atomoxetine is also associated with priapism in young males and appears to carry a higher risk of the condition compared to methylphenidate. Gynecomastia has also been reported with methylphenidate products.

Very rare cases of a neuroleptic malignant syndrome (NMS) have been reported. In most of these cases, patients were concurrently receiving therapies associated with NMS along with methylphenidate. In a single report, a 10-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.

Fever (pyrexia) has also been associated with methylphenidate use. Fever occurred in 2.2% of children and adolescents who received extended-release methylphenidate in clinical trials vs. 0.9% of patients who received placebo. During postmarketing use hyperpyrexia and hot flashes have been reported, although the frequencies of these are unknown. Fever, sometimes severe enough to require external cooling, is also associated with methylphenidate toxicity or may be a symptom of neuroleptic malignant syndrome (NMS); carefully evaluate the patient for other signs and symptoms of overdose or NMS if fever occurs.

Serotonin syndrome in combination with other serotonergic drugs has been reported during postmarketing use of methylphenidate, although the frequency is unknown and causality has not been established. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome becomes evident during methylphenidate treatment, methylphenidate and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.

Rhabdomyolysis has been associated with the use of stimulants used to treat attention-deficit hyperactivity disorder. Stimulant-induced rhabdomyolysis is most often associated with sympathomimetic toxicity and has been reported in methylphenidate overdose. Hyperthermia, sometimes severe enough to require external cooling, is also associated with methylphenidate toxicity. Toxic effects of methylphenidate are more variable in children than in adults and appear to occur over a wide dosage range. Practitioners should be alert to the signs of excessive dosages or overdose which may include any of the following signs of central nervous system (CNS) overstimulation or sympathomimetic effects: angina, anxiety, agitation, blurred vision, confusion, delirium, hyperhidrosis (sweating), dryness of mucous membranes, euphoria, flushing or pallor, hallucinations, headache, hyperthermia, labile blood pressure and heart rate (hypotension or hypertension), mydriasis, palpitations, paranoia, hyperreflexia, psychosis, sinus tachycardia, tachypnea, tremor, or vomiting. Severe manifestations of methylphenidate overdose include cardiac arrhythmias including heart block, circulatory collapse, rhabdomyolysis, seizures, coma, and death. If overdose is suspected with the use of the methylphenidate patch, the patch should be removed immediately and the area cleaned. The continued absorption of methylphenidate from the skin may occur after the patch is removed. Treatment consists of appropriate supportive measures.

Psychological dependence, physiological dependence, and tolerance may occur with methylphenidate therapy. Abrupt discontinuation or a significant dose reduction of CNS stimulants after prolonged use may produce withdrawal symptoms that include dysphoria, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.

Methylphenidate is contraindicated in patients with known hypersensitivity to methylphenidate or any component of this product. Cross-sensitivity with dexmethylphenidate should be expected. Life-threatening hypersensitivity reactions, including angioedema and anaphylaxis, have been reported during methylphenidate administration. The use of transdermal methylphenidate may lead to contact sensitization. If contact sensitization is suspected, the methylphenidate patch should be discontinued. Patients who have previously developed contact dermatitis with transdermal methylphenidate may also be sensitized to oral methylphenidate and should be initiated on oral therapy under close supervision. After initial development of contact dermatitis from the methylphenidate patch, re-exposure to the drug by other routes of administration may result in systemic sensitization or other systemic reactions. Symptoms may include a flare-up of previous dermatitis, generalized skin eruptions to previously unaffected skin, headache, fever, malaise, arthralgia, diarrhea, or vomiting. Some patients who develop sensitization to the patch may not be able to use the oral products. Patients should alternate hip application sites each day to help prevent sensitization.

The Metadate CD products (and approved CD generics) contain sucrose. The manufacturers consider these products contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption, and sucrase-isomaltase insufficiency.

CNS stimulants should be used with caution in those with bipolar disorder or a pre-existing psychotic disorder (e.g., schizophrenia). CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychosis. These medications can also induce mania or a mixed episode in patients with bipolar disorder. Prior to initiating treatment with methylphenidate, screen patients for risk factors for bipolar disorder or developing an episode of mania (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). At recommended doses, CNS stimulants may also cause psychotic or manic symptoms (such as hallucinations, delusions, or mania) in patients without a prior history of psychosis or mania. Advise patients and their caregivers to promptly report suicidal ideation or any changes in mood or behavior and consider discontinuing treatment if these symptoms occur.

CNS stimulants, including methylphenidate products, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported. Prior to initiating any methylphenidate product, carefully assess family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome. Regularly monitor methylphenidate-treated patients for the emergence or worsening of tics or Tourette's syndrome and discontinue treatment if clinically appropriate.
Methylphenidate should be used cautiously in patients at risk of glaucoma. Increased intraocular pressure (IOP) and angle closure glaucoma have been reported in association with methylphenidate treatment. While the mechanism is not clear, methylphenidate-treated patients considered at risk for acute angle closure glaucoma (e.g. patients with significant hyperopia) should be evaluated by an ophthalmologist. Patients with a history of open-angle glaucoma or abnormally increased IOP should only receive methylphenidate if the benefit of treatment outweighs the risk. These patients should be monitored closely for changes in vision. Visual disturbance has been reported with the use of methylphenidate and may present as difficulties with accommodation and blurring of vision.

Central nervous system (CNS) stimulants, such as methylphenidate, have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Caution is recommended in patients with a known history of substance abuse, including alcoholism. Assess each individual's risk for abuse, misuse, or addiction before prescribing a CNS stimulant, and monitor for the development of these behaviors or conditions throughout treatment. Children and adolescents with attention-deficit hyperactivity disorder (ADHD) are more prone to substance abuse compared to those without ADHD, and those with co-occurring mental health conditions (e.g., depression, disruptive behavior disorders) are at even greater risk; however, appropriate treatment of ADHD with medication and behavior therapy may reduce the risk of developing a substance abuse disorder.The American Academy of Pediatrics recommends an active substance abuse disorder be treated appropriately before beginning stimulant medication. In patients with well-documented ADHD that predates the onset of substance abuse, a careful risk/benefit assessment must be conducted and appropriate consultation (e.g., a psychiatrist or addiction specialist) is suggested. To reduce the risk of substance abuse in patients who are prescribed stimulants, prescribers should take special care to 1.) confirm an accurate diagnosis of ADHD, 2.) screen older children and adolescents for use of alcohol, marijuana, and other drugs, 3.) provide age-appropriate anticipatory guidance (e.g., discuss proper medication use, risk of misuse, diversion, and abuse, safe storage of medication, appropriate transition to self-administration in older children), and 4.) carefully document and monitor prescription records closely. Prescribing and dispensing the smallest appropriate quantity may help to minimize abuse, misuse, and overdosage. CNS stimulants can be diverted for non-medical use into illicit channels or distribution. The most common source of non-medical use is sharing from family or friends with misuse of the patient's own prescription or obtaining from illicit channels occurring less frequently. Sharing of CNS stimulant medications can lead to substance abuse disorder and addiction in those they are shared with. Misuse and abuse of CNS stimulants can result in potential for overdose or poisoning and death; the risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Educate patients and their families about these risks, proper storage, and proper disposal of any unused medication. Misuse or abuse may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with stimulant abuse or misuse.

CNS stimulant medications, including methylphenidate, can 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). Some individuals may have larger increases. Monitor all patients receiving methylphenidate for hypertension and tachycardia.

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosages. Avoid use of CNS stimulants in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. Prior to initiating any CNS stimulant, carefully assess patient for the presence of cardiac disease (i.e., perform a careful patient history, assess for any family history of sudden death or ventricular arrhythmia, and complete a physical exam) and counsel patients to report symptoms of cardiac disease (i.e., exertional chest pain, unexplained syncope) immediately. Although it is reasonable for a health care provider to obtain an ECG as part of the cardiovascular evaluation, it is not mandatory. Treatment with stimulant products should not be withheld because an ECG is not performed. However, any patient with significant findings on physical examination, ECG, or from patient or family history (such as known congenital heart disease, structural heart disease, arrhythmias, or a family history of sudden cardiac death in members younger than 35 years of age) should be referred for consultation with a pediatric cardiologist prior to starting the stimulant medication. Overall, studies have not shown an association between the use of ADHD medications and adverse cardiovascular events; however, long-term cardiovascular risks associated with ADHD medications are unknown. Careful monitoring should be performed after initiation of stimulant medications; if any abnormal findings or arrhythmias are diagnosed during treatment, consider discontinuation of the stimulant.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Monitor for growth inhibition by monitoring height and weight parameters relative to age at treatment initiation and periodically thereafter (at minimum yearly). Patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

Methylphenidate may lower the seizure threshold and should be used cautiously in patients with a history of a seizure disorder or EEG abnormalities. Rarely, seizures have occurred in patients with no prior history or EEG evidence of seizure. Concomitant use of methylphenidate and anticonvulsants have not been established. The product labeling for some formulations of methylphenidate recommends discontinuing methylphenidate if seizures occur; the product labeling for other methylphenidate formulations do not contain a precaution for patients with a history of seizures.

Psychological dependence, physiological dependence, and tolerance may occur with methylphenidate therapy. Abrupt discontinuation or a significant dose reduction of CNS stimulants after prolonged use may produce withdrawal symptoms that include dysphoria, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation. Consider monitoring for withdrawal symptoms after significant dose reduction or discontinuation of therapy after prolonged use.

There is a potential for Concerta and Relexxii tablets to cause GI obstruction in susceptible patients. The Concerta extended-release tablet is nondeformable and does not change shape when passing through the GI tract. Use with caution in patients who have a history of severe GI narrowing, such as those patients with inflammatory bowel disease, short gut syndrome, history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, diverticular disease, or ileus. Patients with dysphagia, esophageal motility disorders, or esophageal stricture may not be able to swallow extended-release methylphenidate dosage forms whole and may be at risk for GI obstruction.

In rare instances, stimulant medications may cause prolonged and sometimes painful erections (priapism). All male patients and their caregivers should be counseled on the signs and symptoms of priapism and the importance of seeking immediate medical attention if an erection lasting more than 4 hours occurs. Immediate diagnosis and treatment are essential to avoid tissue damage. Priapism can occur in males of any age; younger males, particularly those who have not reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs. In a review of methylphenidate products by the FDA, the median age of patients who experienced priapism was 12.5 years (range: 8 to 33 years). Reported cases have occurred after a period of time on stimulant therapy and often after a dose increase. Priapism has also been reported during periods of drug withdrawal (e.g., drug holidays or discontinuation). Caution should be used when considering changing male patients from stimulant to non-stimulant medications; atomoxetine is also associated with priapism in young males and appears to carry a higher risk of the condition compared to methylphenidate.

Stimulant medications are associated with peripheral vasculopathy, including Raynaud's phenomenon. Worsening of peripheral vascular disease is possible. Effects on circulation have been observed with therapeutic doses at different times throughout therapy in all age groups. Signs and symptoms are usually intermittent and mild and generally improve after reduction in dose or discontinuation of drug. However, very rare sequelae include digital skin ulcer and/or soft tissue breakdown. Carefully monitor all patients for digital changes during treatment with stimulant medications, especially those with pre-existing circulation problems. Instruct patients to seek immediate medical attention if any new digital numbness, pain, skin discoloration, or temperature sensitivity occur, or if unexplained wounds appear on their fingers or toes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Concomitant use of halogenated anesthetics and methylphenidate may increase the risk of sudden blood pressure and heart rate increase during surgery. Monitor blood pressure and avoid the use of methylphenidate in patients being treated with anesthetics on the day of surgery.

All patients should be advised to avoid exposing the methylphenidate patch application site to direct external heat sources (i.e., a heating pad, electric blanket, heated water bed) while wearing the patch. There is a potential for temperature-dependent increases in methylphenidate release of greater than 2-fold from the patch when there is extreme ambient temperature increase at the site of application.

Methylphenidate chewable tablets (e.g., Methylin, QuilliChew ER) contain aspartame. Phenylalanine is a component of aspartame and can be harmful to patients with phenylketonuria (PKU). Before prescribing these formulations in patients with PKU, consider the combined daily amount of phenylalanine from all sources.

Methylphenidate is contraindicated with concurrent use or use within 14 days of MAOI therapy. Concurrent use may precipitate hypertensive crisis.

Chemical leukoderma, skin hypopigmentation due to repeated exposure to specific chemical compounds, may occur with use of the methylphenidate patch; patients with a personal and/or family history of vitiligo may be more at risk. This condition is not physically harmful, but is disfiguring and is thought to be irreversible, which may cause emotional distress. Advise patients and caregivers to monitor for new areas of skin discoloration, especially under the drug patch, and report any changes to their health care professional immediately. If chemical leukoderma occurs, discontinue the patch and consider alternative treatment options. Chemical leukoderma can mimic the appearance of vitiligo. Areas of skin color loss described have ranged up to 8 inches in diameter and were mostly limited to areas where the patch was rotated; however, a small number of patients have reported discoloration on parts of the body where the patch was never applied. Time to onset has ranged from 2 months to 4 years after patch initiation.

Because stimulants cause vasoconstriction, they may decrease placental perfusion. Neonates born to stimulant-dependent mothers are at increased risk for premature delivery and low birth weight. In addition, neonates with in utero exposure to stimulants may experience withdrawal after delivery; monitor the newborn for symptoms of withdrawal such as feeding difficulty, irritability, agitation, and excessive drowsiness.

Methylphenidate extended-release (Adhansia XR) 45 mg oral capsules contain tartrazine dye and can precipitate bronchial asthma or other allergic reactions in patients with tartrazine dye hypersensitivity.

Description: Methylphenidate is a central nervous system (CNS) stimulant that is chemically similar to the amphetamines. The peripheral pharmacologic actions of methylphenidate are milder than those of the amphetamines; it has more noticeable effects on central functioning than on motor activities. Methylphenidate is indicated for use in attention-deficit hyperactivity disorder (ADHD) and narcolepsy. Methylphenidate and other stimulants are highly effective for the treatment of ADHD, with few comparative differences in efficacy. Two well-controlled trials demonstrate that roughly 70% to 80% of children treated with stimulants will have improvements such that at the end of the treatment phase the child no longer meets criteria for diagnosis of ADHD. Methylphenidate has been shown to have a strong effect on measures of attention, distractibility, impulsivity, and social and classroom behavior. Modest effect sizes have been reported for academic achievement. Stimulants are considered first-line agents for ADHD. Lack of response to 1 stimulant does not predict a response to other stimulants, and a trial with a different agent (i.e., dexmethylphenidate, dextroamphetamine, mixed amphetamine salts) may be warranted if treatment fails with the initial stimulant. The Preschool ADHD Treatment Study (PATS), funded by the National Institute of Mental Health, provides important clinical guidance for children 3 to 5 years of age with ADHD. Stimulants have been associated with sudden death in patients with structural cardiac abnormalities or other serious cardiac disease when used at recommended ADHD doses; patients with structural heart defects, cardiomyopathy, coronary artery disease, serious cardiac arrhythmias, or other serious cardiac disease may be at risk for adverse cardiac events. The American Academy of Pediatrics and the American Heart Association recommend careful screening of all children and adolescents prior to initiating pharmacologic therapy for ADHD, including a detailed patient and family history and physical examination; any significant findings should be further assessed and referred for consultation with a pediatric cardiologist prior to initiating treatment. Methylphenidate is FDA approved for use in pediatric patients as young as 6 years of age; approved age-ranges vary for each specific product.

For the treatment of attention-deficit hyperactivity disorder (ADHD):
-for the treatment of ADHD in persons naive to methylphenidate:
Oral dosage (immediate-release):
Children 3 to 5 years*: 1.25 mg PO 3 times daily, initially. May increase the dose gradually based on clinical response. Max: 30 mg/day. The mean optimal total daily dose was 14.2 +/- 8.1 mg (0.7 +/- 0.4 mg/kg/day). In all cases, start treatment with a low dose and titrate upward slowly. Use the lowest effective dose. Higher doses have lead to social withdrawal in some children. Behavior therapy, parental training, and a structured preschool environment are considered first-line treatment for preschool-aged children with ADHD; lack of significant improvement with such modalities may warrant the addition of methylphenidate.
Children and Adolescents 6 to 17 years weighing 50 kg or less: 5 mg PO twice daily, initially. May increase the dose by 5 to 10 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Children and Adolescents 6 to 17 years weighing more than 50 kg: 5 mg PO twice daily, initially. May increase the dose by 5 to 10 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. However, a maximum dose of 100 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily capsules; Adhansia XR):
Children and Adolescents 6 to 17 years: 25 mg PO once daily in the morning, initially. May increase the dose by 10 to 15 mg/day at intervals of no less than 5 days based on clinical response. Max: 85 mg/day. Although 85 mg was efficacious in short-term controlled trials, dosages above 70 mg daily were associated with a disproportionate increase in the incidence of certain adverse reactions. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily capsules; Aptensio XR):
Children and Adolescents 6 to 17 years weighing 50 kg or less: 10 mg PO once daily in the morning, initially. May increase the dose by 10 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Children and Adolescents 6 to 17 years weighing more than 50 kg: 10 mg PO once daily in the morning, initially. May increase the dose by 10 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. However, a maximum dose of 100 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily capsules; Jornay PM):
Children and Adolescents 6 to 17 years: 20 mg PO once daily in the evening, initially. May increase the dose by 20 mg/day at weekly intervals based on clinical response. Max: 100 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily capsules; Metadate CD):
Children and Adolescents 6 to 15 years weighing 50 kg or less: 20 mg PO once daily in the morning, initially. May increase the dose by 10 to 20 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Children and Adolescents 6 to 15 years weighing more than 50 kg: 20 mg PO once daily in the morning, initially. May increase the dose by 10 to 20 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. However, a maximum dose of 100 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily capsules; Ritalin LA):
Children 6 to 12 years weighing 50 kg or less: 20 mg PO once daily in the morning, initially. When a lower initial dose is appropriate, start treatment with 10 mg PO once daily. May increase the dose by 10 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Children 6 to 12 years weighing more than 50 kg: 20 mg PO once daily in the morning, initially. When a lower initial dose is appropriate, start treatment with 10 mg PO once daily. May increase the dose by 10 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. However, a maximum dose of 100 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily chewable tablets; QuilliChew ER):
Children and Adolescents 6 to 17 years weighing 50 kg or less: 20 mg PO once daily in the morning, initially. May increase the dose by 10, 15, or 20 mg/day at weekly intervals based on clinical response. The 10 and 15 mg doses can each be achieved by breaking in half the functionally scored 20 and 30 mg tablets, respectively. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Children and Adolescents 6 to 17 years weighing more than 50 kg: 20 mg PO once daily in the morning, initially. May increase the dose by 10, 15, or 20 mg/day at weekly intervals based on clinical response. The 10 and 15 mg doses can each be achieved by breaking in half the functionally scored 20 and 30 mg tablets, respectively. Max: 60 mg/day. However, a maximum dose of 100 mg/day of may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily orally disintegrating tablets; Cotempla XR-ODT):
Children and Adolescents 6 to 17 years: 17.3 mg PO once daily in the morning, initially. May increase the dose by 8.6 to 17.3 mg/day at weekly intervals based on clinical response. Max: 51.8 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily suspension; Quillivant XR):
Children and Adolescents 6 to 17 years weighing 50 kg or less: 20 mg PO once daily in the morning, initially. May increase the dose by 10 to 20 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Children and Adolescents 6 to 17 years weighing more than 50 kg: 20 mg PO once daily in the morning, initially. May increase the dose by 10 to 20 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. However, a maximum dose of 100 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release once-daily tablets; Concerta, Relexxii):
Children 6 to 12 years weighing 50 kg or less: 18 mg PO once daily in the morning, initially. May increase the dose by 18 mg/day at weekly intervals based on clinical response. A 27-mg tablet is available for health care providers who wish to utilize a dosage between 18 and 36 mg. Max: 2 mg/kg/day or 54 mg/day, whichever is less. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Children 6 to 12 years weighing more than 50 kg: 18 mg PO once daily in the morning, initially. May increase the dose by 18 mg/day at weekly intervals based on clinical response. A 27-mg tablet is available for health care providers who wish to utilize a dosage between 18 and 36 mg. Max: 2 mg/kg/day or 54 mg/day, whichever is less. However, a maximum dose of 108 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Adolescents weighing 50 kg or less: 18 mg PO once daily in the morning, initially. May increase the dose by 18 mg/day at weekly intervals based on clinical response. A 27-mg tablet is available for health care providers who wish to utilize a dosage between 18 and 36 mg. Max: 2 mg/kg/day or 72 mg/day, whichever is less. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Adolescents weighing more than 50 kg: 18 mg PO once daily in the morning, initially. May increase the dose by 18 mg/day at weekly intervals based on clinical response. A 27-mg tablet is available for health care providers who wish to utilize a dosage between 18 and 36 mg. Max: 2 mg/kg/day or 72 mg/day, whichever is less. However, a maximum dose of 108 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Transdermal dosage:
Children and Adolescents 6 to 17 years: 10 mg/9 hours transdermally once daily in the morning, initially. May increase the dose to 15 mg/9 hours, then 20 mg/9 hours, and then 30 mg/9 hours at weekly intervals based on clinical response. The patch may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. Max: 30 mg/9 hours once daily. In clinical trials, there was no additional benefit of increasing the patch dose from 20 mg/9-hours to 30 mg/9-hours.
-for the treatment of ADHD in persons currently receiving methylphenidate:
Oral dosage (extended-release once-daily capsules; Adhansia XR):
Children and Adolescents 6 to 17 years: 25 mg PO once daily in the morning, initially. May increase the dose by 10 to 15 mg/day at intervals of no less than 5 days based on clinical response. Max: 85 mg/day. Although 85 mg was efficacious in short-term controlled trials, dosages above 70 mg daily were associated with a disproportionate increase in the incidence of certain adverse reactions. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Oral dosage (extended-release once-daily capsules; Jornay PM):
Children and Adolescents 6 to 17 years: 20 mg PO once daily in the evening, initially. May increase the dose by 20 mg/day at weekly intervals based on clinical response. Max: 100 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Oral dosage (extended-release once-daily capsules; Ritalin LA):
Children and Adolescents 6 to 12 years weighing 50 kg or less: 10 mg PO once daily as extended-release for 5 mg PO twice daily immediate-release; 20 mg PO once daily as extended-release for 10 mg PO twice daily immediate-release; 30 mg PO once daily as extended-release for 15 mg PO twice daily immediate-release; 40 mg PO once daily as extended-release for 20 mg PO twice daily immediate-release; or 60 mg PO once daily as extended-release for 30 mg PO twice daily immediate-release. May increase the dose by 10 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Children 6 to 12 years weighing more than 50 kg: 10 mg PO once daily as extended-release for 5 mg PO twice daily immediate-release; 20 mg PO once daily as extended-release for 10 mg PO twice daily immediate-release; 30 mg PO once daily as extended-release for 15 mg PO twice daily immediate-release; 40 mg PO once daily as extended-release for 20 mg PO twice daily immediate-release; or 60 mg PO once daily as extended-release for 30 mg PO twice daily immediate-release. May increase the dose by 10 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. However, a maximum dose of 100 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Oral dosage (extended-release once-daily chewable tablets; QuilliChew ER):
Children 6 to 17 years weighing 50 kg or less: 20 mg PO once daily in the morning, initially. May increase the dose by 10, 15, or 20 mg/day at weekly intervals based on clinical response. The 10 and 15 mg doses can each be achieved by breaking in half the functionally scored 20 and 30 mg tablets, respectively. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Children and Adolescents 6 to 17 years weighing more than 50 kg: 20 mg PO once daily in the morning, initially. May increase the dose by 10, 15, or 20 mg/day at weekly intervals based on clinical response. The 10 and 15 mg doses can each be achieved by breaking in half the functionally scored 20 and 30 mg tablets, respectively. Max: 60 mg/day. However, a maximum dose of 100 mg/day of may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Oral dosage (extended-release once-daily suspension; Quillivant XR):
Children and Adolescents 6 to 17 years weighing 50 kg or less: 20 mg PO once daily in the morning, initially. May increase the dose by 10 to 20 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Children and Adolescents 6 to 17 years weighing more than 50 kg: 20 mg PO once daily in the morning, initially. May increase the dose by 10 to 20 mg/day at weekly intervals based on clinical response. Max: 60 mg/day. However, a maximum dose of 100 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Oral dosage (extended-release once-daily tablets; Concerta, Relexxii):
Children and Adolescents 6 to 17 years weighing 50 kg or less: 18 mg PO once daily as extended-release for 5 mg PO 2 or 3 times daily immediate-release; 36 mg PO once daily as extended-release for 10 mg PO 2 or 3 times daily immediate-release; 54 mg PO once daily as extended-release for 15 mg PO 2 or 3 times daily immediate-release; or 72 mg PO once daily as extended-release for 20 mg PO 2 or 3 times daily immediate-release. May increase the dose by 18 mg/day at weekly intervals based on clinical response. A 27-mg tablet is available for health care providers who wish to utilize a dosage between 18 and 36 mg. Max: 72 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Children and Adolescents 6 to 17 years weighing more than 50 kg: 18 mg PO once daily as extended-release for 5 mg PO 2 or 3 times daily immediate-release; 36 mg PO once daily as extended-release for 10 mg PO 2 or 3 times daily immediate-release; 54 mg PO once daily as extended-release for 15 mg PO 2 or 3 times daily immediate-release; or 72 mg PO once daily as extended-release for 20 mg PO 2 or 3 times daily immediate-release. May increase the dose by 18 mg/day at weekly intervals based on clinical response. A 27-mg tablet is available for health care providers who wish to utilize a dosage between 18 and 36 mg. Max: 72 mg/day. However, a maximum dose of 108 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy. Discontinue other methylphenidate products and titrate using the titration schedule. Do not substitute other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles.
Oral dosage (extended-release tablets; Ritalin SR, Metadate ER, Methylin ER):
Children and Adolescents 6 to 17 years weighing 50 kg or less: The extended-release (ER) tablets have a duration of action of approximately 8 hours. Use in place of immediate-release (IR) tablets when the 8-hour dosage of these ER tablets corresponds to the titrated 8-hour dosage of the IR tablets. Max: 60 mg/day. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Children and Adolescents 6 to 17 years weighing more than 50 kg: The extended-release (ER) tablets have a duration of action of approximately 8 hours. Use in place of immediate-release (IR) tablets when the 8-hour dosage of these ER tablets corresponds to the titrated 8-hour dosage of the IR tablets. Max: 60 mg/day. However, a maximum dose of 100 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Transdermal dosage:
Children and Adolescents 6 to 17 years: 10 mg/9 hours transdermally once daily in the morning, initially. May increase the dose to 15 mg/9 hours, then 20 mg/9 hours, and then 30 mg/9 hours at weekly intervals based on clinical response. The patch may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. Max: 30 mg/9 hours once daily. In clinical trials, there was no additional benefit of increasing the patch dose from 20 mg/9-hours to 30 mg/9-hours. Follow the titration schedule for persons switching from another formulation of methylphenidate due to differences in bioavailability of the methylphenidate transdermal system compared to other products.

For the treatment of narcolepsy:
Oral dosage (immediate-release formulations; e.g., Ritalin, Methylin oral solution, Methylin chewable tablets):
Children < 6 years: Safety and efficacy have not been established.
Children >= 6 years and Adolescents: Initially, 5 mg PO twice daily before breakfast and lunch. May increase by 5-10 mg/day PO at weekly intervals. Max: 60 mg/day.
Oral dosage (extended-release tablets; e.g., Ritalin SR, Metadate ER, Methylin ER):
Children < 6 years: Safety and efficacy have not been established.
Children >= 6 years and Adolescents: The extended-release (ER) tablets have a duration of action of approximately 8 hours. Use in place of immediate-release (IR) tablets when the 8-hour dosage of the ER tablets corresponds to the previously titrated 8-hour dosage of the IR tablets. Max: 60 mg/day.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 2 years: Safety and efficacy have not been established.
3 to 5 years: Safety and efficacy have not been established. Maximum doses have not been adequately studied; however, The Preschool ADHD Treatment Study (PATS) has suggested immediate-release doses up to 30 mg/day PO.
6 to 12 years: 85 mg/day PO for Adhansia XR; 54 mg/day PO for Concerta or Relexxii (FDA-approved labeling); 60 mg/day PO for all other oral formulations excluding Cotempla XR-ODT and Jornay PM (FDA-approved labeling); 51.8 mg/day PO for Cotempla XR-ODT and 100 mg/day PO for Jornay PM; however, doses up to 100 to 108 mg/day PO have been used in patients weighing more than 50 kg for some formulations. For the transdermal patch, 30 mg/9-hour patch per day is the maximum.
-Adolescents
85 mg/day PO for Adhansia XR; 72 mg/day (Max: 2 mg/kg/day) PO for Concerta or Relexxii (FDA-approved labeling); 60 mg/day PO for all other oral formulations excluding Cotempla XR-ODT and Jornay PM (FDA-approved labeling); 51.8 mg/day PO for Cotempla XR-ODT and 100 mg/day PO for Jornay PM; however, doses up to 100 to 108 mg/day PO have been used in patients weighing more than 50 kg for some formulations. For the transdermal patch, 30 mg/9-hour patch per day is the maximum.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Renal clearance is not an important predictor of methylphenidate clearance.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Methylphenidate is a central nervous system (CNS) stimulant that is chemically similar to the amphetamines. Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. The exact mechanism of action of methylphenidate for the treatment of attention-deficit hyperactivity disorder (ADHD) is not established. Methylphenidate is an indirect agonist; it inhibits the reuptake of dopamine and norepinephrine, facilitating their release into the synaptic cleft. As a result, sympathomimetic activity in the CNS is increased. There is some evidence that the alteration of dopamine transport systems by methylphenidate may indirectly augment the action of serotonin, but further pharmacologic research is needed to understand these processes. The main sites of CNS activity appear to be the brain stem arousal system and the cerebral cortex, including the subcortical structures of the thalamus. Methylphenidate-induced CNS stimulation produces a decreased sense of fatigue, an increase in motor activity and mental alertness, and mild euphoria. Improved attention spans, decreased distractibility, increased ability to follow directions or complete tasks, and decreased impulsivity and aggression have been noted when stimulants are prescribed for the treatment of ADHD. Chronic use of methylphenidate may lead to tolerance of side effects and psychological dependence, similar to other psychostimulants. Psychological dependence and addiction are more likely with parenteral or inhalational abuse or other illicit use. In the periphery, the sympathomimetic actions of methylphenidate are minimal at therapeutic doses. Heart rate typically increases slightly with normal therapeutic doses of stimulants (about 3 to 6 bpm); however, a reflexive decrease in heart rate in response to increased blood pressure can also occur. At high doses, such as in overdoses, stimulants can cause significant hypertension, tachycardia, arrhythmias, and other serious complications.

Pharmacokinetics: Methylphenidate is administered orally and transdermally. It is a racemic mixture comprised of the d- and l-threo enantiomers, the d-enantiomer being more pharmacologically active. The distribution of methylphenidate in humans is unknown, but the agent does cross the blood-brain-barrier with high regional uptake in the striatum. The low degree of protein binding and high lipid solubility indicate that methylphenidate largely penetrates the central nervous system (CNS). Plasma protein binding is 10% to 33%. Therapeutic activity is primarily due to the parent compound. Metabolism of methylphenidate occurs in the liver via de-esterification to the primary metabolite alpha-phenyl-piperidine acetic acid (PPA, ritalinic acid), which has little pharmacologic activity. Small amounts of the hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. In studies with methylphenidate tablets and extended-release capsules (Ritalin LA), the average elimination half-life in children is approximately 2.5 hours (range 1.5 to 5 hours). The half-life of methylphenidate after oral administration of Jornay PM is about 5.9 hours. Most of a methylphenidate dose is recovered in urine (90%), primarily as ritalinic acid, which accounts for about 80% of the dose.

Affected cytochrome P450 isoenzymes and drug transporters: None
Methylphenidate is not metabolized by the cytochrome P450 system to a clinically significant extent and does not appear to be a relevant inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.


-Route-Specific Pharmacokinetics
Oral Route
Immediate-release dosage forms (e.g., Methylin, Ritalin)
Immediate-release products are readily absorbed with peak concentrations met at approximately 1 to 2 hours. In adults, the mean Cmax after a 20 mg dose is approximately 10 ng/mL. Presence of food has been shown to delay peak concentrations by approximately 1 hour (fasted 1.7 hours, fed 2.7 hours). Adult studies have shown high fat meals increase Cmax by an average of 13% and AUC by an average of 25%. Mean half-life is approximately 3 hours.

Sustained-release and extended-release tablet dosage forms (e.g., Ritalin SR, Metadate ER, Methylin ER)
Extended-release preparations minimize the fluctuations between peak and trough concentrations associated with short-acting agents. Absorption is extensive but slower. During pharmacokinetic studies in children, time to peak was 4.7 hours (1.3 to 8.2 hours). Duration of action is approximately 8 hours. When compared to immediate-release products, relative bioavailability (measured by the renal excretion of the primary metabolite) in children was 105% (49% to 168%). Mean half-life is approximately 3.5 hours.

Concerta once-daily extended-release tablets
Concerta uses osmotic pressure to produce a biphasic pharmacokinetic profile, providing day-long medication availability with once daily administration and minimizing fluctuations between peak and trough concentrations associated with immediate-release products. Plasma concentrations increase rapidly after administration with an initial maximum at 1 hour that then continues to gradually rise. Tmax occurs between 6 to 10 hours before the drug concentrations start to gradually descend. The half-life of methylphenidate in adolescents after oral administration of Concerta is about 3.5 hours. There is no evidence of dose dumping in the presence or absence of food. Adolescents have demonstrated a 58% increase in oral clearance when compared to children, suggesting patients with higher body weight may have lower exposures to methylphenidate at similar doses.

Metadate CD once-daily extended-release capsules
Metadate CD follows an extended-release biphasic pharmacokinetic profile to provide day-long medication availability with once daily administration. Using Diffucaps technology, the capsules contain the drug in both immediate-release and extended-release beads such that 30% of the dose is rapidly released and 70% of the dose is continuously released. The product demonstrates an initial peak plasma concentration at about 1.5 hours and a second peak at about 4.5 hours. Concentrations gradually decrease thereafter. After 1 week of repeated once-daily dosing to children 7 to 12 years old, a 20 mg dose yielded an early Cmax of 8.6 (+/- 2.2) ng/mL and a late Cmax of 10.9 (+/- 3.9) ng/mL, while a 40 mg dose yielded an early Cmax of 16.8 (+/- 5.1) ng/mL and a late Cmax of 15.1 (+/- 5.8) ng/mL. Approximately 25% to 30% of patients only had one observed Cmax. The mean Cmax and AUC after a 20 mg dose were slightly lower than those observed after administration of 10 mg of the immediate-release formulation dosed at 0 and 4 hours. In a study of adult volunteers, high-fat meals delayed the early peak by approximately 1 hour (range 2 to 5 hours) and increased the Cmax by approximately 30% and the AUC by an average of 17%. The Metadate CD capsule, when opened and sprinkled on a tablespoon of cool applesauce, is bioequivalent to the intact capsule. The mean terminal half-life of Metadate CD in adults is 6.8 hours (compared to 2.9 hours for immediate release and 3.4 hours for sustained release).

Ritalin LA once-daily extended-release capsules
Ritalin LA follows an extended-release biphasic pharmacokinetic profile to provide day-long medication availability with once daily administration. Using Spheroidal Oral Drug Absorption System (SODAS) technology, the capsules contain the drug in both rapid release and continuous release beads such that 50% of the dose is rapidly released and 50% of the dose is continuously released from enteric coated, delayed-release beads. Ritalin LA is readily absorbed, demonstrating an early Tmax of 1 to 3 hours and a late Tmax of 5 to 8 hours after dosing. Though the mean time to interpeak minimum and time to late Tmax are similar with Ritalin LA once daily and Ritalin (2 doses given 4 hours apart), Ritalin LA exhibits a lower late Cmax and a higher interpeak minimum concentration leading to less peak and trough fluctuation. The relative bioavailability of Ritalin LA once daily is comparable to the same total dose of immediate release product (2 doses given 4 hours apart). The absolute oral bioavailability in children is 22 +/- 8% for d-methylphenidate and 5 +/- 3% for l-methylphenidate, suggestive of significant pre-systemic metabolism. In adults, administration with a high fat breakfast delayed absorption time and lowered the late Cmax by approximately 25%. There is no evidence of food dumping in the presence or absence of food. The Ritalin LA capsule, when opened and sprinkled on a tablespoon of cool applesauce, is bioequivalent to the intact capsule.

Aptensio XR once-daily extended-release capsules
Aptensio XR follows an extended-release biphasic pharmacokinetic profile to provide day-long medication availability with once daily administration. Aptensio XR capsules contain multilayer beads, which are composed of an immediate-release layer containing approximately 40% of the methylphenidate dose, and a controlled-release layer which contains the remaining 60% of the dose. After oral administration, an initial peak plasma concentration occurs at about 2 hours, with a gradual descending concentration over the next 4 to 6 hours, after which a gradual increase begins reaching a second peak at about 8 hours. The relative bioavailability of Aptensio XR given once daily compared to a methylphenidate immediate-release oral product given 3 times daily in adults is approximately 102%. The pharmacokinetic profile of Aptensio XR administered as a whole capsule or opened and sprinkled onto applesauce under fasting conditions is similar. After a single dose administered to healthy adults under fasting conditions, the following pharmacokinetic parameters were calculated: Cmax = 23.47 (+/- 11.4) ng/mL, AUC = 258.1 (+/- 94.2) ng x hour/mL, and half-life = 5.09 hours. During pharmacokinetic trials, administration with a high fat meal decreased or diminished the second peak and increased the average Cmax and AUC by 28% and 19%, respectively. At an alcohol concentration up to 40%, there was 96% release of methylphenidate from Aptensio XR capsules within 2 hours; similar results are expected with other capsule strengths.

QuilliChew ER once-daily extended-release chewable tablets
After a single 40 mg dose under fasting conditions, Cmax was obtained at a median time of 5 hours. Compared to immediate-release chewable tablets (two 20 mg doses given 6 hours apart), methylphenidate mean peak concentration and exposure (AUC) was about 20% and 11% lower, respectively, after a single dose administration of 40 mg QuilliChew ER. Administration with a high-fat meal had no effect on Tmax, and increased Cmax and AUC by about 20% and 4%, respectively, after a single 40 mg dose. Plasma methylphenidate concentrations declined monophasically. The mean elimination half-life was 5.2 hours in healthy volunteers. The presence of alcohol increases release of methylphenidate. At an alcohol concentration up to 40%, there was 90% release of methylphenidate from QuilliChew ER within half an hour; similar results are expected with other available tablet strengths.

Quillivant XR once-daily extended-release oral suspension
Quillivant XR is an extended-release suspension for once-daily administration. Single dose pharmacokinetics of the d-isomer (pharmacologically active) after a 60 mg dose were studied in a small population of children (ages 9 to 12 years) and adolescents (ages 13 to 15 years). Children displayed a mean peak plasma concentration of 34.4 (+/- 14) ng/mL over a median time of 4 hours, while adolescents exhibited mean peak concentrations of 21.1 (+/- 5.9) ng/mL over a median time of 2 hours. Plasma concentrations in adolescents were comparable to that of adults. The relative bioavailability of Quillivant XR compared to immediate-release methylphenidate oral solution is 95%. Food has no clinically significant effect on bioavailability. Elimination half-life is approximately 5 hours.

Cotempla XR-ODT once-daily extended-release orally disintegrating tablets
Cotempla XR-ODT is an extended-release orally disintegrating tablet for once-daily administration. Single dose pharmacokinetics of the d-isomer (pharmacologically active) after a 51.8 mg dose were studied in a small population of children (ages 6 to 12 years) and adolescents (ages 13 to 17 years). Children displayed a mean peak plasma concentration of 32.7 (+/- 9.83) ng/mL over a median time of 4.6 hours, while adolescents exhibited mean peak concentrations of 20.2 (+/- 5.79) ng/mL over a median time of 5.31 hours. Methylphenidate plasma concentrations in the children were approximately twice those seen in adults, while adolescents had plasma concentrations comparable to that of adults. Administration with a high-fat meal shorted the median time to peak concentration (Tmax) by 0.5 hours and decreased the Cmax and increased AUC of total methylphenidate by approximately 24% and 16%, respectively, after a 51.8 mg dose. Plasma methylphenidate concentrations declined monophasically. Elimination half-life is approximately 4 hours. The presence of alcohol potentially increases release of methylphenidate. At an alcohol concentration of 40%, an in vitro dissolution study showed alcohol-induced dose dumping potential; dose dumping was not observed with lower alcohol concentrations.

Jornay PM once-daily evening-dosed extended-release oral capsules
After a single 100 mg oral dose of Jornay PM administered to healthy adults at 9 PM, the initial absorption of methylphenidate into plasma was delayed such that no more than 5% of total drug was available within the first 10 hours after dosing. After the lag period, the absorption of methylphenidate occurs with a single peak and a median Tmax of 14 hours, followed by a gradual decline throughout the rest of the day. The relative bioavailability of Jornay PM administered once daily compared to the same daily dose of an oral immediate-release methylphenidate product given 3 times/day in adults is 73.9%. Administration with a high-fat meal at night resulted in a similar mean AUC, a 14% lower mean Cmax, and a median Tmax extended by about 2.5 hours compared to a fasting state. A morning meal has no effect on the kinetics of Jornay PM taken at night. The kinetic parameters of Jornay PM are similar when taken as a whole capsule versus sprinkled on applesauce. The presence of alcohol increases release of methylphenidate in vitro. At an alcohol concentration of 40%, there was a 97% release of methylphenidate from Jornay PM within 2 hours; the increased release rate of methylphenidate was not seen with lower alcohol concentrations.

Adhansia XR once-daily extended-release capsules
Adhansia XR is an extended-release capsule for once-daily administration. It produces 2 distinct peak concentrations. After Adhansia XR administration, the first median time to Cmax occurs at about 2 (1 to 4) hours and the second at about 10 (8 to 14) hours in pediatric patients 6 to 12 years and 2 (1 to 4) hours for the first and the 11 (8 to 14) hours for the second in pediatric patients 13 to 17 years. The results of pharmacokinetic studies in pediatric patients (6 to 12 years) were comparable to that in adolescents and adults. Elimination half-life is approximately 4 to 7 hours in pediatric patients (6 to 12 years) and 5 hours in adolescents. The AUC and Cmin of d,l-methylphenidate were about 50% and 288% higher, respectively, for Adhansia XR compared to immediate-release methylphenidate at steady state, which was reached on day 3. Administration with a high-fat, high caloric meal did not affect Cmax and AUC. The presence of alcohol increases release of methylphenidate in vitro. At an alcohol concentration of 40%, there was a 71% and 61% release of methylphenidate for Adhansia XR 70 mg and 100 mg, respectively, at 2 hours; the increased release rate of methylphenidate was not seen with lower alcohol concentrations.

Other Route(s)
Transdermal Route
Systemic absorption of transdermal methylphenidate is dependent on both patch size and length of time worn. During pharmacokinetic studies in children and adolescents, d-methylphenidate was detectable in the circulation after an average delay time of 2 hours. Carry-over effect was observed with repeat dosing, as low concentrations were observed earlier. Peak plasma concentrations of methylphenidate are reached approximately 8 hours after patch application. Cmax and AUC increase significantly with repeated daily administration compared to single dose administration, suggesting transdermal absorption of methylphenidate increases with repeat dosing. AUC increased 13% in children and 14% in adolescents (compared to the anticipated AUC expected based on single dose pharmacokinetics) after 1 week of continuous daily administration. AUC increments increased to 64% (children) and 76% (adolescents) after 28 days of administration while Cmax increased by 69% (children) and 100% (adolescents). In clinical pharmacokinetic studies, when the 10 mg/9-hour methylphenidate patch was worn on the hip for 9 hours per day for 4 weeks, the mean d-methylphenidate Cmax at steady state was 15.7 (+/- 9.39) ng/mL in children and 8.32 (+/- 4.6) ng/mL in adolescents. In patients who escalated up to the 30 mg/9-hour patch every week for 4 weeks, the mean d-methylphenidate Cmax was 42.9 (+/- 22.4) ng/mL in children and 16.5 (+/- 6.94) ng/mL in adolescents. After either a 1-day or 7-day patch administration, the Cmax and AUC of d-methylphenidate were approximately 50% lower in adolescents than in children. Steady-state is approximately 14 days after repeat dosing. The absorption (rate and extent) is increased when methylphenidate patch is applied to inflamed skin or exposed to heat. Absorption characteristics in areas other than the hip are not known. The transdermal form of methylphenidate bypasses the liver upon first pass, unlike the oral formulation, resulting in higher serum concentrations with lower initial doses. In addition, transdermal administration of methylphenidate results in nearly equivalent exposure of l- and d-methylphenidate. Though the pharmacological activity of l-methylphenidate is less than d-methylphenidate, l-methylphenidate is minimally available after oral administration due to first pass metabolism. With transdermal administration in pediatric patients, the mean elimination half-life of l-methylphenidate was shorter than for d-methylphenidate and ranged from 1.4 to 2.9 hours; whereas the mean elimination half-life of d-methylphenidate was about 4 to 5 hours. Once the methylphenidate patch is removed, plasma concentrations decline in a biexponential manner due to distribution of drug from the skin after patch removal.


-Special Populations
Pediatrics
In studies with methylphenidate tablets and methylphenidate extended-release capsules (Ritalin LA), the average elimination half-life was about 2.5 hours (range: 1.5 to 5 hours) in children. In general, the Cmax and AUC of d-methylphenidate were approximately 50% lower in adolescents than in children after administration of the transdermal methylphenidate patch. When a single oral dose of extended-release suspension (Quillivant XR) was given to children (9 to 12 years) and adolescents (13 to 15 years), methylphenidate plasma concentrations in the children were approximately twice those seen in adults, while adolescents had plasma concentrations similar to adults. When a single oral dose of extended-release ODT tablet (Cotempla XR-ODT) was given to children (6 to 12 years) and adolescents (13 to 17 years), methylphenidate plasma concentrations in the children were approximately twice those seen in adults, while adolescents had plasma concentrations similar to adults. In a study of extended-release capsules (Aptensio XR), systemic drug exposures in 4 and 5-year-olds were higher than those in older children and adolescents at the same dose (2 to 3 fold higher Cmax and AUC). The kinetics of a single 54 mg dose of Jornay PM were evaluated in 2 separate studies in adults and in children and adolescents 8 to 17 years of age with ADHD. The qualitative plasma methylphenidate concentration curves and body weight dose-normalized AUC and Cmax were similar between adults, children, and adolescents; however, there were differences in mean kinetic parameters resulting in children being exposed to higher systemic concentrations of methylphenidate than adolescents or adults and adolescents exposed to higher concentrations of methylphenidate than adults when administered the same dose of Jornay PM.

Hepatic Impairment
There is no experience with methylphenidate in hepatic insufficiency.

Renal Impairment
Since renal clearance is not an important predictor of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of the drug. However, specific experience in the use of methylphenidate during renal insufficiency is not available.