Brand names: Adhansia, Aptensio, Concerta, Cotempla, Daytrana, ... show all 10 brands Jornay, Methylin, QuilliChew, Quillivant, Ritalin
Drug class: Respiratory and CNS Stimulants
VA class: CN802
Chemical name: d,l (racemic) methyl a-phenyl-2-piperidineacetate hydrochloride
Molecular formula: C₁₄H₁₉NO₂•ClH
CAS number: 298-59-9

Medically reviewed by Drugs.com on Dec 4, 2023. Written by ASHP.

Introduction

Piperidine-derivative stimulant; ¹¹⁸ pharmacologic actions qualitatively similar to those of amphetamines.^a

Uses for Methylphenidate

Attention Deficit Hyperactivity Disorder (ADHD)

Treatment of ADHD in children ≥6 years of age, adolescents, and adults.^{101 102 103 107 114 115 116 117 118 125 129 145 147 152 157 158 168} Multimodal, multidisciplinary treatment approaches that may include pharmacotherapy, behavioral treatment, and psychological, educational, social, and other measures are recommended.^{500 504 506}

Patients with ADHD may exhibit pronounced difficulties and impairment across their lifespan.^{100 506 513 517} Choice of therapeutic intervention(s) depends on patient's age, comorbid conditions, specific target symptoms, and strengths and weaknesses of the patient, family, school, and community.^{500 504}

Wide variety of treatments have been employed, including stimulants (e.g., amphetamines, methylphenidate, dexmethylphenidate), psychotropic drugs (e.g., antidepressants), and other drugs (e.g., atomoxetine, clonidine, guanfacine, viloxazine); psychosocial treatment; and other measures.^{101 102 103 105 106 107 115 116 500 505 506 511 516}

Stimulants remain the most effective and most commonly used first-line drugs for management of ADHD in pediatric patients and adults.^{101 102 103 105 106 107 110 115 116 122 504 510 511 518} Methylphenidate and amphetamines provide moderate to large improvements in ADHD symptoms in children and adolescents and moderate improvements in adults.^{504 517} Response to methylphenidate versus amphetamines is idiosyncratic.^{500 505 510}

AAP states methylphenidate may be considered for treatment of ADHD in preschool-aged children^{† [off-label]} (4 years of age to sixth birthday) if first-line treatments (i.e., parent training in behavior management and/or behavioral classroom interventions) do not provide substantial improvement and there is continued, moderate to severe disturbance in the child's functioning.⁵⁰⁰ Methylphenidate may be slightly less effective and less well tolerated in preschool-aged children than in school-aged children.⁵¹² (See Pediatric Use under Cautions.) AAP states that nonstimulants and stimulants other than methylphenidate have not been adequately studied in this age group.⁵⁰⁰

For elementary and middle school-aged children (6 years of age to 12th birthday), AAP recommends that drugs with FDA-approved labeling for treatment of ADHD be used in conjunction with parent training in behavior management and/or behavioral classroom intervention (preferably both).⁵⁰⁰ Educational interventions and individualized instructional supports are necessary treatment components.⁵⁰⁰ AAP states that evidence supporting use of stimulants in elementary school-aged children is particularly strong and evidence is sufficient, but not as strong, for atomoxetine, extended-release guanfacine, and extended-release clonidine, in that order.⁵⁰⁰

For adolescents (12 years of age to 18th birthday), AAP recommends that drugs with FDA-approved labeling for treatment of ADHD be used with the adolescent's assent.⁵⁰⁰ Concurrent use of evidence-based training interventions and/or behavioral interventions is encouraged.⁵⁰⁰ Educational interventions and individualized instructional supports are necessary treatment components.⁵⁰⁰ If concerned about drug diversion or misuse, may consider nonstimulant drugs.⁵⁰⁰ Use of longer-acting preparations or addition of a late-afternoon dose of a short-acting preparation may provide symptom control while adolescent is driving.⁵⁰⁰

Some clinicians recommend long-acting stimulants as first-line pharmacologic therapy for adult ADHD, with long-acting nonstimulants (e.g., atomoxetine) and short- or intermediate-acting stimulants used as second-line or adjunctive therapy.^{505 518} Nonpharmacologic therapies (e.g., cognitive behavioral therapy, psychoeducation) also are essential.^{506 513 518} Because of high frequency of comorbid disorders, consider potential effects on comorbid psychiatric symptoms.^{506 513}

Nonstimulant drugs may be used alone or in combination with stimulants in patients with ADHD and comorbid conditions (e.g., aggression, anxiety, depression, tic disorders).^{107 122 511 513}

Although current evidence indicates that stimulants do not worsen comorbid tic disorders in most patients, some patients receiving stimulants may experience worsening of tics, and central α₂-adrenergic agonists (e.g., clonidine, guanfacine) or atomoxetine may be alternative treatment options.^{505 511 529}

In patients with comorbid bipolar disorder, initiating mood stabilizing therapy prior to stimulant therapy may reduce risk of stimulants precipitating manic episodes.^{506 511 513}

When substance abuse is a concern, avoid immediate-release stimulants; may consider drugs with lower abuse potential (e.g., central α₂-adrenergic agonists, atomoxetine, bupropion).^{500 506 513 518 528} Alternatively, since some evidence indicates reduced substance use during periods of ADHD stimulant therapy, may consider stimulant formulations that are less readily abused (e.g., extended-release formulations, the prodrug lisdexamphetamine) if stimulants are required for potentially greater and more rapid onset of effect.^{506 511 513 527 528}

Narcolepsy

Symptomatic treatment of narcolepsy.^{114 145}

Some experts consider methylphenidate and amphetamines to be second-line therapies in adults and treatment options in pediatric patients for the management of excessive daytime sleepiness associated with narcolepsy.^{550 551 552}

Related/similar drugs

Xyrem, Xywav, sertraline, trazodone, Lexapro, citalopram, Zoloft

Methylphenidate Dosage and Administration

General

Pretreatment Screening

• Evaluate pediatric patients and adults for cardiac disease (i.e., obtain careful medical history, perform physical examination, and screen for family history of sudden death or ventricular arrhythmias).¹¹⁴

• Evaluate risk of abuse.¹¹⁴

Patient Monitoring

• Monitor for signs of abuse and dependence during therapy.¹¹⁴

Administration

Administer orally^{114 118 125 129 145 157 158 168} or percutaneously by topical application of a transdermal system.¹⁴⁷

Oral Administration

Immediate-release Preparations (Conventional Tablets, Chewable Tablets, or Oral Solution)

Administer 2 or 3 times daily.^{114 145 152}

The manufacturers recommend that conventional tablets, chewable tablets, or oral solution be taken 30–45 minutes before meals.^{114 145 152}

To avoid insomnia, administer the last daily dose before 6 p.m.^{114 145 152}

Administer chewable tablets with a full glass (i.e., ≥240 mL [8 ounces]) of water or other fluid to avoid choking.¹⁵² (See Swelling of Chewable Tablets in GI Tract under Cautions and also see Advice to Patients.)

Extended-release Tablets (Generics)

Swallow tablets whole; do not crush or chew.¹⁵⁸

May be used when the 8-hour dosage of the extended-release preparation corresponds to the titrated 8-hour dosage of the conventional tablets.¹⁵⁸

Administer 30–45 minutes before a meal.¹⁵⁸

Extended-release Trilayer Core Tablets (Concerta; Generics)

Administer once daily in the morning without regard to meals.¹¹⁸

Swallow tablets whole; do not crush, divide, or chew.¹¹⁸

Extended-release Orally Disintegrating Tablets (Cotempla XR-ODT)

Administer once daily in the morning in a consistent manner relative to food intake.¹⁷²

Administer immediately following removal from the blister package; do not save for later use.¹⁷² Remove tablet from blister package with dry hands by peeling back the foil and not by pushing the tablet through the foil.¹⁷² Place tablet on patient's tongue and allow to disintegrate in saliva without chewing or crushing.¹⁷² Administration of liquid with the tablet is not required.¹⁷²

Powder for Extended-release Suspension (Quillivant XR)

Administer once daily in the morning without regard to meals.¹⁵⁷

Must be reconstituted prior to dispensing.¹⁵⁷

To reconstitute powder, tap bottle until the powder flows freely, then remove bottle cap and add appropriate amount of water (53, 105, 131, or 158 mL of water to a bottle containing 300, 600, 750, or 900 mg, respectively, of the drug) to yield an extended-release suspension containing 25 mg/5 mL.¹⁵⁷ Insert adapter into neck of bottle and replace bottle cap.¹⁵⁷ Shake vigorously with back and forth motion for ≥10 seconds.¹⁵⁷

Use the bottle adapter and oral dosing dispenser supplied by manufacturer to administer the oral suspension.¹⁵⁷ Adapter should remain in place as long as the bottle is in use (up to 4 months).¹⁵⁷

Keep bottle tightly closed and vigorously shake for ≥10 seconds before each use.¹⁵⁷

To dispense a dose, insert the oral dosing dispenser into the adapter in the upright bottle, then invert the bottle and withdraw the appropriate dose into the oral dosing dispenser.¹⁵⁷ Consult manufacturer's patient information for more detailed information on administration.¹⁵⁷

Extended-release Capsules (Adhansia XR, Aptensio XR, Ritalin LA; Generics, including Equivalents of Metadate CD [Methylphenidate Hydrochloride CD])

Administer orally once daily in the morning.^{125 129 168 169}

Manufacturer states that methylphenidate hydrochloride CD extended-release capsules should be administered before breakfast.¹²⁵ Manufacturer states that administration of Ritalin LA relative to timing and composition of meals may need to be individually adjusted.¹²⁹ Manufacturers state that Adhansia XR and Aptensio XR may be administered without regard to meals, but Aptensio XR should be administered in a consistent manner relative to food intake.^{168 169}

Swallow capsules whole; do not crush, chew, or divide.^{125 129 168 169}

Alternatively, open capsule and sprinkle contents on a small amount (e.g., one tablespoonful) of applesauce; swallow immediately (or within 10 minutes for Adhansia XR) without chewing.^{125 129 168 169} Alternatively, may sprinkle contents of Adhansia XR capsules on a tablespoonful of yogurt.¹⁶⁹ Manufacturer states that contents of Ritalin LA capsules should not be mixed with warm applesauce because release properties of the formulation could be affected.¹²⁹

One manufacturer suggests that patient should drink fluids immediately after swallowing the intact capsule or sprinkle/applesauce mixture.¹²⁵

Patients receiving extended-release capsules should avoid consuming alcohol; alcohol may result in more rapid release of drug from these formulations.^{125 129 168 169} (See Absorption under Pharmacokinetics.)

If a dose is missed, resume the regular schedule the following morning; do not administer the missed dose later in the day and do not administer an extra dose to make up for the missed dose.^{168 169}

Delayed- and Extended-release Capsules (Jornay PM)

Administer once daily in the evening in a consistent manner relative to food intake.¹⁷⁰

If a dose is missed, administer the missed dose the same evening as soon as it is remembered; if the missed dose is not remembered until the following morning, omit the missed dose and administer the next dose at the regularly scheduled time.¹⁷⁰

Initially, administer at 8:00 p.m.; adjust administration time within the range of 6:30–9:30 p.m. to optimize tolerability and efficacy the next morning and throughout that day.¹⁷⁰ Once administration time has been optimized, administer at the same time each day.¹⁷⁰ In clinical trials in children 6–12 years of age, >70% of patients received the drug at 8 p.m.¹⁷⁰

Swallow capsules whole.¹⁷⁰

Alternatively, open capsule and sprinkle entire contents onto applesauce; swallow immediately without chewing.¹⁷⁰

Transdermal Administration

Apply once daily in the morning, 2 hours before an effect is needed; remove 9 hours after application.¹⁴⁷

Apply system immediately after opening individually sealed package and removing protective liner.¹⁴⁷

Do not use if package seal is broken.¹⁴⁷ Do not cut transdermal systems.¹⁴⁷ After separating the system from the protective liner, inspect the liner to ensure that no adhesive (which contains the drug) has been transferred to the liner.¹⁴⁷ Discard the transdermal system if adhesive transfer has occurred or if the system is torn, appears to be damaged, or is difficult to separate from the liner.¹⁴⁷ Use only intact transdermal systems.¹⁴⁷

Apply the transdermal system to a clean, dry area of the hip that is not oily, damaged, or irritated; avoid applying to the waistline or to areas under tight clothing, since system may rub off.¹⁴⁷ Press system firmly in place with palm of hand for approximately 30 seconds, ensuring good contact with the skin, particularly around the edges.¹⁴⁷ Alternate application sites daily (e.g., opposite hip) if possible.¹⁴⁷

Do not apply topical preparations (e.g., corticosteroids) immediately prior to system application; effects on adhesion, methylphenidate absorption, or adverse corticosteroid effects are not known.¹⁴⁷

Exposure to water during bathing, swimming, or showering can affect adherence to the skin.¹⁴⁷ Do not apply or reapply transdermal systems with dressings, tape, or other common adhesives.¹⁴⁷ If a system does not fully adhere to the skin upon application or becomes partially or fully dislodged during the intended period of use, replace it with a new system applied at a different site; do not exceed total wear time of 9 hours per day regardless of number of systems used.¹⁴⁷

Remove system by slowly peeling it off the skin.¹⁴⁷ If necessary to facilitate removal, gently apply an oil-based product (i.e., petroleum jelly, olive oil, mineral oil) to the edges of the system and gently work the oil underneath the edges.¹⁴⁷ To remove any adhesive remaining on the skin after system removal, apply an oil-based product to the application site to gently loosen and remove residual adhesive.¹⁴⁷ In the unlikely event that a system remains tightly adhered to the skin despite these measures, patient's clinician or pharmacist should be consulted.¹⁴⁷ Do not use nonmedical adhesive removers and acetone-based products (i.e., nail polish remover) to remove the system or adhesive.¹⁴⁷

After removal, fold system so that the adhesive side adheres to itself, then flush down the toilet or dispose of in an appropriate lidded container.¹⁴⁷ For unused systems, remove from packaging, separate from the protective liner, fold so that the adhesive side adheres to itself, and then flush down the toilet or dispose of in an appropriate lidded container.¹⁴⁷

Encourage parents or caregiver to record and monitor the application and removal times and method of disposal for each system.¹⁴⁷

Dosage

Available as methylphenidate (transdermal) and methylphenidate hydrochloride (oral); dosage of transdermal systems is expressed in terms of methylphenidate, and dosage of oral formulations generally is expressed in terms of the salt.^{114 118 125 129 145 147 157 158 168 169 170 171} However, dosage of methylphenidate hydrochloride extended-release orally disintegrating tablets (Cotempla XR-ODT) is expressed in terms of methylphenidate; each 8.6, 17.3, or 25.9 mg of methylphenidate is equivalent to 10, 20, or 30 mg, respectively, of methylphenidate hydrochloride.¹⁷²

Carefully adjust dosage according to individual requirements and response.^{118 125 129}

Discontinue therapy if a beneficial effect is not attained after appropriate dosage adjustment over 1 month.^{114 169}

If paradoxical aggravation of symptoms occurs, reduce dosage or discontinue the drug.^{114 169}

Periodically reevaluate long-term usefulness and adjust dosage as needed.¹¹⁴

Pediatric Patients

ADHD

Extended-release formulations are used more commonly,^{510 518} but may initiate therapy in some patients with an immediate-release formulation to assess tolerability and determine approximate dosage requirements.⁵¹⁰

Some patients receiving intermediate- or long-acting preparations may require supplemental therapy with an immediate-release formulation of the drug to increase efficacy, particularly in the morning, or to extend the duration of therapeutic effects later in the day.^{137 500 510}

Extended-release oral formulations may contain both immediate-release and extended-release methylphenidate in various proportions, generally ranging from 20% immediate-release and 80% extended-release drug to equal proportions of each (see Preparations) in various delivery systems.^{125 129 157 168 169 171 172} Differences in methylphenidate preparations (e.g., method of drug delivery, drug release characteristics, onset and duration of activity, ease of administration) allow for individualization of therapy based on patient needs.⁵⁰⁹ (See Pharmacokinetics.)

For patients whose symptoms are not severe outside school, may attempt planned breaks in drug treatment (i.e., drug holidays) to assess continuing efficacy and need for therapy, as well as to minimize adverse effects.^{501 502 503 504 505}

Initial Therapy with Immediate-release Preparations (Conventional Tablets, Chewable Tablets, or Oral Solution)

Oral

Pediatric patients ≥6 years of age: Initially, 5 mg twice daily, before breakfast and lunch.^{114 145 152} Increase dosage by 5–10 mg daily at weekly intervals based on response and tolerance, up to 60 mg daily; administer daily dosage in 2 or 3 divided doses.^{114 145 152} Duration of action is approximately 3–4 hours.^{509 510}

Some clinicians have recommended weight-based dosing, but variations in dosage not found to be weight related.⁵⁰⁰

Alternatively, dosage has been titrated over 28 days via daily-switch titration involving 5 randomly ordered repeats each of placebo and 5-, 10-, 15-, or 20-mg daily dosages (higher for children weighing >25 kg); each dose is repeated at breakfast and lunch, with a half dose given in the afternoon.¹¹⁵ The best dosage is selected based on clinical assessment of response.¹¹⁵

Also may use immediate-release formulations to supplement therapy with intermediate- or long-acting preparations to increase efficacy, particularly in the morning, or to extend the duration of therapeutic effects later in the day.^{137 500 510}

Switching to Extended-release Tablets (Generics)

Oral

Pediatric patients ≥6 years of age: Extended-release tablets can be substituted for conventional tablets when the 8-hour dosage of methylphenidate hydrochloride as extended-release tablets corresponds to the titrated 8-hour dosage of the drug administered as conventional tablets.¹⁵⁸

Usual dosage: 20–60 mg daily, given as 20–40 mg once daily or as 40 mg in the morning and 20 mg in the early afternoon.

Some patients may require supplemental doses of a short-acting (conventional) preparation.¹³⁷

Initial Therapy with Extended-release Chewable Tablets (QuilliChew ER)

Oral

Pediatric patients ≥6 years of age: Initially, 20 mg once daily in the morning.¹⁷¹ Clinical studies suggest duration of action is 8–12 hours.^{171 509 510} Adjust dosage by 10, 15, or 20 mg daily at weekly intervals, up to 60 mg daily.¹⁷¹

Switching to Extended-release Chewable Tablets (QuilliChew ER)

Oral

Pediatric patients ≥6 years of age: Do not substitute for other methylphenidate preparations on mg-for-mg basis because of different methylphenidate base compositions and pharmacokinetic profiles.¹⁷¹ (See Pharmacokinetics.) In patients being transferred from other methylphenidate formulations, use same initial dosage and follow same dosage titration schedule recommended for patients receiving extended-release chewable tablets as their initial methylphenidate regimen.¹⁷¹

Initial Therapy with Extended-release Trilayer Core Tablets (Concerta; Generics)

Oral

Pediatric patients 6–17 years of age: Initially, 18 mg once daily in the morning.¹¹⁸ Duration of action is approximately 10–12 hours.^{118 509} If adequate response does not occur, increase dosage at weekly intervals in increments of 18 mg daily up to 54 mg daily in children 6–12 years of age or 72 mg daily (maximum 2 mg/kg daily) in adolescents 13–17 years of age.¹¹⁸

Switching to Extended-release Trilayer Core Tablets (Concerta; Generics)

Oral

For manufacturer's recommendations for switching from conventional methylphenidate preparations to extended-release trilayer core tablets, see Table 1.¹¹⁸

Initial dosage as extended-release trilayer core tablets in patients being switched from conventional tablets should not exceed 72 mg daily.¹¹⁸ Adjust dosage at weekly intervals in increments of 18 mg daily, up to 54 mg daily in children 6–12 years of age and 72 mg (maximum 2 mg/kg) daily in adolescents.¹¹⁸

A 27-mg extended-release trilayer core tablet also is available for patients who require a dosage in between 18 mg daily and 36 mg daily.¹¹⁸

Initial Therapy with Extended-release Orally Disintegrating Tablets (Cotempla XR-ODT)

Oral

Pediatric patients 6–17 years of age: Initially, 17.3 mg of methylphenidate (equivalent to 20 mg of methylphenidate hydrochloride) once daily in the morning.¹⁷² Adjust dosage by 8.6–17.3 mg daily at weekly intervals, up to 51.8 mg daily (equivalent to 60 mg of methylphenidate hydrochloride daily).¹⁷² Duration of action is approximately 12 hours.^{172 509}

Initial Therapy with Extended-release Oral Suspension (Quillivant XR)

Oral

Pediatric patients ≥6 years of age: Initially, 20 mg once daily in the morning.¹⁵⁷ Increase dosage by 10–20 mg daily at weekly intervals, up to 60 mg daily.¹⁵⁷ Duration of action is approximately 10–12 hours.^{157 509 510}

Switching to Extended-release Oral Suspension (Quillivant XR)

Oral

Pediatric patients ≥6 years of age: Do not substitute for other methylphenidate preparations on mg-for-mg basis because of different methylphenidate base compositions and pharmacokinetic profiles.¹⁵⁷ (See Pharmacokinetics.) In patients being transferred from other methylphenidate formulations, use same initial dosage and follow same dosage titration schedule recommended for patients receiving extended-release suspension as their initial methylphenidate regimen.¹⁵⁷

Initial Therapy with Extended-release Capsules (Adhansia XR, Aptensio XR, Methylphenidate Hydrochloride CD, Ritalin LA; Other Generics)

Oral

Adhansia XR in pediatric patients ≥6 years of age: Initially, 25 mg once daily in the morning.¹⁶⁹ Increase dosage by 10–15 mg daily at intervals of ≥5 days, up to 85 mg daily.¹⁶⁹ Efficacy demonstrated in short-term controlled trials at dosages of 70 mg daily in pediatric patients, but dosages ≥70 mg daily associated with disproportionate increase in certain adverse effects.¹⁶⁹ Individualize dosage adjustments based on clinical benefit and tolerability; carefully consider dose-related adverse effects.¹⁶⁹ Duration of action is approximately 13–16 hours.^{169 509 510}

Aptensio XR or generic equivalents in pediatric patients ≥6 years of age: Initially, 10 mg once daily in the morning.¹⁶⁸ Increase dosage by 10 mg daily at weekly intervals, up to 60 mg daily.¹⁶⁸ Duration of action is approximately 12 hours.^{168 509 510}

Methylphenidate hydrochloride CD in pediatric patients ≥6 years of age: Initially, 20 mg once daily in the morning.^{125 126} Increase dosage by 10–20 mg daily at weekly intervals, up to 60 mg daily.¹²⁵ Duration of action is approximately 6–8 hours.⁵⁰⁹

Ritalin LA in children 6–12 years of age: Initially, 20 mg once daily in the morning.¹²⁹ Alternatively, initiate with 10 mg once daily when a lower initial dosage is appropriate.¹²⁹ Increase dosage by 10 mg daily at weekly intervals, up to 60 mg daily.¹²⁹ Duration of action is approximately 6–8 hours.⁵⁰⁹

Switching to Extended-release Capsules (Adhansia XR)

Oral

Pediatric patients ≥6 years of age: Do not substitute for other methylphenidate preparations on mg-for-mg basis because of different methylphenidate base compositions and pharmacokinetic profiles.¹⁶⁹ (See Pharmacokinetics.) In patients being transferred from other methylphenidate formulations, use same initial dosage and follow same dosage titration schedule recommended for patients receiving Adhansia XR as their initial methylphenidate regimen.¹⁶⁹

Switching to Extended-release Capsules (Methylphenidate Hydrochloride CD)

Oral

For manufacturer's recommendations for switching from conventional methylphenidate hydrochloride tablets to methylphenidate hydrochloride CD extended-release capsules in pediatric patients ≥6 years of age, see Table 2.¹²⁶

Switching to Extended-release Capsules (Ritalin LA; Generics)

Oral

For manufacturer's recommendations for switching from conventional or extended-release methylphenidate hydrochloride tablets to Ritalin LA in children 6–12 years of age, see Table 3.¹²⁹

Do not substitute for other methylphenidate preparations on mg-for-mg basis because of different methylphenidate base compositions and pharmacokinetic profiles.¹²⁹ (See Pharmacokinetics.) In patients being transferred from therapy with other methylphenidate formulations, use same initial dosage and follow same dosage titration schedule recommended for patients receiving Ritalin LA as their initial methylphenidate regimen.¹²⁹

Initial Therapy with Delayed- and Extended-release Capsules (Jornay PM)

Oral

Pediatric patients 6–17 years of age: Initially, 20 mg once daily in the evening (see Delayed- and Extended-release Capsules [Jornay PM] under Dosage and Administration).¹⁷⁰ Adjust dosage by 20 mg daily at weekly intervals, up to 100 mg daily.¹⁷⁰ Following an initial delay in absorption of approximately 8–10 hours,^{170 173 510} duration of clinical response is approximately 10–12 hours.^{509 510}

Switching to Delayed- and Extended-release Capsules (Jornay PM)

Oral

Do not substitute for other methylphenidate preparations on mg-for-mg basis because of different methylphenidate base compositions and pharmacokinetic profiles.¹⁷⁰ (See Pharmacokinetics.) In patients being transferred from therapy with other methylphenidate formulations, use same initial dosage and follow same dosage titration schedule recommended for patients receiving delayed- and extended-release capsules as their initial methylphenidate regimen.¹⁷⁰

Initial Therapy with or Switching to Transdermal System

Transdermal

Individualize dosage titration, final dosage, and wear time according to patient’s needs and response.¹⁴⁷

Initially, apply one system delivering 10 mg/9 hours once daily (for initial therapy or for patients switching from other methylphenidate preparations).¹⁴⁷ Increase dosage at weekly intervals, based on response and tolerance, by using the next larger dosage system (i.e., 1 system delivering 15 mg/9 hours, then 1 system delivering 20 mg/9 hours, and then 1 system delivering 30 mg/9 hours).¹⁴⁷

If shorter duration of effect is desired or if late-day adverse effects appear, may remove system earlier than 9 hours.¹⁴⁷ If aggravation of symptoms or other adverse events occur, reduce dosage or wear time or, if necessary, discontinue therapy.¹⁴⁷

Adults

ADHD

Extended-release formulations are used more commonly,^{510 518} but may initiate therapy in some patients with an immediate-release formulation to assess tolerability and determine approximate dosage requirements.⁵¹⁰

Some patients receiving intermediate- or long-acting preparations may require supplemental therapy with an immediate-release formulation of the drug to increase efficacy, particularly in the morning, or to extend the duration of therapeutic effects later in the day.^{137 500 510}

Extended-release oral formulations may contain both immediate-release and extended-release methylphenidate in various proportions, generally ranging from 20% immediate-release and 80% extended-release drug to equal proportions of each (see Preparations) in various delivery systems.^{125 129 157 168 169 171 172} Differences in methylphenidate preparations (e.g., method of drug delivery, drug release characteristics, onset and duration of activity, ease of administration) allow for individualization of therapy based on patient needs.⁵⁰⁹ (See Pharmacokinetics.)

Therapy with Immediate-release Preparations (Conventional Tablets, Chewable Tablets, or Oral Solution)

Oral

Usual dosage is 20–30 mg administered in 2 or 3 divided doses daily, up to 60 mg daily.^{114 145 152} Some patients may require 40–60 mg daily, while others may require only 10–15 mg daily.^{145 152}

Also may use immediate-release formulations to supplement therapy with intermediate- or long-acting preparations to increase efficacy, particularly in the morning, or to extend the duration of therapeutic effects later in the day.^{137 500 510}

Switching to Extended-release Tablets (Generics)

Oral

Extended-release tablets can be substituted for conventional tablets when the 8-hour dosage of methylphenidate hydrochloride as extended-release tablets corresponds to the titrated 8-hour dosage of the drug administered as conventional tablets.¹⁵⁸

Usual dosage: 20–60 mg daily, given as 20–40 mg once daily or as 40 mg in the morning and 20 mg in the early afternoon.^a

Some patients may require supplemental doses of a short-acting (conventional) preparation.¹³⁷

Initial Therapy with Extended-release Chewable Tablets (QuilliChew ER)

Oral

Initially, 20 mg once daily in the morning.¹⁷¹ Duration of action is 8–12 hours.^{171 509 510} Adjust dosage by 10, 15, or 20 mg daily at weekly intervals, up to 60 mg daily.¹⁷¹

Switching to Extended-release Chewable Tablets (QuilliChew ER)

Oral

Do not substitute for other methylphenidate preparations on mg-for-mg basis because of different methylphenidate base compositions and pharmacokinetic profiles.¹⁷¹ (See Pharmacokinetics.) In patients being transferred from other methylphenidate formulations, use same initial dosage and follow same dosage titration schedule recommended for patients receiving extended-release chewable tablets as their initial methylphenidate regimen.¹⁷¹

Initial Therapy with Extended-release Trilayer Core Tablets (Concerta; Generics)

Oral

Initially, 18 or 36 mg once daily in the morning.¹¹⁸ Duration of action is approximately 10–12 hours.^{118 509} If adequate response does not occur, increase dosage by 18 mg daily at weekly intervals, up to 72 mg daily.¹¹⁸

Switching to Extended-release Trilayer Core Tablets (Concerta; Generics)

Oral

For manufacturer's recommendations for switching from conventional methylphenidate preparations to extended-release trilayer core tablets, see Table 4.¹¹⁸

Initial dosage as extended-release trilayer core tablets in patients being switched from conventional tablets should not exceed 72 mg daily.¹¹⁸ Adjust dosage at weekly intervals in increments of 18 mg daily, up to 72 mg daily.¹¹⁸

A 27-mg extended-release trilayer core tablet also is available for patients who require a dosage in between 18 mg daily and 36 mg daily.¹¹⁸

Initial Therapy with Extended-release Capsules (Adhansia XR)

Oral

Initially, 25 mg once daily in the morning.¹⁶⁹ Increase dosage by 10–15 mg daily at intervals of ≥5 days, up to 100 mg daily.¹⁶⁹ Efficacy demonstrated in short-term controlled trials at dosages of 100 mg daily in adults, but dosages >85 mg daily associated with disproportionate increase in certain adverse effects.¹⁶⁹ Individualize dosage adjustments based on clinical benefit and tolerability; carefully consider dose-related adverse effects.¹⁶⁹ Duration of action is approximately 13–16 hours.^{169 509 510}

Switching to Extended-release Capsules (Adhansia XR)

Oral

Do not substitute for other methylphenidate preparations on mg-for-mg basis because of different methylphenidate base compositions and pharmacokinetic profiles.¹⁶⁹ (See Pharmacokinetics.) In patients being transferred from other methylphenidate formulations, use same initial dosage and follow same dosage titration schedule recommended for patients receiving Adhansia XR as their initial methylphenidate regimen.¹⁶⁹

Narcolepsy

Oral

Usual dosage of 10 mg (as conventional tablets or oral solution) 2 or 3 times daily; dosage range of 10–60 mg daily.^{114 145}

Prescribing Limits

Pediatric Patients

ADHD

Conventional Tablets, Chewable Tablets, Oral Solution, Extended-release Chewable Tablets (Quillichew ER), Extended-release Capsules (Aptensio XR, Methylphenidate Hydrochloride CD, Ritalin LA), and Extended-release Oral Suspension (Quillivant XR)

Oral

Maximum 60 mg daily.^{114 125 129 145 152 157 168 171}

Extended-release Orally Disintegrating Tablets (Cotempla XR-ODT)

Oral

Maximum 51.8 mg daily of methylphenidate (equivalent to 60 mg of methylphenidate hydrochloride daily).¹⁷²

Extended-release Trilayer Core Tablets (Concerta; Generics)

Oral

Maximum 54 mg daily for children 6–12 years of age or 72 mg daily (maximum 2 mg/kg daily) for adolescents 13–17 years of age.¹¹⁸

Extended-release Capsules (Adhansia XR)

Oral

Maximum 85 mg daily, but dosages ≥70 mg daily associated with disproportionate increase in certain adverse effects.¹⁶⁹

Delayed- and Extended-release Capsules (Jornay PM)

Oral

Maximum 100 mg daily.¹⁷⁰

Adults

ADHD

Conventional Tablets, Chewable Tablets, Oral Solution, and Extended-release Chewable Tablets (Quillichew ER)

Oral

Maximum 60 mg daily.^{114 145 152 171}

Extended-release Trilayer Core Tablets (Concerta; Generics)

Oral

Maximum 72 mg daily.¹¹⁸

Extended-release Capsules (Adhansia XR)

Oral

Maximum 100 mg daily, but dosages >85 mg daily associated with disproportionate increase in certain adverse effects.¹⁶⁹

Narcolepsy

Oral

Maximum 60 mg daily.¹¹⁴

Cautions for Methylphenidate

Contraindications

• Concomitant or recent (within 14 days) administration of MAO inhibitors.^{114 118 125 129 145 147 152 168} (See Specific Drugs under Interactions.)

• Known hypersensitivity to methylphenidate or any ingredient in the formulation.^{114 118 129 145 147 152}

Warnings/Precautions

Warnings

Potential for Abuse and Dependence

High potential for abuse and dependence.¹¹⁴

Some evidence indicates that stimulant use does not lead to increased risk of substance abuse and that effective stimulant therapy for ADHD actually may reduce the risk for subsequent substance use disorders.^{133 134 504 513 525 526 527} However, diversion of stimulants for nonmedical uses has increased in recent decades, and is a particular concern among adolescents and young adults seeking enhanced academic or work performance.^{500 506 528} Ensure that individuals are diagnosed and treated for ADHD when appropriate while limiting the risk of diversion and misuse.^{500 506 513 528}

Assess risk of abuse prior to initiating therapy and monitor for signs of abuse and dependence during therapy.¹¹⁴

Maintain careful prescription records, educate patients and their families about CNS stimulant abuse and about proper storage and disposal of the drugs, monitor for signs of abuse and overdosage, and periodically reevaluate the need for continued stimulant therapy.¹¹⁴

Abuse by unintended routes of administration (e.g., chewing, snorting, or injecting formulation) can result in overdosage and death.^{157 168} Manifestations of stimulant abuse include increased heart rate, respiratory rate, BP, and/or sweating; dilated pupils; hyperactivity, restlessness, insomnia, loss of coordination, and tremors; flushed skin; and vomiting and/or abdominal pain.^{114 157 168} Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation also observed.^{114 157 168}

Abrupt cessation of therapy, rapid dosage reduction, or administration of an antagonist in patients physically dependent on CNS stimulants may result in withdrawal syndrome (e.g., dysphoric mood, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, psychomotor retardation or agitation).¹¹⁴

Other Warnings and Precautions

Sudden Death and Serious Cardiovascular Events

Sudden unexplained death, stroke, and MI reported in adults with ADHD receiving usual dosages of stimulants; sudden death also reported in pediatric patients with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of the drugs.^{114 118 147 164 165 168}

Although an initial epidemiologic study showed an association between use of stimulants (e.g., methylphenidate) and sudden unexplained death in healthy children and adolescents,^{153 154 155} several subsequent large epidemiologic studies in children and young adults or in adults 25–64 years of age found no association between ADHD drug use (stimulants, atomoxetine, pemoline [no longer commercially available in US]) and serious cardiovascular events (MI, stroke, sudden cardiac death), although small increases in cardiovascular risk could not be excluded.^{164 165 166 167}

Thoroughly review medical history (including evaluation for family history of sudden death or ventricular arrhythmia) and perform physical examination in all children, adolescents, and adults being considered for stimulant therapy; if initial findings suggest presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).^{114 118 147 153 168}

In general, avoid use of CNS stimulants in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, CAD, or other serious cardiac conditions.^{114 118 147 152 164 165 168}

Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.^{114 118 147 153 168}

Effects on BP and Heart Rate

Possible modest increases in average BP (i.e., by about 2–4 mm Hg) and heart rate (i.e., by about 3–6 bpm); larger increases may occur.^{114 118 147 168} Modest increases not expected to have short-term sequelae; however, monitor all patients for hypertension and tachycardia.^{114 118 147 164 165 168}

Caution advised in patients with underlying medical conditions that might be affected by increases in BP or heart rate (e.g., hypertension, heart failure, recent MI, ventricular arrhythmia).^{164 165}

Psychiatric Effects

May exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.^{114 118 147 152 157 168}

May precipitate mixed or manic episodes in ADHD patients with comorbid bipolar disorder.^{114 118 147 157 168} Prior to initiating therapy, carefully screen patients with ADHD to determine if they are at risk for developing a manic episode; screening should include a detailed psychiatric history (e.g., current or prior depressive symptoms; family history of suicide, bipolar disorder, or depression).^{114 118 147 168}

Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, mania) also may occur with usual dosages in patients without history of psychotic illness.^{114 118 147 168} If psychotic or manic symptoms occur, consider discontinuance of therapy.^{114 118 147}

Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, reported in adult and pediatric patients.^{114 118 125 145 147 152 157 158 159 168} Priapism often reported following an increase in dosage; also has occurred during temporary interruptions in therapy (e.g., drug holidays) or following drug discontinuance.^{114 118 125 145 147 152 157 158 159 168} Risk of permanent penile damage if not treated immediately.¹⁵⁹

Use caution if considering change in therapy because of this risk; certain alternative ADHD treatments (e.g., atomoxetine) also may cause priapism.¹⁵⁹

Peripheral Vascular Effects

Peripheral vascular disorders, including Raynaud’s phenomenon, reported in patients in all age groups receiving stimulants at therapeutic dosages and at various times throughout treatment course.^{114 118 125 145 147 152 157 158 168} Manifestations usually intermittent and mild, but ulceration of digits and/or breakdown of soft tissue occur rarely.^{114 118 125 145 147 152 157 158 168} Carefully observe for digital changes.^{114 118 125 145 147 152 157 158 168}

Improvement generally occurs following dosage reduction or drug discontinuance; however, some patients may require further evaluation (e.g., referral to rheumatologist).^{114 118 125 145 147 152 157 158 168}

Growth Suppression

Long-term administration of stimulants associated with at least a temporary suppression of normal weight and/or height patterns in some children.^{114 118 147}

In the Multimodal Treatment Study of Children with ADHD (MTA), slowing in growth rate (on average, height gain suppressed by about 2 cm and weight gain suppressed by 2.7 kg over 3 years) observed with methylphenidate treatment for up to 3 years in children 7–13 years of age, without evidence of growth rebound during this period of development.^{114 118 507} Longer-term follow-up into early adulthood suggested that consistent extended use of stimulants from childhood through adolescence may be associated with suppression of adult height.⁵⁰⁸

Manufacturers recommend monitoring growth during treatment; patients not growing or gaining weight as expected may require temporary discontinuance of treatment.^{114 118 147} Clinicians also suggest considering alteration of drug administration and eating patterns (e.g., administration of the stimulant during or after meals rather than before meals, additional meals or snacks when stimulant effects have worn off, high-calorie foods with good nutritional value) or switching to alternative therapy if weight loss is a concern.⁵⁰⁵

Disorders Causing Severe GI Narrowing

Extended-release trilayer core tablets generally should not be used in patients with severe preexisting GI narrowing; obstruction may occur.¹¹⁸

Hereditary Disorders of Carbohydrate Metabolism

Some extended-release capsules may contain sucrose and should not be used in those with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.¹²⁵

Chemical Leukoderma

Permanent depigmentation or hypopigmentation reported in patients receiving methylphenidate transdermal system.¹⁶³ Usually limited to application sites,¹⁶³ but skin color changes affecting other areas of the body also reported.¹⁶³ Time to onset has ranged from 2 months to 4 years; affected areas up to 8 inches in diameter reported.¹⁶³

Monitor skin for loss of pigmentation, especially at application sites.¹⁶³ If such changes occur, discontinue transdermal methylphenidate and consider alternative therapy.¹⁶³

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, reported.^{114 125 129 145 147 152 157 158 168}

Contact Sensitization

Possible contact sensitization following use of transdermal system.¹⁴⁷ Discontinue transdermal therapy if contact sensitization is suspected (erythema accompanied by evidence of a more intense local reaction [e.g., edema, papules, vesicles] that does not substantially improve within 48 hours or that spreads beyond the application site).¹⁴⁷

Development of localized contact sensitization to methylphenidate during transdermal therapy may be associated with development of systemic sensitization with subsequent oral administration.¹⁴⁷ 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.¹⁴⁷ Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting.¹⁴⁷

If contact sensitization occurs with transdermal therapy, monitor patients closely if oral therapy with the drug is initiated.¹⁴⁷ Some patients sensitized to methylphenidate by exposure to transdermal system may not be able to receive methylphenidate in any form.¹⁴⁷

Tartrazine Sensitivity

Adhansia XR 45-mg extended-release capsules contain tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals.¹⁶⁹ Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients with aspirin sensitivity.¹⁶⁹

Tic Disorders

High frequency of comorbidity of chronic tic disorders and ADHD.⁵²⁹ While most manufacturers previously warned against methylphenidate use in patients with motor tics or with a family history or personal diagnosis of Tourette's syndrome,^{118 529} newer evidence suggests stimulant therapy generally is not associated with new onset or worsening of tics, although exacerbation of tics may occur in some individuals.⁵²⁹

Radiographic Examinations

Extended-release trilayer core tablet may be visible on abdominal radiographs under certain circumstances, particularly when digital enhancing techniques are utilized.¹¹⁸

Swelling of Chewable Tablets in GI Tract

Administration of chewable tablets without adequate fluid may cause tablet contents to swell, resulting in blockage of throat or esophagus and, possibly, choking.¹⁵² Therefore, administer with a full glass (i.e., ≥240 mL [8 ounces]) of water or other fluid.¹⁵² Do not administer in patients with difficulty swallowing.¹⁵² (See Advice to Patients.)

Phenylketonuria

Some oral formulations may contain aspartame, which is metabolized in the GI tract to provide phenylalanine.¹⁷¹ Each 20-, 30-, or 40-mg extended-release chewable tablet (QuilliChew ER) provides 3, 4.5, or 6 mg of phenylalanine, respectively.¹⁷¹

Exposure of Transdermal Application Site to External Heat

Percutaneous absorption of methylphenidate from the transdermal system may be increased, potentially resulting in overdosage, if the application site is exposed to direct external heat sources (e.g., hair dryers, heating pads, electric blankets, heated water beds) while the transdermal system is being worn.¹⁴⁷

Specific Populations

Pregnancy

Available data on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, spontaneous abortion, or adverse maternal or fetal outcomes; however, there may be fetal risks associated with CNS stimulant use.¹¹⁴ CNS stimulants can cause vasoconstriction and thereby decrease placental perfusion.^{114 168}

No fetal and/or neonatal adverse reactions reported with therapeutic dosages of methylphenidate during pregnancy, but premature delivery and low birth-weight infants reported in amphetamine-dependent women.^{114 168}

In animal studies, increased incidence of spina bifida observed in rabbits with methylphenidate administration.¹¹⁴

National Pregnancy Registry for ADHD Medications at 866-961-2388 or [Web].¹¹⁴

Lactation

Limited data (case reports) suggest breast-fed infants receive 0.2–0.7% of the maternal weight-adjusted dosage of methylphenidate; milk-to-plasma ratios of 1.1–2.7 reported.¹⁶⁸ Adverse effects on breast-fed infants or on milk production not reported to date; however, any long-term neurodevelopmental effects are unknown.¹⁶⁸

Consider developmental and health benefits of breast-feeding, the importance of methylphenidate to the woman, and any potential adverse effects of either the drug or the underlying maternal condition on the breast-fed infant.¹⁶⁸

If used in a nursing woman, monitor breast-fed infant for adverse effects (e.g., agitation, anorexia, reduced weight gain).¹⁶⁸

Pediatric Use

Although safety and efficacy not established in children <6 years of age, AAP states methylphenidate may be considered for treatment of ADHD in preschool-aged children^{† [off-label]} (4 years of age to the sixth birthday) if first-line treatments (i.e., parent training in behavior management and/or behavioral classroom interventions) do not provide substantial improvement and there is continued, moderate to severe disturbance in the child's functioning.⁵⁰⁰ Some studies suggest increased incidence of adverse effects (e.g., weight loss, increased mood lability and dysphoria ) and possibly different adverse effects in preschool-aged children.^{140 168 500 512} Systemic exposure may be increased in preschool-aged children.¹⁶⁸ (See Special Populations, under Pharmacokinetics: Absorption.) Initiate at low dosage and increase in smaller increments in preschool-aged children; maximum dosages not adequately studied.⁵⁰⁰ Additional study and experience required to further elucidate safety and efficacy in this age group.⁵¹²

Long-term administration associated with at least a temporary suppression of normal weight and/or height patterns in children.^{114 118 125 129 147 152} (See Growth Suppression under Cautions.)

Sudden death reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.^{114 118 147 152} (See Sudden Death and Serious Cardiovascular Events under Cautions.)

In toxicity studies in juvenile rats, methylphenidate associated with long-term behavioral effects (decreased spontaneous locomotor activity in adulthood, deficit in acquisition of a specific learning task in female rats).¹¹⁴ Clinical relevance unknown.¹¹⁴

Common Adverse Effects

Nervous system (insomnia, delayed sleep onset, headache, nervousness, anxiety, restlessness, affect lability, agitation, irritability, dizziness), cardiovascular (increased BP, increased heart rate, tachycardia, palpitations), GI (decreased appetite/anorexia, nausea, abdominal pain, dyspepsia, vomiting), and other (weight loss, hyperhidrosis) effects.^{114 118 125 126 129 147 157 158 168}

Drug Interactions

Not metabolized by CYP isoenzymes; does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A to a clinically important extent.¹⁷⁴

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP inducers and inhibitors: Not expected to substantially affect pharmacokinetics of methylphenidate.¹⁷⁴

Specific Drugs

Methylphenidate Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.^{118 125 126 129 130 152} Low oral bioavailability (10–52%) suggests substantial first-pass metabolism.^{129 147}

Oral solution and chewable tablets are bioequivalent to conventional tablets.^{145 152}

Extended-release tablets are absorbed more slowly but to the same extent as conventional tablets.¹⁵⁸

Peak concentration and AUC were about 20 and 11% lower, respectively, for QuilliChew ER extend-release chewable tablets (single 40-mg dose) than for immediate-release chewable tablets (two 20-mg doses given 6 hours apart).¹⁷¹

Peak concentration and AUC were about 26 and 6% higher, respectively, for Cotempla XR-ODT (single dose of two 25.9-mg extended-release orally disintegrating tablets [equivalent to 60 mg of methylphenidate hydrochloride]) than for a 60-mg extended-release capsule formulation of methylphenidate hydrochloride.¹⁷²

Relative bioavailability of Concerta extended-release trilayer core tablets given once daily is comparable to that of conventional tablets administered 3 times daily.¹¹⁸ No substantial accumulation observed with repeated once-daily dosing over dose range of 18–144 mg.¹¹⁸

Relative bioavailability of Quillivant XR extended-release oral suspension (single 60-mg dose) is 95% that of immediate-release oral solution (two 30-mg doses given 6 hours apart).¹⁵⁷

Second peak concentration for Adhansia XR extended-release capsules (100 mg once daily) was comparable to steady-state concentrations achieved with immediate-release formulation (60 mg daily given in 3 divided doses 4 hours apart), but first peak concentration, AUC, and trough concentrations were approximately 22, 50, and 288% higher, respectively, with the extended-release capsules.¹⁶⁹

Relative bioavailability of Aptensio XR extended-release capsules given once daily is comparable to that of conventional tablets administered 3 times daily.¹⁶⁸

Peak plasma concentrations and AUC were slightly lower for methylphenidate hydrochloride CD extended-release capsules (20 mg once daily) than for conventional tablets (10 mg twice daily).^{125 126}

Relative bioavailability of Ritalin LA extended-release capsules given once daily is similar to that of conventional tablets administered at the same total daily dosage in 2 divided doses given 4 hours apart.¹²⁹

Relative bioavailability of Jornay PM delayed- and extended-release capsules administered once daily is approximately 74% that of an immediate-release formulation administered in 3 divided doses daily.¹⁷⁰

Alcohol increases the rate of drug release in vitro from many extended-release preparations (see Table 5).^{125 129 157 168 169 170 171 172} Results provided in Table 5 for specific strengths generally are considered representative for available strengths of the respective preparations.^{118 125 129 168 171} In healthy adults, administration of Adhansia XR 70-mg extended-release capsules with 40% alcohol in the fasted state resulted in a 1.4-fold increase in peak plasma methylphenidate concentration and a 1.3-fold increase in the extent of absorption.¹⁶⁹

For timing of peak plasma concentrations for oral formulations, see Table 6.

Peak plasma methylphenidate concentrations for transdermal systems are attained in about 10 hours (single-dose application) or 8 hours (repeated applications of systems worn for up to 9 hours).¹⁴⁷ Average lag of 2 hours until d-methylphenidate is detectable in plasma after single-dose application; with repeated administration, low concentrations of the drug are detected earlier because of carryover effect.¹⁴⁷

When applied to inflamed skin, time to peak plasma concentrations decreases (to 4 hours) and peak plasma concentration and AUC increase by threefold compared with application to intact skin.¹⁴⁷ When heat is applied to transdermal system after application, peak plasma concentration occurs 0.5 hour earlier, and median peak plasma concentration and AUC are 2-fold and 2.5-fold higher, respectively, compared to application without heat.¹⁴⁷

Possible increased transdermal absorption following repeated administration.¹⁴⁷ Steady state likely to be achieved by approximately day 14 of dosing.¹⁴⁷

Because of substantially greater first-pass metabolism following oral compared with transdermal administration, a lower transdermal dose of methylphenidate may result in greater systemic exposure to d-methylphenidate than a higher (on a mg/kg basis) oral dose of the drug.¹⁴⁷ Little, if any, l-methylphenidate is systemically available following oral administration; however, systemic exposure to l-methylphenidate following transdermal administration is almost as great as that to d-methylphenidate.¹⁴⁷

Duration

For duration of effects for various oral methylphenidate formulations, see Table 7.

Food

Chewable tablets: Administration with high-fat meal delays time to peak plasma concentration by approximately 1 hour and increases AUC by about 20%; magnitude of food effect is comparable to that observed with conventional tablets.¹⁵²

Oral solution: Administration with high-fat meal delays time to peak plasma concentration by approximately 1 hour and increases peak plasma concentration and AUC by about 13 and 25%, respectively.¹⁴⁵

Extended-release chewable tablets (QuilliChew ER): Administration with high-fat meal increases peak concentration and AUC by about 20% and 4%, respectively, but does not affect time to peak concentration.¹⁷¹

Extended-release orally disintegrating tablets (Cotempla XR-ODT): Administration with high-fat meal decreases peak concentration by approximately 24%, increases AUC by approximately 16%, and decreases time to peak concentration by about 30 minutes (from 5 hours in fasted state to 4.5 hours in fed state).¹⁷²

Extended-release trilayer core tablets (Concerta): High-fat meal does not alter pharmacokinetics.¹¹⁸

Extended-release oral suspension (Quillivant XR): Administration with high-fat meal reduces time to peak concentration by approximately 1 hour and increases peak plasma concentration and AUC by approximately 28 and 19%, respectively; not considered clinically important.¹⁵⁷

Extended-release capsules (Adhansia XR): Administration with high-fat meal delays first and second peak concentrations by approximately 1 hour, but does not affect peak concentrations or extent of absorption.¹⁶⁹ Opening the capsules and sprinkling the contents onto applesauce or yogurt does not alter bioavailability.¹⁶⁹

Extended-release capsules (Aptensio XR): Administration with high-fat meal decreases second peak plasma concentration, increases the average peak concentration by about 28%, and increases AUC by about 19%; this formulation was administered without regard to meals in clinical trials.¹⁶⁸ Opening the capsules and sprinkling the contents on applesauce does not alter bioavailability.¹⁶⁸

Extended-release capsules (methylphenidate hydrochloride CD): Administration with high-fat meal delays first peak plasma concentration by approximately 1 hour and increases average peak plasma concentration and AUC by 30 and 17%, respectively.¹²⁵ Opening the capsules and sprinkling the contents on applesauce does not alter bioavailability.¹²⁵

Extended-release capsules (Ritalin LA): Administration with high-fat meal delays first and second peak plasma concentrations and decreases second mean peak plasma concentration by 25%.¹²⁹ Opening the capsules and sprinkling the contents on applesauce does not alter bioavailability.¹²⁹

Delayed- and extended-release capsules (Jornay PM): Administration at night with high-fat meal decreases mean peak concentration by 14% and delays peak concentration by approximately 2.5 hours, but does not alter extent of absorption.¹⁷⁰ Following administration at night, a morning meal does not affect pharmacokinetics.¹⁷⁰ Opening the capsules and sprinkling the contents on applesauce does not alter pharmacokinetics.¹⁷⁰

Special Populations

Age and body weight: Systemic exposure may be higher in children than in adults following equivalent oral dosages, but pharmacokinetic profiles generally similar following adjustment for differences in body weight.^{129 157 168 169 170 171 172} Systemic exposure in preschool-aged children receiving Aptensio XR extended-release capsules approximately twofold to threefold higher than in older children and adolescents receiving same dosage.¹⁶⁸

Distribution

Extent

Extent of distribution in humans is unknown.^a

Plasma Protein Binding

About 10–33%.¹²⁹

Elimination

Metabolism

Metabolized primarily by de-esterification by carboxylesterase 1A1 to form d-ritalinic acid, which has little or no pharmacologic activity.^{118 125 129 145 147 152}

Elimination Route

Excreted as metabolites (principally as ritalinic acid), mostly in urine^{a 118 125} and a small amount in feces.¹²⁹

Half-life

For methylphenidate elimination half-lives reported for various methylphenidate formulations, see Table 8.

Special Populations

Renal impairment: Expected to have minimal effect on pharmacokinetics since <1% of dose excreted in urine as unchanged drug and major metabolite (ritalinic acid) has little or no pharmacologic activity.¹¹⁴

Hepatic impairment: Expected to have minimal effect on pharmacokinetics since main metabolic pathway involves de-esterification by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.¹¹⁴

Body weight: Clearance increases with increasing weight; thus, patients with higher body weight may have lower exposures to total methylphenidate at similar doses.¹¹⁸ (See Special Populations under Pharmacokinetics: Absorption.)

Stability

Storage

Oral

Conventional, Chewable, and Extended-release Tablets

Room temperature, generally 20–25°C; consult manufacturer's labeling for specific recommendation.^{114 152 158} Protect from moisture.^{114 152 158}

Delayed- and Extended-release Capsules

20–25°C (may be exposed to 15–30°C).¹⁷⁰ Protect from moisture.¹⁷⁰

Extended-release Capsules

Room temperature, generally 20–25°C; consult manufacturer's labeling for specific recommendation.^{125 129 168 169}

Extended-release Orally Disintegrating Tablets

20–25°C (may be exposed to 15–30°C).¹⁷² Store blister packages in reusable travel case after removal from carton.¹⁷²

Extended-release Trilayer Core Tablets

25°C (may be exposed to 15–30°C).¹¹⁸ Protect from moisture.¹¹⁸

Powder for Extended-release Suspension

25°C (may be exposed to 15–30°C).¹⁵⁷

Following reconstitution, 25°C (may be exposed to 15–30°C) in original container for up to 4 months.¹⁵⁷

Solution

20–25°C.¹⁴⁵

Topical

Transdermal System

25°C (may be exposed to 15–30°C).¹⁴⁷ Use all the systems in a tray within 2 months of opening the tray.¹⁴⁷ Apply the system to the skin immediately after removal from the individually sealed package.¹⁴⁷ Do not freeze or refrigerate.¹⁴⁷

Actions

• Appears to block norepinephrine and dopamine reuptake into the presynaptic neuron and increases their release into the extraneuronal space.^{118 125 129} Mechanism of action involved in the central effect not determined.^a

• Pharmacologic actions include CNS stimulation (e.g., increased motor activity, mental alertness, diminished sense of fatigue, brighter spirits, mild euphoria), respiratory stimulation, and weak sympathomimetic activity;^a also produces an anorexigenic effect.¹¹⁴

• At usual therapeutic dosages, exhibits only moderate effects on the peripheral circulatory system.^a

• Racemic mixture; the d-enantiomer is the more pharmacologically active enantiomer.^{118 125 129}

• No clinically important changes in corrected QT (QT_c) interval observed in healthy individuals following 40-mg dose of extended-release dexmethylphenidate hydrochloride (the more active enantiomer).^{114 158}

Advice to Patients

• Provide patient or caregiver with a copy of the manufacturer’s patient information (medication guide).^{118 125 129 147}

• Risk of abuse and dependence.¹¹⁴ Importance of not sharing methylphenidate with others and of storing the drug in a safe (preferably locked) location to prevent abuse.¹¹⁴ Advise patient or caregiver on proper disposal of any remaining unused or expired drug.¹¹⁴

• Potential risk for serious cardiovascular events, including sudden death, MI, stroke, and hypertension.¹¹⁴ Importance of informing clinicians immediately of adverse cardiovascular effects (e.g., exertional chest pain, unexplained syncope, other symptoms suggestive of cardiac disease).^{114 118 125 147}

• Inform patient or caregiver that methylphenidate can increase BP and pulse rate.^{157 168}

• Potential for recommended dosages of methylphenidate to cause psychotic or manic symptoms, even in patients without a history of psychotic symptoms or mania.¹¹⁴

• Inform male patients and their caregivers about the signs and symptoms of priapism, stressing the need for immediate medical treatment if it occurs.^{114 125 145 147 152 157 158 159 168} Younger males, especially prepubertal males, may not recognize the problem or may be embarrassed to tell anyone if it occurs.¹⁵⁹

• Inform patients and caregivers about the risk of peripheral vascular disorders, including Raynaud's phenomenon, and the associated signs and symptoms (e.g., feelings of numbness, coolness, or pain in fingers or toes; changes in color from pale to blue to red).^{114 125 145 147 152 157 158 168} Advise patients to report any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes and to immediately contact their clinician if any signs of unexplained wounds appear on fingers or toes; further clinical evaluation may be appropriate.^{114 125 145 147 152 157 158 168}

• Potential for methylphenidate to slow growth and cause weight loss.¹¹⁴

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, as well as any concomitant illnesses/conditions (e.g., cardiac/cardiovascular disease, mental/psychiatric disorder, suicidal ideation or behaviors, history of substance abuse).^{114 118 125 129 147}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{114 118 125 129 158} Inform women about pregnancy registry for ADHD medications.¹¹⁴ (See Pregnancy under Cautions.) Advise nursing women to monitor their infants for agitation, poor feeding, and reduced weight gain.¹¹⁴

• Importance of informing patients or caregivers of other important precautionary information.^{114 118 125 129 158} (See Cautions.)

Advice Concerning Specific Oral Preparations

• In patients receiving conventional tablets or oral solution, importance of administering the last daily dose of these preparations before 6 p.m.^{114 145 152}

• In patients receiving chewable tablets, importance of administering with a full glass (i.e., ≥240 mL [8 ounces]) of water or other fluid to avoid choking.¹⁵² Importance of seeking immediate medical attention if chest pain, vomiting, or difficulty in swallowing or breathing occurs following administration.¹⁵²

• Importance of not crushing or chewing extended-release tablets, extended-release capsules, extended-release trilayer core tablets, or delayed- and extended-release capsules.^{118 125 129 158 168 169 170} Capsules may be opened and the contents sprinkled on applesauce; contents of Adhansia XR capsules also may be sprinkled on yogurt.^{125 129 168 169 170}

• In patients receiving extended-release capsules or delayed- and extended-release capsules, importance of not consuming alcohol, since alcohol may result in more rapid release of the drug dose.^{125 129 168 169 170}

• In patients receiving extended-release oral suspension, importance of instructing patients and/or their caregivers on proper use of the dosing dispenser for administration.¹⁵⁷ Provide patient and/or caregiver with a copy of the manufacturer's instructions for administration.¹⁵⁷

• In patients receiving extended-release trilayer core tablets, presence of tablet-like substance in stool is not cause for concern.¹¹⁸

• In patients receiving extended-release orally disintegrating tablets, importance of instructing patient or caregiver on appropriate administration technique.¹⁷² (See Oral Administration under Dosage and Administration.)

• Advise patients with phenylketonuria that QuilliChew ER extended-release chewable tablets contain aspartame.¹⁷¹

Advice Specific to Transdermal Therapy

• Importance of instructing patients and/or their caregivers regarding application and removal of the transdermal system (see Transdermal Administration under Dosage and Administration).¹⁴⁷ Provide patient and/or caregiver with a copy of the manufacturer's instructions for use.¹⁴⁷ Importance of not touching the adhesive layer during application to avoid absorption of the drug; if contact occurs, wash hands immediately after application.¹⁴⁷

• Importance of monitoring for changes in skin color (depigmentation, hypopigmentation) while receiving transdermal methylphenidate and informing clinician if such changes occur.¹⁶³

• Importance of not exposing the application site to direct external heat sources (e.g., hair dryers, heating pads, electric blankets, heated water beds) while wearing the transdermal system.¹⁴⁷

• Possibility of dermatologic reactions in patients receiving transdermal therapy; importance of discontinuing use and contacting clinician if swelling or blistering occurs.¹⁴⁷

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Methylphenidate hydrochloride is subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Frequently asked questions

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