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Methylphenidate: Drug information

Methylphenidate: Drug information
(For additional information see "Methylphenidate: Patient drug information" and see "Methylphenidate: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Abuse and dependence:

CNS stimulants, including methylphenidate-containing products and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy.

Methylphenidate should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

Brand Names: US
  • Adhansia XR;
  • Aptensio XR;
  • Concerta;
  • Cotempla XR-ODT;
  • Daytrana;
  • Jornay PM;
  • Metadate ER [DSC];
  • Methylin;
  • QuilliChew ER;
  • Quillivant XR;
  • Relexxii;
  • Ritalin;
  • Ritalin LA
Brand Names: Canada
  • ACT Methylphenidate ER;
  • APO-Methylphenidate;
  • APO-Methylphenidate ER;
  • APO-Methylphenidate SR;
  • Biphentin;
  • Concerta;
  • Foquest;
  • PMS-Methylphenidate;
  • PMS-Methylphenidate ER [DSC];
  • RATIO-Methylphenidate [DSC];
  • Ritalin;
  • Ritalin SR;
  • SANDOZ Methylphenidate SR;
  • TEVA-Methylphenidate ER-C
Pharmacologic Category
  • Central Nervous System Stimulant
Dosing: Adult

Note: Due to pharmacokinetic differences, many products are not bioequivalent and not interchangeable on a mg-per-mg basis; when available, dosing conversion information is provided.

Attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (alternative agent [Cortese 2018]):

Short-acting immediate release: Chewable tablets, Methylin (oral solution), and Ritalin (tablets): Oral: Initial: 10 to 20 mg/day in 2 divided doses before breakfast and lunch; may increase based on response and tolerability in 5 to 10 mg increments at weekly or greater intervals up to a maximum dose of 60 mg/day in 2 to 3 divided doses (Steingard 2019).

Intermediate-acting extended release :

Metadate ER (tablets): Oral: Initial: 10 mg twice daily; may increase dose based on response and tolerability in 10 mg increments at weekly or greater intervals up to a maximum dose of 60 mg/day. Some experts suggest a further increase up to 100 mg/day may be necessary in some patients for optimal response (BAP [Bolea-Alamañac 2014b]; Bukstein 2019; Huss 2017).

Ritalin SR (tablets) [Canadian product]: Oral: Initial: 20 mg once daily in the morning; may increase dose based on response and tolerability in 10 mg increments at weekly or greater intervals up to a maximum dose of 60 mg/day. Some experts suggest a further increase up to 100 mg/day may be necessary in some patients for optimal response (BAP [Bolea-Alamañac 2014b]; Bukstein 2019; Huss 2017).

Conversion from IR methylphenidate to Metadate ER or Ritalin SR [Canadian product]: To substitute the intermediate-acting ER formulation for the short-acting IR formulation, the dose of the ER formulation (8-hour duration) should correspond to the total 8-hour IR dose.

Long-acting extended release and transdermal:

Adhansia XR (capsules): Oral: Initial: 25 mg once daily in the morning; may increase dose based on response and tolerability in 10 to 15 mg increments at intervals of ≥5 days up to a maximum dose of 100 mg/day. Doses >85 mg are associated with higher rate of side effects.

Conversion from IR methylphenidate to Adhansia XR: Discontinue previous formulation and titrate using above schedule; do not substitute on a mg-per-mg basis.

Aptensio XR (capsules): Oral: Initial: 10 mg once daily in the morning; may increase dose based on response and tolerability in 10 mg increments at weekly or greater intervals up to a maximum dose of 60 mg/day.

Conversion from other methylphenidate products to Aptensio XR: There are no conversion recommendations in the manufacturer's labeling.

Biphentin [Canadian product] (capsules): Oral: Initial: 10 to 20 mg once daily in the morning; may increase dose based on response and tolerability in 10 mg increments at weekly or greater intervals up to a maximum dose of 80 mg/day.

Conversion from IR methylphenidate to Biphentin: Use equivalent total daily dose (TDD) administered once daily.

Concerta (tablets): Oral: Initial: 18 to 36 mg once daily in the morning; may increase dose based on response and tolerability in increments of 18 mg at weekly or greater intervals up to a maximum dose of 72 mg/day.

Conversion from IR methylphenidate and intermediate-acting ER methylphenidate (eg, Metadate ER, Ritalin SR [Canadian product]) to Concerta:

Concerta Dosing Conversion

IR methylphenidate (current dose)

Intermediate-acting ER methylphenidate (Metadate ER, Ritalin SR [Canadian product]) (current dose)a

Concerta initial dose

aConcerta Canadian product labeling.

5 mg 2 to 3 times daily

20 mg daily

18 mg once daily in the morning

10 mg 2 to 3 times daily

40 mg daily

36 mg once daily in the morning

15 mg 2 to 3 times daily

60 mg daily

54 mg once daily in the morning

20 mg 2 to 3 times daily

--

72 mg once daily in the morning

Daytrana transdermal patch: Topical: Initial: 10 mg patch once daily; apply to hip 2 hours before effect is needed and remove 9 hours after application (eg, 3 hours before bedtime); may increase dose based on response and tolerability to the next transdermal patch dosage at intervals of ≥1 week up to 30 mg/day (Marchant 2011; McRae-Clark 2011). Some patients may require up to 60 mg/day for optimal response (Bukstein 2019; Huss 2017). Patch may be removed before 9 hours if a shorter duration of action is required or if late-day adverse effects appear, or it may be worn for up to 16 hours if extended duration of effects is needed (Arnold 2007). Plasma concentrations usually start to decline when the patch is removed but drug absorption may continue for several hours after patch removal.

Conversion from IR methylphenidate or from Concerta (long-acting extended release) to the transdermal patch: Discontinue previous formulation and titrate using above schedule; do not substitute on a mg-per-mg basis per manufacturer's labeling. Alternatively, some clinicians support higher starting patch doses for patients converting from oral methylphenidate doses of >20 mg/day. Approximate equivalent doses, with a 9-hour patch wear time, are as follows below (Arnold 2007):

Transdermal Dosing Conversion

Immediate release (mg/day)

Concerta (mg/day)

Patch size (Daytrana)

15

18

10 mg (12.5 cm2)

22.5

27

15 mg (18.75 cm2)

30

36

20 mg (25 cm2)

45

54

30 mg (37.5 cm2)

Foquest [Canadian product] (capsules): Oral: Initial: 25 mg once daily in the morning; may increase dose based on response and tolerability at ≥5-day intervals up to a maximum dose of 100 mg/day.

Conversion from IR, intermediate-acting ER, or long-acting ER methylphenidate to Foquest: Using available Foquest capsule strengths, initiate at a TDD that is close to but does not exceed the current total methylphenidate daily dose; do not substitute on a mg-per-mg basis.

Jornay PM (capsules): Oral: Initial: 20 mg once daily in the evening between 6:30 PM and 9:30 PM (eg, 8:00 PM); may increase dose based on response and tolerability in increments of 20 mg at weekly or greater intervals up to a maximum dose of 100 mg/day.

Conversion from IR methylphenidate to Jornay PM: Discontinue previous formulation and titrate using above schedule; do not substitute on a mg-per-mg basis.

Metadate CD (capsules), QuilliChew ER (chewable tablets), Quillivant XR (oral suspension): Oral: Initial: 20 mg once daily in the morning; may increase dose based on response and tolerability in 10 to 20 mg increments at weekly or greater intervals up to a maximum dose of 60 mg/day. Some experts suggest a further increase up to 100 mg/day with Metadate CD may be necessary in some patients for optimal response (BAP [Bolea-Alamañac 2014b]; Bukstein 2019). Note: QuilliChew ER tablets are scored and may be broken in half for 10 mg and 15 mg doses.

Conversion from IR, intermediate-acting ER, or long-acting ER methylphenidate to QuilliChew ER or Quillivant XR: Discontinue previous formulation and titrate using above schedule; do not substitute on a mg-per-mg basis. There are no conversion recommendations in the manufacturer's labeling for Metadate CD.

Ritalin LA (capsules): Oral: Initial: 10 to 20 mg once daily in the morning; may increase dose based on response and tolerability in 10 mg increments at weekly or greater intervals up to a maximum dose of 60 mg/day. Some experts suggest a further increase up to 100 mg/day may be necessary in some patients for optimal response (BAP [Bolea-Alamañac 2014b]; Bukstein 2019).

Conversion from IR or intermediate-acting ER methylphenidate (eg, Metadate ER, Ritalin SR [Canadian product]) to Ritalin LA: Use equivalent TDD administered once daily.

Fatigue, severe, cancer related or in palliative care setting

Fatigue, severe, cancer related or in palliative care setting (off-label use):

Immediate release (Methylin, Ritalin): Oral: Initial: 5 mg once daily or 5 mg twice daily before breakfast and lunch; may increase dose based on response and tolerability in increments of 5 to 10 mg every 3 days up to a maximum dose of 40 mg/day in divided doses (Bruera 2021: Kerr 2012).

Major depressive disorder in medically ill, palliative care, terminal illness, or elderly patients

Major depressive disorder (unipolar) in medically ill, palliative care, terminal illness, or elderly patients (monotherapy or adjunctive therapy) (off-label use):

Note: Use as monotherapy only in patients with anticipated short remaining lifetime that would preclude onset of effect of an antidepressant; otherwise use as adjunct to antidepressant.

Immediate release (Methylin, Ritalin): Oral: Initial: 2.5 to 5 mg once daily before breakfast or twice daily before breakfast and lunch; may increase dose based on response and tolerability in increments of 2.5 to 5 mg every 1 to 4 days up to 40 mg/day in divided doses (Hardy 2009; Kerr 2012; Lavretsky 2006; Lavretsky 2015). Some experts suggest a further increase up to 60 mg/day may be necessary in some patients for optimal response (Roy-Byrne 2021). Do not use sustained-release product.

Narcolepsy

Narcolepsy (alternative agent [EFNS (Billiard 2006)]):

Immediate release (Methylin, Ritalin): Oral: Initial: 10 mg twice daily before breakfast and lunch; may increase dose based on response and tolerability in increments of 5 to 10 mg at intervals of ≥1 week up to a maximum dose of 60 mg/day in 2 to 3 divided doses with the last dose given no later than about 3:00 PM (Mitler 1986; Scammell 2021).

Intermediate-acting extended release (Metadate ER, Ritalin SR [Canadian product]): Oral: Substitute the intermediate-acting ER formulation in place of the short-acting immediate release when the total 8-hour IR dose corresponds to the ER tablet strength (usually dosed as 20 mg twice daily; duration of action: ~8 hours); maximum: 60 mg/day (Scammell 2021).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Oral: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); undergoes extensive metabolism to a renally eliminated metabolite with little or no pharmacologic activity.

Transdermal: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Oral: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Transdermal: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Pediatric

(For additional information see "Methylphenidate: Pediatric drug information")

Attention deficit-hyperactivity disorder (ADHD): Methylphenidate is recommended as first-line therapy for children and adolescents; dosage should be individualized; a discontinuation trial after 6 months of therapy is also recommended to reassess underlying psychopathology (AACAP [Pliszka 2007]; AAP 2011; Cortese 2018; NICE 2018). Note: Discontinue medication if no improvement is seen after appropriate dosage adjustment over a 1-month period of time.

Due to pharmacokinetic differences, many products are not bioequivalent and not interchangeable on a mg per mg basis; when available, dosing conversion information is provided. Presented maximum doses are primarily based on manufacturer's labeling from clinical trials, however, higher maximum doses from guidelines are also included; dose titration should be optimized for efficacy and tolerability (AAP 2011; Cortese 2018; NICE 2018).

Oral:

Immediate-release products (eg, Methylin, Ritalin):

Children 3 to 5 years, moderate to severe dysfunction: Limited data available; AAP considers first-line agent in this patient population if pharmacological treatment deemed necessary (AAP 2011); the American Academy of Child and Adolescent Psychiatry Preschool Psychopharmacology Working Group recommends a discontinuation trial after 6 months of treatment in preschoolers to reassess underlying psychopathology (Gleason 2007). Response may be variable and less robust than that observed in older pediatric patients (Ghuman 2008); of note, response to methylphenidate was predicted by the number of comorbidities (eg, no or 1 comorbidity predicted a large treatment response [similar to school-aged children] vs ≥3 comorbidities predicted no treatment response) (Ghuman 2008).

Initial: 2.5 mg twice daily, may gradually titrate to 7.5 mg 2 or 3 times daily over 2 to 4 weeks; others have used a rapid titration to 7.5 mg 3 times daily within 1 week (Ghuman 2008; Greenhill 2006); a small percentage of preschool children may benefit from 1.25 mg 3 times daily (Ghuman 2008). In the largest trial, a multicenter, randomized, placebo-controlled, crossover study of 165 preschool children (age range: 3 to 5.5 years) treated with methylphenidate 3.75 to 30 mg/day in 3 divided doses, statistically and clinically significant improvements in ADHD scores were reported with doses of 2.5 mg, 5 mg, and 7.5 mg 3 times daily. In some patients (n=7 [4%]), dose titration to 10 mg 3 times daily was necessary; the mean effective total daily dose: 14.2 ± 8.1 mg/day. Although ADHD scores were statistically and clinically improved with methylphenidate use, the effect size was smaller with this younger patient population than that seen in school-age children (Greenhill 2006). The 10-month continuation phase trial reported continued or stable clinical improvement at a mean dose of 19.98 mg/day at month 10 (Vitiello 2007).

Children ≥6 years and Adolescents: Initial: 2.5 to 5 mg twice daily administered before breakfast and lunch; increase by 5 to 10 mg/day at weekly intervals; some patients may require 3 doses/day (eg, additional dose after school); usual maximum daily dose: 60 mg/day, not to exceed 2 mg/kg/day; however, some patients weighing >50 kg may require and tolerate daily doses up to 100 mg/day with frequent monitoring (AACAP [Pliszka 2007])

Extended-release, sustained-release, and long-acting products:

Adhansia XR: Children ≥6 years and Adolescents: Initial: 25 mg once daily in the morning; may titrate in 10 to 15 mg increments at ≥5-day intervals; maximum daily dose: 85 mg/day; doses ≥70 mg/day, although efficacious, were associated with disproportionate increase in adverse reaction; monitor tolerability closely in these patients. To convert from other methylphenidate products, discontinue that treatment and begin Adhansia XR with titration schedule previously described.

Aptensio XR: Children ≥6 years and Adolescents: Initial: 10 mg once daily in the morning; may titrate in 10 mg increments at weekly intervals; maximum daily dose: 60 mg/day

Concerta: Children ≥6 years and Adolescents:

Methylphenidate-naive patients: Initial: 18 mg once daily

Patients currently using immediate-release methylphenidate: Initial dose: Dosing based on current regimen and clinical judgment; suggested dosing listed below, monitor closely with any therapy change:

Switching from methylphenidate immediate release 5 mg 2 to 3 times daily: Concerta 18 mg once daily

Switching from methylphenidate immediate release 10 mg 2 to 3 times daily: Concerta 36 mg once daily

Switching from methylphenidate immediate release 15 mg 2 to 3 times daily: Concerta 54 mg once daily

Switching from methylphenidate immediate release 20 mg 2 to 3 times daily: Concerta 72 mg once daily

Dosage adjustment: May increase by Concerta 18 mg/day increments at weekly intervals to effect not to exceed the following maximum daily dose for age. Note: A dosage strength of 27 mg is available for situations in which a dosage between 18 and 36 mg is desired.

Maximum daily dose of Concerta:

Children 6 to 12 years: Usual maximum daily dose: 54 mg/day; however, some patients may require and tolerate daily doses up to 108 mg/day (AACAP [Pliszka 2007])

Adolescents: Usual maximum daily dose: 72 mg/day; however, some patients may require and tolerate daily doses up to 108 mg/day (AACAP [Pliszka 2007])

Cotempla XR-ODT: Children ≥6 years and Adolescents ≤17 years: Initial: 17.3 mg once daily in the morning; may titrate in 8.6 or 17.3 mg increments at weekly intervals; maximum daily dose: 51.8 mg/day

Jornay PM: Children ≥6 years and Adolescents: Initial: 20 mg once daily in the evening between 6:30 and 9:30 PM (eg, 8:00 PM); may increase in increments of 20 mg/day at weekly intervals; maximum daily dose: 100 mg/day. Note: If converting from another methylphenidate formulation, discontinue previous formulation and titrate Jornay PM using above schedule; do not substitute on a milligram-per-milligram basis.

Metadate CD: Children ≥6 years and Adolescents: Initial: 20 mg once daily; may increase by 10 to 20 mg/day increments at weekly intervals; usual maximum daily dose: 60 mg/day; however, some patients weighing >50 kg may require and tolerate daily doses up to 100 mg/day with frequent monitoring (AACAP [Pliszka 2007])

Metadate ER, Ritalin-SR: Children ≥6 years and Adolescents: Replace immediate-release tablets when the 8-hour dosage corresponds to sustained-/extended-release tablet size; Ritalin SR may be administered once or twice daily (AAP 2011). Usual maximum daily dose: 60 mg/day; however, some patients weighing >50 kg may require and tolerate daily doses up to 100 mg/day with frequent monitoring (AACAP [Pliszka 2007]).

QuilliChew ER: Children ≥6 years and Adolescents: Initial: 20 mg once daily in the morning; may be adjusted in 10, 15, or 20 mg increments at weekly intervals (tablets are scored and may be broken in half to achieve dose); maximum daily dose: 60 mg/day. Note: If converting from another methylphenidate formulation, discontinue previous formulation and titrate QuilliChew ER using above schedule; do not substitute on a milligram-per-milligram basis.

Quillivant XR: Children ≥6 years and Adolescents: Initial: 20 mg once daily in the morning; may increase by 10 to 20 mg/day increments at weekly intervals; maximum daily dose: 60 mg/day

Ritalin LA: Children ≥6 years and Adolescents:

Methylphenidate-naive patients: Initial: 20 mg once daily; may increase by 10 mg/day increments at weekly intervals; usual maximum daily dose: 60 mg/day; however, some patients weighing >50 kg may require and tolerate daily doses up to 100 mg/day with frequent monitoring (AACAP [Pliszka 2007]). Note: If a lower initial dose is desired, patients may begin with Ritalin LA 10 mg once daily. Alternatively, patients may begin therapy with an immediate-release product, and switch to Ritalin LA once immediate-release dosage is titrated to 5 mg twice daily (see below).

Patients currently receiving immediate-release methylphenidate: The same total daily dose of Ritalin LA should be used.

Patients currently receiving methylphenidate sustained release (SR): The same total daily dose of Ritalin LA should be used.

Canadian labeling:

Concerta: Children ≥6 years and Adolescents:

Sustained-release methylphenidate [Canadian product] to Concerta: Oral:

Switching from methylphenidate SR 20 mg daily: Concerta 18 mg once every morning

Switching from methylphenidate SR 40 mg daily: Concerta 36 mg once every morning

Switching from methylphenidate SR 60 mg daily: Concerta 54 mg once every morning

Biphentin [Canadian product]: Children ≥6 years and Adolescents:

Methylphenidate naive patients: Oral: Initial: 10 to 20 mg once daily; may be adjusted in 10 mg increments at weekly intervals; maximum daily dose: 60 mg/day. Note: In some children and adolescents, higher doses may be necessary; do not exceed 1 mg/kg/day or the adult maximum of 80 mg/day; monitor closely for adverse events, reduce dose or discontinue if adverse events occur.

Patients currently receiving immediate-release methylphenidate: Use equivalent total daily dose administered once daily.

Topical: Transdermal patch (Daytrana): Children and Adolescents 6 to 17 years: Initial: 10 mg (12.5 cm2) patch once daily; apply to hip 2 hours before effect is needed and remove 9 hours after application (eg, 3 hours before bedtime); titrate dose based on response and tolerability; may increase to next transdermal patch dosage size no more frequently than every week. Patch may be removed before 9 hours if a shorter duration of action is required or if late day adverse effects appear or may be worn for up to 16 hours if extended duration of effects are needed (Arnold 2007). Plasma concentrations usually start to decline when the patch is removed but drug absorption may continue for several hours after patch removal. Note: The manufacturer's labeling recommends patients converting from another formulation of methylphenidate to the transdermal patch should be initiated at 10 mg regardless of their previous dose and titrated as needed due to the differences in bioavailability of the transdermal formulation. However, some clinicians have supported higher starting patch doses for patients converting from oral methylphenidate doses of >20 mg/day; for example, the 15 mg (18.75 cm2) patch has been investigated to have the same effect as 22.5 mg daily of the immediate-release preparation, 27 mg daily of the osmotic-release preparation (Concerta), or 20 mg daily of the encapsulated bead preparation (Metadate CD) (Arnold 2007).

Approximate oral methylphenidate equivalents, with a 9-hour patch wear time, for the 20 mg and 30 mg patches are (Arnold 2007):

Approximate oral equivalent daily dose

Patch size (Daytrana)

Immediate release (mg/day)

Osmotic release (eg, Concerta) (mg/day)

15 mg (18.75 cm2)

22.5

27

20 mg (25 cm2)

30

36

30 mg (37.5 cm2)

45

54

Narcolepsy: Children ≥6 years and Adolescents: Oral:

Immediate-release tablets and oral solution (Methylin, Ritalin): Initial: 5 mg twice daily given before breakfast and lunch; increase by 5 to 10 increments mg/day at weekly intervals; 2 to 3 times per day; maximum daily dose: 60 mg/day (in 2 to 3 divided doses)

Extended-/sustained-release tablets (Metadate ER, Ritalin-SR): May be given in place of immediate-release products, once the immediate-release formulation daily dose is titrated and the titrated 8-hour dosage corresponds to sustained- or extended-release tablet size; maximum daily dose: 60 mg/day

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Oral: There are no dosage adjustments provided in manufacturer's labeling (has not been studied); undergoes extensive metabolism to a renally eliminated metabolite with little or no pharmacologic activity.

Transdermal: There are no dosage adjustments provided in manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Pediatric

Oral, Transdermal: There are no dosage adjustments provided in manufacturer's labeling (has not been studied).

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release, Oral, as hydrochloride:

Generic: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Adhansia XR: 25 mg [contains brilliant blue fcf (fd&c blue #1)]

Adhansia XR: 35 mg [contains fd&c yellow #6 (sunset yellow)]

Adhansia XR: 45 mg [contains tartrazine (fd&c yellow #5)]

Adhansia XR: 55 mg [contains brilliant blue fcf (fd&c blue #1)]

Adhansia XR: 70 mg, 85 mg

Aptensio XR: 10 mg [contains brilliant blue fcf (fd&c blue #1)]

Aptensio XR: 15 mg [contains fd&c red #40, fd&c yellow #10 (quinoline yellow)]

Aptensio XR: 20 mg [contains fd&c yellow #10 (quinoline yellow)]

Aptensio XR: 30 mg [contains brilliant blue fcf (fd&c blue #1)]

Aptensio XR: 40 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Aptensio XR: 50 mg [contains fd&c yellow #10 (quinoline yellow)]

Aptensio XR: 60 mg

Jornay PM: 20 mg, 40 mg, 60 mg, 80 mg, 100 mg [contains brilliant blue fcf (fd&c blue #1)]

Ritalin LA: 10 mg, 20 mg, 30 mg, 40 mg

Generic: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg

Patch, Transdermal:

Daytrana: 10 mg/9 hr (1 ea, 30 ea); 15 mg/9 hr (30 ea); 20 mg/9 hr (1 ea, 30 ea); 30 mg/9 hr (30 ea)

Solution, Oral, as hydrochloride:

Methylin: 5 mg/5 mL (500 mL); 10 mg/5 mL (500 mL) [contains polyethylene glycol; grape flavor]

Generic: 5 mg/5 mL (5 mL, 500 mL); 10 mg/5 mL (500 mL)

Suspension Reconstituted ER, Oral:

Quillivant XR: 25 mg/5 mL (60 mL, 120 mL, 150 mL, 180 mL) [contains corn starch, sodium benzoate; banana flavor]

Quillivant XR: 25 mg/5 mL (60 mL [DSC], 120 mL [DSC], 150 mL [DSC], 180 mL [DSC]) [contains sodium benzoate]

Tablet, Oral, as hydrochloride:

Ritalin: 5 mg

Ritalin: 10 mg, 20 mg [scored]

Generic: 5 mg, 10 mg, 20 mg

Tablet Chewable, Oral, as hydrochloride:

Generic: 2.5 mg, 5 mg, 10 mg

Tablet Chewable Extended Release, Oral, as hydrochloride:

QuilliChew ER: 20 mg [DSC] [contains aspartame]

QuilliChew ER: 20 mg [scored; contains aspartame]

QuilliChew ER: 30 mg [DSC] [contains aspartame]

QuilliChew ER: 30 mg [scored; contains aspartame]

QuilliChew ER: 40 mg [contains aspartame]

Tablet Extended Release, Oral, as hydrochloride:

Concerta: 18 mg, 27 mg, 36 mg, 54 mg

Metadate ER: 20 mg [DSC] [additive free, color free]

Relexxii: 72 mg [contains fd&c blue #1 aluminum lake]

Generic: 10 mg, 18 mg, 20 mg, 27 mg, 36 mg, 54 mg, 72 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Generic: 18 mg, 27 mg, 36 mg, 54 mg

Tablet Extended Release Disintegrating, Oral:

Cotempla XR-ODT: 8.6 mg, 17.3 mg, 25.9 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms Considerations

Aptensio XR capsules contain multi layered beads. The immediate release layer delivers approximately 40% of the methylphenidate dose, and the controlled release layer delivers approximately 60% of the methylphenidate dose.

Concerta is an osmotic controlled release formulation (OROS) of methylphenidate. The tablet has an immediate-release overcoat providing an initial dose of methylphenidate within 1 hour, and the remaining is released at a controlled rate over 5-9 hours. The overcoat covers a trilayer core. The trilayer core is composed of two layers containing the drug and excipients, and one layer of osmotic components. As water from the gastrointestinal tract enters the core, the osmotic components expand and methylphenidate is released.

Metadate CD capsules contain a mixture of immediate release and extended release beads, designed to release 30% of the dose immediately and 70% over an extended period.

Ritalin LA uses Spheroidal Oral Drug Absorption System (SODAS) design to deliver a bimodal release of medication, intended to mimic twice-daily administration of immediate-release methylphenidate. Fifty percent of the drug is delivered in immediate-release beads, and the remaining half is delivered in delayed-release beads approximately 4 hours after administration.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release, Oral:

Biphentin: 15 mg [contains d&c red #28, fd&c red #40, fd&c yellow #10 aluminum lake]

Biphentin: 80 mg [contains fd&c red #40, fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Capsule Extended Release, Oral, as hydrochloride:

Biphentin: 10 mg [contains fd&c blue #1 aluminum lake]

Biphentin: 20 mg [contains d&c red 33, fd&c yellow #10 aluminum lake]

Biphentin: 30 mg [contains fd&c blue #1 aluminum lake]

Biphentin: 40 mg [contains d&c red #28, fd&c blue #1 aluminum lake, fd&c red #40]

Biphentin: 50 mg [contains fd&c yellow #10 aluminum lake]

Biphentin: 60 mg

Capsule Extended Release 24 Hour, Oral:

Foquest: 100 mg

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Foquest: 25 mg [contains brilliant blue fcf (fd&c blue #1)]

Foquest: 35 mg [contains fd&c yellow #6 (sunset yellow)]

Foquest: 45 mg [contains tartrazine (fd&c yellow #5)]

Foquest: 55 mg [contains brilliant blue fcf (fd&c blue #1)]

Foquest: 70 mg, 85 mg

Tablet, Oral, as hydrochloride:

Ritalin: 10 mg

Ritalin: 20 mg [DSC] [contains fd&c yellow #10 (quinoline yellow)]

Generic: 5 mg, 10 mg, 20 mg

Tablet Extended Release, Oral, as hydrochloride:

Concerta: 18 mg, 27 mg, 36 mg, 54 mg

Ritalin SR: 20 mg

Generic: 18 mg, 20 mg, 27 mg, 36 mg, 54 mg

Controlled Substance

C-II

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Adhansia XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212038s002lbl.pdf#page=25

Aptensio XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/205831s005lbl.pdf#page=22

Concerta: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021121s038lbl.pdf#page=30

Cotempla XR-ODT: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205489s000lbl.pdf#page=21

Daytrana: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021514s028lbl.pdf#page=23

Jornay PM: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209311s003lbl.pdf#page=19

Metadate CD: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021259s030lbl.pdf#page=20

Methylin chewable tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021475s010lbl.pdf#page=13

Methylin immediate release oral solution: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021419s010lbl.pdf#page=16

QuilliChew ER: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207960s005lbl.pdf

Quillivant XR extended release oral suspension: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202100s012lbl.pdf#page=14

Ritalin: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/010187s071s082,018029s041s051lbl.pdf#page=14

Ritalin LA: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021284s016s029lbl.pdf#page=17

Administration: Adult

Oral:

Short-acting immediate release: Chewable tablets, Methylin (oral solution), and Ritalin (tablets): Administer each dose 30 to 45 minutes before a meal. Ensure last daily dose is administered before 6:00 PM if difficulty sleeping occurs. Administer chewable tablet with ≥8 ounces of water or other fluid.

Intermediate-acting extended release :

Metadate ER: Administer 30 to 45 minutes before a meal. Swallow whole with water or other fluid; do not crush or chew tablet.

Ritalin SR [Canadian product]: Swallow whole; do not crush or chew tablet.

Long-acting extended release:

Adhansia XR: Administer in the morning with or without food. Swallow whole with full glass of water; do not crush or chew capsules. Alternatively, capsules may be opened and the contents sprinkled onto a tablespoon of applesauce or yogurt. Swallow mixture immediately or within 10 minutes without chewing; discard if not administered within 10 minutes of mixing. Do not crush, chew, or divide capsule contents.

Aptensio XR, Jornay PM, Metadate CD, Ritalin LA: Administer Aptensio XR, Metadate CD, and Ritalin LA in the morning and Jornay PM in the evening between 6:30 PM to 9:30 PM. Administer with or without food; capsules may be opened, and the contents sprinkled onto a small amount (equal to 1 tablespoon) of cold applesauce. Swallow applesauce mixture immediately without chewing. Do not crush, chew, or divide capsule contents.

Biphentin, Foquest [Canadian products]: Administer in the morning. Swallow whole with full glass of water; do not crush or chew capsules. Alternatively, capsules may be opened, and the contents sprinkled onto applesauce, ice cream, or yogurt, but the beads must not be crushed or chewed.

Biphentin should be administered immediately after or within 30 minutes of sprinkling capsule contents on food; after administration patients should rinse their mouths with water and swallow. Discard if not administered within 30 minutes of mixing.

Foquest should be administered immediately after or within 10 minutes of sprinkling capsule contents on food; after administration patients should rinse their mouths with water and swallow. Discard if not administered within 10 minutes of mixing.

Concerta: Administer in the morning. May be taken with or without food but must be taken with water or other fluid. Do not crush, chew, or divide tablet.

QuilliChew ER: Administer in the morning with or without food. Tablets are scored and may be halved.

Quillivant XR: Administer in the morning with or without food. Shake bottle ≥10 seconds prior to administration. Use the oral dosing dispenser provided; wash after each use.

Bariatric surgery:

Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablets should be swallowed whole. Do not cut, chew, or crush. IR tablet, chewable tablet, oral solution, and oral suspension formulations are available. ER chewable tablet, ER orally dissolvable tablet, and transdermal formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, close clinical monitoring is advised in the immediate postoperative phase for the theoretical circumstance of altered absorption after bariatric surgery.

Topical: Long-acting transdermal: Daytrana: Apply to clean, dry, non-oily, intact skin to the hip area, avoiding the waistline; do not premedicate the patch site with hydrocortisone or other solutions, creams, ointments, or emollients. Apply at the same time each day to alternating hips. Press firmly for 30 seconds to ensure proper adherence. Avoid exposure of application site to external heat source, which may increase the amount of drug absorbed. If difficulty is experienced when separating the patch from the liner or if any medication (sticky substance) remains on the liner after separation, discard that patch and apply a new patch. Do not use a patch that has been damaged or torn; do not cut patch. If patch should dislodge, may replace with new patch (to different site) but total wear time should not exceed 9 hours; do not reapply with dressings, tape, or common adhesives. Patch may be removed early if a shorter duration of effect is desired or if late day side effects occur. Wash hands with soap and water after handling. Avoid touching the sticky side of the patch. If patch removal is difficult, an oil-based product (eg, petroleum jelly, olive oil) may be applied to the patch edges to aid removal; never apply acetone-based products (eg, nail polish remover) to patch. Dispose of used patch by folding adhesive side onto itself, and discard in toilet or appropriate lidded container.

Administration: Pediatric

Oral: To avoid insomnia, last daily dose of all products except Jornay PM should be administered several hours before retiring.

Immediate-release formulations:

Tablet (Ritalin), oral solution (Methylin): Administer ~30 to 45 minutes before meals. Ensure last daily dose is administered before 6 PM if difficulty sleeping occurs.

Chewable tablet (Methylin): Administer ~30 to 45 minutes before meals with at least 8 ounces of water or other fluid; choking may occur if not enough fluids are taken. Ensure last daily dose is administered before 6 PM if difficulty sleeping occurs.

Extended-/sustained-release formulations:

Tablets:

Concerta: May be administered without regard to food, but must be taken with liquids; administer dose once daily in the morning; do not crush, chew, or divide tablets.

Metadate ER: May be taken with or without food. Swallow whole; do not crush, chew, or break tablets.

Ritalin SR: Administer 30 to 45 minutes before a meal. Swallow whole; do not crush, chew, or break tablets.

Capsules:

Adhansia XR: Administer in the morning with or without food; swallow capsule whole; do not crush, chew, or divide capsule or its contents. Capsules may be opened and entire contents sprinkled onto a tablespoon of applesauce or yogurt; use within 10 minutes (immediately use is preferable); mixture must be consumed without chewing; do not store for future use. Missed doses should not be administered later in the day, and do not administer additional doses to make up for missed dose; resume normal dosing regimen the next morning.

Aptensio XR: Administer in the morning with or without food; swallow capsule whole; do not crush, chew, or divide capsule or its contents; capsules may be opened and the contents sprinkled onto applesauce; mixture must be consumed immediately without chewing; do not store for future use.

Biphentin [Canadian product]: Administer in the morning; do not crush or chew capsule or its contents; capsules may be opened and the contents sprinkled onto applesauce, ice cream, or yogurt; mixture must be consumed immediately without chewing; do not store for future use.

Foquest [Canadian product]: Adults: Administer in the morning with a full glass of water; do not crush or chew capsule or its contents; capsules may be opened and the contents sprinkled onto a tablespoon of applesauce, ice cream, or yogurt; mixture must be consumed within 10 minutes without chewing.

Jornay PM: Administer dose once daily in the evening between 6:30 and 9:30 PM; administer consistently either with or without food; swallow capsule whole; do not crush, chew, or divide capsule or its contents; capsules may be opened and the contents sprinkled onto applesauce; mixture must be consumed immediately without chewing; do not store for future use. Missed doses should be taken as soon as remembered if the same evening; if missed dose remembered the following morning, it should be skipped.

Metadate CD: Administer dose once daily in the morning, before breakfast, with liquids; capsule may be swallowed whole; do not crush, chew, or divide or its capsule contents; capsules may be opened and contents sprinkled on a small amount (one tablespoonful) of applesauce; immediately consume drug/applesauce mixture; do not store for future use; swallow applesauce without chewing; drink fluids after consuming drug/applesauce mixture to ensure complete swallowing of beads.

Ritalin LA: Administer dose once daily in the morning; may be administered with or without food (but some food consumed at breakfast may delay absorption); capsule may be swallowed whole; do not crush, chew, or divide capsule or its contents; may be opened and contents sprinkled on a small amount (one spoonful) of applesauce. Note: Applesauce should not be warm; immediately consume drug/applesauce mixture; do not store for future use.

Orally disintegrating tablet (Cotempla XR-ODT): Administer in the morning consistently with or without food. Remove the tablet from blister pack with dry hands by peeling back (do not push tablet through foil), and administer immediately. Allow the tablet to dissolve on the tongue without chewing or crushing; no liquid is needed.

Powder for oral suspension (Quillivant XR): Administer in the morning with or without food. Shake bottle ≥10 seconds prior to administration. Use the oral dosing dispenser provided; wash after each use.

Topical: Transdermal (Daytrana): Apply patch immediately after opening pouch and removing protective liner; do not use patch if pouch seal is broken; do not cut patch; do not use patches that are cut or damaged. If difficulty is experienced when separating the patch from the liner or if any medication (sticky substance) remains on the liner after separation, discard that patch and apply a new patch. Apply to clean, dry, healthy skin on the hip; do not apply to oily, damaged, inflamed, or irritated skin; do not apply to the waistline; do not premedicate the patch site with hydrocortisone or other solutions, creams, ointments, or emollients. Apply at the same time each day, 2 hours before effect is needed. Alternate site of application daily (ie, use alternate hip). Press patch firmly for 30 seconds to ensure proper adherence, especially around the edges. Remove patch typically 9 hours after application. Patch may be removed earlier if a shorter duration of action is required or if late day adverse effects occur or may be worn for up to 16 hours if extended duration of effects are needed (Arnold 2007).

Avoid exposure of application site to external heat source (eg, hair dryers, electric blankets, heating pads, heated water beds), which may significantly increase the rate and amount of drug absorbed. Exposure of patch to water during swimming, bathing, or showering may affect patch adherence. Do not reapply patch with dressings, tape, or other adhesives. If patch should become dislodged, may replace with new patch (to different site) but total wear time for the day should not exceed 9 hours, even if more than one patch is used.

During removal, peel off patch slowly. If needed, patch removal may be helped by applying an oil-based product (ie, mineral oil, olive oil, or petroleum jelly) to the patch edges, gently working it underneath the patch edges. If a patch is not able to be removed, contact a physician or pharmacist. Nonmedical adhesive removers and acetone-based products, such as nail polish remover, should not be used to remove patches or adhesive. If adhesive residue remains on the skin after patch removal, use an oil-based product and gently rub area to remove adhesive. Avoid touching the sticky side of the patch. Wash hands with soap and water after handling.

Dispose of used patch by folding adhesive side onto itself, and flush down the toilet or discard in appropriate lidded container; discard unused patches that are no longer needed in the same manner; protective pouch and liner should be discarded in an appropriate lidded container. Note: Used patches contain residual drug; keep all transdermal patches out of the reach of children.

Use: Labeled Indications

Attention-deficit/hyperactivity disorder: Treatment of attention-deficit/hyperactivity disorder (ADHD).

Narcolepsy (Methylin, Metadate ER, Ritalin, and Ritalin SR [Canadian product]): Symptomatic management of narcolepsy.

Use: Off-Label: Adult

Fatigue, severe, cancer related or in palliative care setting; Major depressive disorder (unipolar) in medically ill, palliative care, terminal illness, or elderly patients

Medication Safety Issues
Sound-alike/look-alike issues:

Metadate CD may be confused with Metadate ER

Metadate ER may be confused with methadone

Methylphenidate may be confused with methadone

QuilliChew ER may be confused with Quillivant XR

Ritalin may be confused with Rifadin

Ritalin LA may be confused with Ritalin SR

Adverse Reactions (Significant): Considerations
Cardiovascular events

Cardiovascular events, including acute myocardial infarctions [MI], sudden cardiac death, stroke, increased heart rate, and increased blood pressure, have been reported in adult and pediatric patients (Ref). Methylphenidate, similar to other CNS stimulants, has been associated with sudden death in children and adolescents with preexisting structural cardiac abnormalities. Available data in patients without congenital heart disease are conflicting (Ref). A large retrospective cohort study showed an overall low incidence and risk of serious cardiovascular events in children and young adults (Ref); similarly, retrospective claims databases have not shown an increase in serious cardiovascular events (MI, sudden death, stroke) with stimulant use in young and middle-aged adults (Ref).

Mechanism: Methylphenidate increases the mean heart rate and systolic blood pressure by mediating the sympathetic, central and peripheral catecholaminergic systems (Ref). This increase in heart rate and blood pressure can ultimately lead to cardiovascular events such as arrhythmias and/or MI.

Onset: Increased risk for MI appeared after 1 week of treatment and persisted over 2 months. Arrhythmias and hypertension were reported to be more immediate adverse effects (day 1 to 3) and (day 4 to 7) after initiation of treatment respectively (Ref).

Risk factors:

• Patients with prior structural heart disease (Ref)

• Concomitant use of QTc prolonging medications may increase the risk of arrhythmias

Growth suppression

Some studies have reported growth retardation in pediatric patients. Decreased height and weight changes have been described in children <12 years receiving long-term treatment (ie, ≥3 years) (Ref). Similarly, statistically significant reductions in total femoral, femoral neck, and lumbar bone mineral density (BMD) were observed in pediatric patients (age range: 8 to 17 years) actively treated with stimulants (including but not limited to methylphenidate) when compared to matched unmedicated controls; also reported were significantly more subjects in the stimulant-treated group with BMD measurements in the osteopenic range compared to matched controls (38.3% to 21.6%) (Ref). An association has been observed between cumulative methylphenidate exposure in childhood and decreased height velocity, decreased adult height, and increased weight in adulthood (Ref). In contrast, a longitudinal cohort-controlled trial reported no difference in peak height velocity and final adult height in subjects with ADHD and/or treated with stimulants (Ref). In adults, methylphenidate has been shown to cause anorexia with weight loss (Ref).

Mechanism: Possibly due to effects on central nervous system growth factors and hepatic growth factors and direct cartilage effects. Weight loss may result from appetite suppression, reduced food intake, increased activity, and metabolic shifts (Ref).

Onset: Growth suppression in children: Delayed; appears to occur after months of active treatment (Ref). Appetite suppression in adults: Immediate; occurs within hours of initiation of therapy and after only one dose (Ref).

Risk factors:

• Duration of treatment/cumulative methylphenidate exposure (Ref)

Priapism

Priapism associated with neurostimulants like methylphenidate has been reported in the literature and published in an FDA Drug Safety Communication. The presentation of priapism has ranged in severity, occurred with dose changes and withdrawal of the medication, and has been reported with different dosage forms and products (Ref). The overall incidence of methylphenidate-induced priapism is unknown. In severe cases, priapism (ischemic) can be a urological emergency and may require surgical interventions to prevent permanent erectile dysfunction, fibrosis, and impotence.

Mechanism: Prolonged erections occur when the balance of the smooth muscle cell (SMC) control system is altered towards SMC relaxation; ischemic priapism results when the inflow and outflow of blood is halted (Ref).

Onset: Rapid; may be related to the half-life of the medication/formulation. Case reports have reported onset of priapism within a few hours of ingesting immediate-release methylphenidate or the day after taking sustained release methylphenidate (Ref).

Risk factors:

• Hematological dyscrasias (eg, sickle cell disease) (Ref)

• Malignancies (Ref)

• Perineal trauma (Ref)

• Alcohol use (Ref)

• Concomitant use of illicit drugs known to cause priapism (eg, cocaine, ecstasy, marijuana) (Ref)

• Concomitant use of prescription medications associated with priapism (eg, psychotropic medications [typical and atypical antipsychotics, antidepressants, and anxiolytics], alpha-adrenergic agents, anticoagulants) (Ref)

Psychiatric/behavioral effects

New-onset psychosis or mania and exacerbation of psychotic or manic symptoms (eg, delusional thinking, auditory hallucination and visual hallucination, mania) may occur with neurostimulant use in all ages; methylphenidate has also been associated with aggressive behavior or hostility in children; however, a causal relationship has not been established (Ref). A recent cohort study in adolescents and young adults failed to show any evidence that the initiation of methylphenidate increased the risk of psychosis (Ref). Patients with ADHD are at increased risk for suicidal ideation and suicide attempt; however, neither increased risk nor a causal relationship with methylphenidate and attempted suicide has been observed in large cohort trials (Ref). The risk of psychosis may be lower with methylphenidate compared to amphetamine products (Ref).

Mechanism: Psychosis: Central stimulants amplify neuronal signaling by increasing in dopamine concentration in the prefrontal cortex of the brain. Increased dopamine levels have been associated with the development of psychotic and manic symptoms (Ref).

Onset: Days to weeks (Ref).

Risk factors:

• Preexisting history of psychosis (Ref)

• Family history of mood and psychotic disorders (eg, major depression, bipolar disorder, schizophrenia) (Ref)

• Young age (children, adolescents, and young adults) (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Gastrointestinal: Decreased appetite (2% to 26%), nausea (2% to 13%), xerostomia (oral: 3% to 14%)

Nervous system: Headache (2% to 22%, including migraine; tension headache: oral: 1%), insomnia (including initial insomnia; oral: 2% to 33%; transdermal: 6% to 13%), irritability (2% to 11%)

1% to 10%:

Cardiovascular: Increased blood pressure (≥2%), increased diastolic blood pressure (oral: 7%), increased heart rate (oral: ≥2%), palpitations (3%), tachycardia (oral: 5%; transdermal: ≤1%) (table 1)

Methylphenidate: Adverse Reaction: Tachycardia

Drug (Methylphenidate)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Methylphenidate)

Number of Patients (Placebo)

1%

0%

Children

N/A

Transdermal patch

Attention deficit hyperactivity disorder

98

85

0.7%

0%

Adolescents

N/A

Transdermal patch

Attention deficit hyperactivity disorder

145

72

5%

0%

Adults

N/A

Extended-release tablets

Attention deficit hyperactivity disorder

415

212

Dermatologic: Excoriation of skin (oral: 4%), hyperhidrosis (oral: 5%), skin rash (oral: 2%)

Endocrine & metabolic: Decreased libido (oral: 2%), weight loss (2% to 9%) (table 2)

Methylphenidate: Adverse Reaction: Weight Loss

Drug (Methylphenidate)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Methylphenidate)

Number of Patients (Placebo)

9%

0%

Children

N/A

Transdermal patch

Attention deficit hyperactivity disorder

98

85

2%

0%

Children

20 to 60 mg/day

Extended-release chewable tablets

Attention deficit hyperactivity disorder

42

44

7%

0%

Adolescents

25 to 85 mg/day

Extended-release capsules

Attention deficit hyperactivity disorder

293

74

6%

1%

Adolescents

N/A

Transdermal patch

Attention deficit hyperactivity disorder

145

72

7%

3%

Adults

N/A

Extended-release tablets

Attention deficit hyperactivity disorder

415

212

4%

1%

Adults

25 to 100 mg/day

Extended-release capsules

Attention deficit hyperactivity disorder

297

78

Gastrointestinal: Abdominal pain (5% to 7%), anorexia (2% to 9%), bruxism (oral: 2%), constipation (oral: 1%), diarrhea (oral: 4%), dyspepsia (oral: 2%), motion sickness (oral: 2%), upper abdominal pain (oral: 4% to 9%), vomiting (2% to 10%)

Genitourinary: Dysmenorrhea (oral: 2%)

Hematologic & oncologic: Bruise (oral: 3%)

Nervous system: Aggressive behavior (oral: 2%) (table 3), agitation (oral: 2%), anxiety (oral: 8%), confusion (oral: 1%), depressed mood (oral: 4%), depression (2%), dizziness (2% to 7%), emotional lability (1% to 9%), fatigue (3%), hypertonia (oral: 2%), jitteriness (oral: 4%), lack of emotion (oral: 2%), nervousness (3%) paresthesia (1%), psychomotor agitation (oral: 5%), restlessness (oral: 3%), sedated state (oral: 1%), tension (oral: 1%), tic disorder (1% to 9%), vertigo (oral: 2%)

Methylphenidate: Adverse Reaction: Aggressive Behavior

Drug (Methylphenidate)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Methylphenidate)

Number of Patients (Placebo)

2%

0%

Children

20 to 60 mg/day

Extended-release chewable tablets

Attention deficit hyperactivity disorder

42

44

2%

0.5%

Adults

N/A

Extended-release tablets

Attention deficit hyperactivity disorder

415

212

Neuromuscular & skeletal: Back pain (oral: 3%), tremor (oral: 3%)

Ophthalmic: Blurred vision (2%), eye pain (oral: 2%)

Respiratory: Cough (oral: 2%), nasopharyngitis (oral: 3%), oropharyngeal pain (oral: 1% to 2%), streptococcal pharyngitis (oral: 3%), upper respiratory tract infection (oral: 2%)

Miscellaneous: Fever (oral: 2%)

<1%: Dermatologic: Contact hypersensitivity (transdermal)

Frequency not defined:

Cardiovascular: Cardiac arrhythmia, heart murmur, hypertension

Dermatologic: Macular eruption

Endocrine & metabolic: Gynecomastia, hot flash, increased thirst

Gastrointestinal: Abdominal distress, viral gastroenteritis

Genitourinary: Erectile dysfunction, hematuria

Hematologic & oncologic: Anemia, leukopenia

Hepatic: Increased serum alanine aminotransferase

Hypersensitivity: Fixed drug eruption

Infection: Viral infection

Nervous system: Delirium, drug abuse, drug dependence, Gilles de la Tourette syndrome (rare), hypervigilance, hypomania, lethargy, mood changes, outbursts of anger, panic attack, psychosis, sleep disorder, toxic psychosis

Neuromuscular & skeletal: Asthenia, muscle cramps, muscle spasm

Ophthalmic: Dry eye syndrome

Respiratory: Bronchitis, dyspnea, sinusitis

Miscellaneous: Drug tolerance

Postmarketing:

Cardiovascular: Acute myocardial infarction (Thompson 2010), angina pectoris, bradycardia, chest discomfort, chest pain, extrasystoles, necrotizing angiitis, peripheral vascular insufficiency, Raynaud's disease (Goldman 2008), supraventricular tachycardia, ventricular arrhythmia (Schelleman 2012), ventricular premature contractions

Dermatologic: Alopecia (Ardic 2017), bullous skin disease, erythema multiforme, erythema of skin, exfoliative dermatitis, leukoderma (transdermal: chemical) (Cheng 2017; FDA Safety Alert 2015), pruritus, urticaria (Storebo 2018)

Endocrine & metabolic: Growth retardation (Poulton 2016; Storebo 2015)

Genitourinary: Priapism (Eiland 2014)

Hematologic & oncologic: Immune thrombocytopenia (Grossman 1985), pancytopenia, thrombocytopenia (Ercan 2017)

Hepatic: Hepatic failure (acute), increased serum bilirubin

Hypersensitivity: Anaphylaxis, angioedema (Goyal 2015)

Local: Application site reaction (transdermal)

Nervous system: Abnormal behavior, auditory hallucination (Mosholder 2009), cerebral arteritis (Storebo 2018), disorientation, drowsiness, extrapyramidal reaction, hyperactive behavior, hyperpyrexia, mania (Mosholder 2009), obsessive compulsive disorder, seizure, talkativeness, visual hallucination (Mosholder 2009)

Neuromuscular & skeletal: Arthralgia, dyskinesia (including choreiform movements) (Storebo 2018), muscle twitching, myalgia, rhabdomyolysis

Ophthalmic: Diplopia, mydriasis

Otic: Swelling of the ear

Contraindications

US labeling: Hypersensitivity (eg, angioedema, anaphylaxis) to methylphenidate or any component of the formulation; use during or within 14 days following MAOI therapy

Additional contraindications:

Concerta, Daytrana, Metadate CD, Metadate ER, methylphenidate chewable tablets: Marked anxiety, tension, and agitation; glaucoma; family history or diagnosis of Tourette syndrome or tics

Metadate CD: Severe hypertension, heart failure, arrhythmia, hyperthyroidism or thyrotoxicosis, recent MI or angina; concomitant use of halogenated anesthetics; patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrose-isomaltase insufficiency

Canadian labeling: Hypersensitivity to methylphenidate or any component of the formulation; marked anxiety, tension, and agitation; glaucoma; use during or within 14 days following MAO inhibitor therapy; family history or diagnosis of Tourette syndrome or tics (excluding Concerta), thyrotoxicosis, advanced arteriosclerosis, symptomatic cardiovascular disease, or moderate to severe hypertension

Additional contraindications:

Foquest: Known hypersensitivity or idiosyncrasy to sympathomimetic amines; history of drug abuse

Ritalin and Ritalin SR: Pheochromocytoma

Warnings/Precautions

Concerns related to adverse effects:

• Peripheral vasculopathy: Stimulants are associated with peripheral vasculopathy, including Raynaud phenomenon; signs/symptoms are usually mild and intermittent, and generally improve with dose reduction or discontinuation. Peripheral vasculopathy effects have been observed at different times, at therapeutic doses, and in all age groups. Digital ulceration and/or soft tissue breakdown have been observed rarely; monitor for digital changes during therapy and refer for further evaluation (eg, rheumatology) if necessary.

• Visual disturbance: Difficulty in accommodation and blurred vision have been reported with the use of stimulants.

Disease-related concerns:

• Bipolar Disorder: May precipitate a mixed ormanic episode in patients with bipolar illness.

• Cardiovascular disorders: Use with caution in patients with hypertension, ventricular arrhythmia, and other cardiovascular conditions that might be exacerbated by increases in blood pressure or heart rate.

• Seizure disorder: Use with caution in patients with a history of seizure disorder; may lower seizure threshold leading to new onset or breakthrough seizure activity. Discontinue in the presence of seizures.

• Tourette syndrome/tics: Use with caution in patients with Tourette syndrome or other tic disorders. Stimulants may exacerbate tics (motor and phonic) and Tourette syndrome; however, evidence demonstrating increased tics is limited. Evaluate for tics and Tourette syndrome prior to therapy initiation; use is contraindicated with some products.

Dosage form specific issues:

• Adhansia XR: 45 mg capsules contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

• Biphentin, Foquest [Canadian products]: Controlled-release capsules are not interchangeable with other controlled-release formulations.

• Concerta: Should not be used with preexisting severe gastrointestinal narrowing conditions, such as esophageal motility disorders, small bowel disease, “short” gut syndrome, cystic fibrosis, history of peritonitis, chronic intestinal pseudo-obstruction, or Meckel diverticulum.

• Daytrana: Transdermal system may cause dermal reactions: Chemical leukoderma and contact sensitization; in a one-year tolerability study, the majority of subjects who withdrew (7%) did so due to dermal reactions (Findling 2009). Chemical leukoderma is a persistent loss of skin pigmentation at and around the application site, as well as at distant sites from the application site, that may resemble vitiligo, especially if loss of skin pigmentation occurs at areas distant from application site; patients with a personal and/or family history of vitiligo may be at more risk; patients should monitor for signs of skin depigmentation and immediately inform their health care provider if observed; discontinue use if patient experiences chemical leukoderma; loss of skin pigmentation may continue after discontinuation. Contact sensitization is characterized by erythema plus an intense local reaction (eg, edema, papules, vesicles) that does not improve within 48 hours or spreads beyond the patch site; sensitization may subsequently manifest systemically with other routes of methylphenidate administration; if using oral methylphenidate, initiate under medical supervision and monitor closely, as some sensitized patients may not be able to take methylphenidate in any form. Avoid exposure of application site to any direct external heat sources (eg, hair dryers, heating pads, electric blankets) while wearing patch; heat may increase the rate and extent of absorption more than 2-fold and result in overdose.

• Lactose/sucrose: Some dosage forms may contain lactose or sucrose; use with caution in patients intolerant to either component (some manufacturer labels recommend avoiding use in such patients).

• Metadate CD: Concomitant use with halogenated anesthetics is contraindicated; may cause sudden elevations in blood pressure; if surgery is planned, do not administer Metadate CD on the day of surgery.

• Phenylketonuria: Some dosage forms contain phenylalanine, which can be harmful to patients with phenylketonuria. Before prescribing, consider the combined daily amount of phenylalanine from all sources.

Other warnings/precautions:

• ADHD treatment: Appropriate use: Recommended to be used as part of a comprehensive treatment program for attention deficit disorders.

Warnings: Additional Pediatric Considerations

CNS stimulant treatment has been associated with sudden death in children and adolescents with preexisting structural cardiac abnormalities; one study reported methylphenidate increased risk for arrhythmia and MI in youth without congenital heart disease (Shin 2016) and a retrospective case-control study reported an association with stimulants and sudden unexplained death in youth (Gould 2009). However, as noted in reviews (Martinez-Raga 2013, Westover 2012) several large studies have not found an association between prescription stimulants and cardiovascular events; though most retrospective studies were large (n=55,383 to 2,131,953), some had statistical power or methodological limitations (Westover 2012). A large retrospective cohort study involving 1,200,438 children and young adults (aged 2 to 24 years) prescribed ADHD medication (methylphenidate, dexmethylphenidate, dextroamphetamines, amphetamine salts, pemoline, or atomoxetine) found no evidence that ADHD medication was associated with an increased risk of serious cardiovascular events (ie, acute MI, sudden cardiac death, stroke) in current (adjusted hazard ratio: 0.75; 95% CI: 0.31 to 1.85) or former (adjusted hazard ratio: 1.03; 95% CI: 0.57 to 1.89) users compared with nonusers, nor in current compared with former users. Results were similar with multiple alternative analyses to assess for bias or study assumptions. While point estimates of relative risks for ADHD drugs did not demonstrate increased risk, the upper limit of the 95% CI suggested a doubling of the risk could not be ruled out, although absolute magnitude of increased risk would be low. Data on any individual medication, other than methylphenidate, were too sparse for separate regression analyses (Cooper 2011). Prior to treatment with medications for ADHD, the American Heart Association and the American Academy of Pediatrics recommend that all children and adolescents diagnosed with ADHD have a thorough cardiovascular assessment, including patient and family health histories, determination of all medications used (prescribed and over-the-counter), and a physical examination focused on cardiovascular disease risk factors. An ECG is not mandatory but is reasonable to consider prior to stimulant medication therapy. Prompt evaluation and appropriate referral and testing, if warranted, should occur if any cardiac symptoms present (Vetter 2008).

Evaluation of the effect of stimulants on growth in ADHD diagnosed children <12 years receiving treatment for at least 3 years with stimulants has shown decreased height and weight changes over time compared to age matched control; height: 4.7 to 5.5 cm/year compared to 6.3 cm/year and 2.1 to 3.3 kg/year compared to 4.4 kg/year (Poulton 2016). In 5,315 pediatric patients (age range: 8 to 17 years) actively treated with stimulants (methylphenidate, dexmethylphenidate, dextroamphetamine, atomoxetine, lisdexamfetamine), significant reductions in total femoral, femoral neck, and lumbar bone mineral density (BMD) were observed compared to matched unmedicated controls (n=1,967); also reported were significantly more subjects in the stimulant-treated group with BMD measurements in the osteopenic range compared to matched controls (38.3% to 21.6%); of note, there was no data on duration of medication treatment, dosing, or therapy changes (Howard 2017). A longitudinal cohort-controlled trial reported no difference in peak height velocity and final adult height in subjects with ADHD and/or treated with stimulants (Harstad 2014).

Use with caution in preschool-age children; some clinical trials have reported higher rates of adverse events in children 3 to 5 years of age, compared with older children, and some trials have noted a greater discontinuation of therapy compared to school-age children, though adverse event reports may have been a proxy for inefficacy, rebound, or other underlying causes (Greenhill 2006; Wigal 2006). The moderate to severe adverse effect profiles in children are age-related; in preschool children, the most commonly reported adverse effects were crabbiness/irritability, emotional outbursts, difficulty falling asleep, repetitive behavior/thoughts, and decreased appetite; in school-age children, they were decreased appetite, delay of sleep onset, headache, and stomach ache (Wigal 2006).

Metabolism/Transport Effects

None known.

Drug Interactions

Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Risk X: Avoid combination

Alcohol (Ethyl): May enhance the adverse/toxic effect of Methylphenidate. Alcohol (Ethyl) may increase the serum concentration of Methylphenidate. Risk X: Avoid combination

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Antihypertensive Agents: Methylphenidate may diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Methylphenidate may enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy

Antipsychotic Agents: May enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor therapy

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

CloNIDine: Methylphenidate may enhance the adverse/toxic effect of CloNIDine. Risk C: Monitor therapy

Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider therapy modification

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Risk C: Monitor therapy

Esketamine: May enhance the hypertensive effect of CNS Stimulants. Risk C: Monitor therapy

Fosphenytoin: Methylphenidate may increase the serum concentration of Fosphenytoin. Risk C: Monitor therapy

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy

Inhalational Anesthetics: Dexmethylphenidate-Methylphenidate may enhance the hypertensive effect of Inhalational Anesthetics. Risk X: Avoid combination

Iobenguane Radiopharmaceutical Products: CNS Stimulants may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid combination

Ioflupane I 123: Methylphenidate may diminish the diagnostic effect of Ioflupane I 123. Risk C: Monitor therapy

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Kratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combination

Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of Methylphenidate. Risk X: Avoid combination

Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy

PHENobarbital: Methylphenidate may increase the serum concentration of PHENobarbital. Risk C: Monitor therapy

Phenytoin: Methylphenidate may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Primidone: Methylphenidate may increase serum concentrations of the active metabolite(s) of Primidone. Specifically, phenobarbital concentrations could become elevated. Methylphenidate may increase the serum concentration of Primidone. Risk C: Monitor therapy

Quinolones: Methylphenidate may enhance the cardiotoxic effect of Quinolones. Risk C: Monitor therapy

Serotonergic Agents (High Risk): Dexmethylphenidate-Methylphenidate may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy

Solriamfetol: CNS Stimulants may enhance the hypertensive effect of Solriamfetol. CNS Stimulants may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Methylphenidate may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Food Interactions

Ethanol: Alcohol consumption increases the rate of methylphenidate release from Adhansia XR (ER capsules), Jornay PM (ER capsules), Metadate CD (ER capsules), Ritalin LA (ER capsules), and QuilliChew ER (ER chewable tablet), but not from Concerta (ER tablet); in vitro studies showed that an alcohol concentration of 40% resulted in 84%, and 98% of the methylphenidate being released in the first hour with Metadate CD and Ritalin LA, respectively, and 97% of the methylphenidate being released in 2 hours with Jornay PM; a study involving Adhansia XR showed that an alcohol concentration of 40% resulted in 71% of a 70 mg dose and 61% of a 100 mg dose being released in the first 2 hours; a study involving QuilliChew ER showed that an alcohol concentration of 40% resulted in 90% of the methylphenidate being released in the first half hour. Management: Avoid consuming alcohol during therapy.

Food: Food may increase oral absorption of IR tablet/solution/chewable tablet and Metadate ER. Management: Administer 30 to 45 minutes before meals.

Pregnancy Considerations

Information related to the use of methylphenidate in pregnant women with attention-deficit/hyperactivity disorder (Ornoy 2018) or narcolepsy (Calvo-Ferrandiz 2018; Maurovich-Horvat 2013; Thorpy 2013) is limited and outcome data is conflicting (Ornoy 2018). If treatment of ADHD in pregnancy is needed, methylphenidate may be considered (Larsen 2015; McAllister-Williams 2017).

Data collection to monitor pregnancy and infant outcomes following exposure to methylphenidate is ongoing. Health care providers are encouraged to enroll females exposed to methylphenidate during pregnancy in the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.

Breastfeeding Considerations

Methylphenidate is present in breast milk.

The relative infant dose (RID) of methylphenidate is 0.7% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 52 mg/day.

In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

The RID of methylphenidate was calculated using a milk concentration of 19 mcg/L, providing an absolute daily infant dose via breast milk of 2.9 mcg/kg/day. This milk concentration was obtained following maternal administration methylphenidate to three women for ADHD. Maternal doses ranged from 35 to 80 mg/day (Hackett 2006). Authors of two additional case reports calculated the RID of methylphenidate <1% (Hackett 2006; Spigset 2007). In a case report, methylphenidate was no longer detectable in breast milk 20 to 21 hours after the maternal dose following administration of the immediate release tablet (Spigset 2007).

Adverse events were not noted in three case reports (Bolea-Alamanac 2014a; Hackett 2006; Spigset 2007); however, infants in two cases were older (6 months of age and 11 months of age) and exposure was limited (Hackett 2006; Spigset 2007). Long-term developmental effects have not been studied. Growth and medical development were normal in one child up to 1 year of age (Bolea-Alamanac 2014a).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Monitor breastfeeding infants for adverse reactions, such as agitation, anorexia, insomnia, and reduced weight gain.

Dietary Considerations

Administer the short-acting IR tablet (Ritalin), IR solution (Methylin), and IR chewable tablet 30 to 45 minutes before meals. Some products may contain phenylalanine.

Monitoring Parameters

Cardiac evaluation (including medical or family history of sudden death or ventricular arrhythmia; ECG as indicated) should be completed at baseline and on any patient who develops exertional chest pain, unexplained syncope, and any symptom of cardiac disease during treatment with stimulants. Monitor blood pressure and heart rate (baseline, following dose increases and periodically during treatment); growth rate (height and weight) and appetite in children; weight in adults; signs of peripheral vasculopathy (eg, digital changes); sleep and behavioral changes. Assess for risk of abuse prior to prescribing and signs of misuse, abuse, or addiction throughout treatment (NICE 2018). Screen for bipolar disorder and risk factors for developing a manic episode prior to treatment; monitor for psychotic or manic symptoms (eg, delusional thinking, hallucinations, mania) or suicide-related behavior; in children monitor for development or worsening of aggressive behavior or hostility.

Transdermal: Signs of worsening erythema, blistering or edema which does not improve within 48 hours of patch removal, or spreads beyond patch site.

Mechanism of Action

Mild CNS stimulant; blocks the reuptake of norepinephrine and dopamine into presynaptic neurons; appears to stimulate the cerebral cortex and subcortical structures similar to amphetamines

Pharmacokinetics

Onset of action (AAP [Wolraich 2011]):

Children:

Oral:

ER formulations (capsule [Metadate CD, Ritalin LA], tablets [Concerta]): 20 to 60 minutes

IR formulations (chewable tablet, oral solution, tablet [Methylin, Ritalin]): 20 to 60 minutes

Sustained-release tablet (Ritalin SR [Canadian product]): 60 to 180 minutes

Transdermal (Daytrana): 60 minutes

Adults: Oral: Controlled-release: Foquest [Canadian product]: Within 1 hour

Maximum effect: Oral: IR tablet: Within 2 hours; Sustained-release tablet (Ritalin SR [Canadian product]): Within 4 to 7 hours

Duration of action:

Oral:

Controlled-release capsule (Foquest [Canadian product]): 16 hours

ER capsule: Metadate CD, Ritalin LA: 6 to 8 hours (AAP [Wolraich 2011]); Aptensio XR: ≤16 hours

ER tablet (Concerta): 8 to 12 hours (AAP [Wolraich 2011]; Jain 2017)

ER tablet (Metadate ER): 8 hours

IR formulations (chewable tablet, oral solution, IR tablet [Methylin, Ritalin]): 3 to 5 hours (AAP [Wolraich 2011]; Jain 2017)

Sustained-release tablet (Ritalin SR [Canadian product]): 2 to 8 hours (AAP [Wolraich 2011]; Jain 2017)

Transdermal (Daytrana): 11 to 12 hours (AAP [Wolraich 2011])

Absorption:

Oral: Readily absorbed

Controlled-release capsule:

Biphentin [Canadian product]: Food delayed initial peak slightly (~18 minutes); relative to immediate-release tablets, AUC is similar in fed or fasted state (~100%)

Foquest [Canadian product]: Food does not significantly affect AUC and Cmax

ER capsule:

Adhansia XR: A high fat meal increased the time to first and second Cmax by about 1 hour. When administered with a 40% alcohol concentration in fasted healthy adults, there was a 1.4-fold increase in the peak plasma methylphenidate concentration and a 1.3-fold increase in the extent of absorption; in vitro studies at an alcohol concentration of 40% also demonstrated faster release with 71% of a 70 mg dose and 61% of a 100 mg dose of methylphenidate released at hour 2.

Aptensio XR: A high-fat meal increased Cmax (~28%) and AUC (~19%). At an alcohol concentration up to 40% there was 96% release of methylphenidate within 2 hours.

Jornay PM: Initial absorption is delayed with ≤5% of total drug available within first 10 hours after dosing. A high-fat meal at night decreased Cmax (14%) and extended the median Tmax by ~2.5 hours; a high-fat morning meal had no effect on the pharmacokinetics. At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate, resulting in 97% of the methylphenidate being released in 2 hours.

Metadate CD: A high-fat meal delayed the early peak (~1 hour), and increased Cmax (~30%) and AUC (~17%). At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released.

Ritalin LA: A high-fat meal delayed absorption and peak times, but not the amount absorbed nor initial peak concentration (second peak lowered by ~25%). At an alcohol concentration of 40%, there was a 98% release of methylphenidate in the first hour.

ER chewable tablet: A high-fat meal increased Cmax (~20%) and AUCinf (~4%). At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first half hour, resulting in 90% of the methylphenidate being released.

ER orally disintegrating tablet: Cotempla XR-ODT: A high-fat meal decreased Cmax (24%) and increased AUCinf (16%) and led to an earlier peak (~0.5 hour).

ER suspension: Quillivant XR: A high-fat meal led to an earlier peak (~1 hour), and increased Cmax (~28%) and AUC (~19%).

ER tablet: Metadate ER: Food resulted in greater Cmax and AUC compared to fasting.

IR chewable tablet: A high-fat meal delayed peak time (~1 hour) and increased AUC (~20%).

IR solution: Methylin: A high-fat meal delayed peak time (~1 hour), and increased Cmax (~13%) and AUC (~25%).

IR tablet: A high-fat meal, increased the AUC (25%) and Cmax (27%).

Transdermal: Absorption increased when applied to inflamed skin or exposed to heat. Absorption is continuous for 9 hours after application.

Distribution: Vd: d-methylphenidate: 2.65 ± 1.11 L/kg, l-methylphenidate: 1.80 ± 0.91 L/kg

Protein binding: 10% to 33%

Metabolism: Extensive metabolism, predominately via de-esterification by carboxylesterase CES1A1 to alpha-phenyl-piperidine acetic acid (PPAA; ritalinic acid) which has little to no pharmacologic activity.

Bioavailability:

ER capsule:

Aptensio XR: 102% (relative to IR oral product)

Jornay PM: 73.9% (relative to IR oral product)

ER suspension: Quillivant XR: 95% (relative to IR oral solution)

IR chewable tablets and oral solution: Bioequivalent to IR tablets

Sustained-release tablet (Ritalin SR [Canadian product]): 105% (49% to 168%) in children and 101% (85% to 152%) in adults (relative to IR oral product)

Transdermal patch (Daytrana): Lower first-pass effect compared to oral administration; thus, much lower doses (on a mg/kg basis) given via the transdermal route may still produce higher AUCs, compared to the oral route

Half-life elimination:

Controlled-release capsule: Biphentin [Canadian product]: Children: 2.4 hours; Adults: 2.1 hours; Foquest [Canadian product]: Adults: 6.95 ± 3.25 hours

ER capsule:

Adhansia XR:

Children 6 to 12 years of age: ~4 to 7 hours

Adolescents ≤17 years of age: ~5 hours

Adults: 7 hours

Aptensio XR: Adults: ~5 hours

Jornay PM: Adults: ~5.9 hours

Metadate CD: Adults: 6.8 hours

Ritalin LA: Children: 1.5 to 4 hours; Adults: 3 to 4.2 hours

ER chewable tablets: ~5.2 hours

ER orally disintegrating tablet: 4 to 4.5 hours

ER suspension: Quillivant XR: Children ≥9 years of age, Adolescents, and Adults: ~5 hours

ER tablet: Concerta: Adolescents and Adults: ~3.5 hours

IR chewable tablet: Adults: 3 hours

IR solution: Methylin: Adults: 2.7 hours

IR tablet:

Children: 3.5 hours (1.5 to 5 hours)

Adults: 3.5 hours (1.3 to 7.7 hours)

Transdermal: Children and Adolescents 6 to 17 years of age: d-methylphenidate ~4 to 5 hours, l-methylphenidate 1.4 to 2.9 hours

Time to peak:

Controlled-release capsule:

Biphentin [Canadian product]: Children: Initial: ~2.5 hours; Adults: Initial: ~2 hours

Foquest [Canadian product]: Children: Initial peak between 1.5 to 2.0 hours followed by a second peak between 9 to 11 hours; Adults: Initial peak at ~1.6 hours followed by second peak at ~12.5 hours (range: 11 to 16 hours)

ER capsule:

Adhansia XR:

Children 6 to 12 years of age: Initial: 2 hours (range: 1 to 4 hours); Second peak: 10 hours (8 to 14 hours)

Adolescents ≤17 years of age: Initial: 2 hours (range: 1 to 4 hours); Second peak: 11 hours (8 to 14 hours)

Adults: Initial: 1.5 hours (range: 1 to 2.5 hours); Second peak: ~12 hours (range: 8.5 to 16 hours)

Aptensio XR: Adults: Initial: ~2 hours; Second peak: ~8 hours

Jornay PM: Adults: 14 hours

Metadate CD: Children: Initial: ~1.5 hours; Second peak: ~4.5 hours

Ritalin LA:

Children: Initial: 1 to 3 hours; Second peak: 5 to 11 hour

Adults: Initial: 1.3 to 4 hours; Second peak: 4.3 to 6.5 hours

ER chewable tablet: QuilliChew ER: Adults: 5 hours (median)

ER orally disintegrating tablet: Cotempla XR-ODT: ~5 hours

ER suspension: Quillivant XR: Children (9 to 12 years of age): 4.05 hours (range: 3.98 to 6 hours); Adolescents (13 to 15 years of age): 2 hours (range: 1.98 to 4 hours); Adults: 4 hours (range: 1.3 to 7.3 hours)

ER tablet: Concerta: Initial: ~1 hours, followed by gradually ascending concentrations over 5 to 9 hours; Mean peak: 6 to 10 hours

IR chewable tablet: ~1 to 2 hours

IR solution: Methylin: 1 to 2 hours

IR tablet: Children: 1.9 hours (range: 0.3 to 4.4 hours); time to peak is faster after a high-fat meal as compared to without food (median Tmax: 2.5 hours versus 3 hours, respectively).

Sustained-release tablet (Ritalin SR [Canadian product]): Children: 4.7 hours (range: 1.3 to 8.2 hours)

Transdermal: ~8 to 10 hours

Excretion: Urine (78% to 97% as metabolites and unchanged drug); Feces (1% to 3%)

Pharmacokinetics: Additional Considerations

Pediatric:

ER capsule: Ritalin LA: Time until the between peak minimum and the time until the second peak were delayed and more variable in children 10 to 12 years of age compared to adults. After a 20 mg dose, concentrations in children were approximately twice the concentrations observed in adults 18 to 35 years of age.

ER suspension: Quillivant XR: After a single oral dose of 60 mg plasma concentrations of methylphenidate in children (9 to 12 years of age) were approximately twice the concentrations observed in adults.

Transdermal: The Cmax and AUC of d-methylphenidate were ~50% lower in adolescents, compared to children, following either a 1-day or 7-day administration of 10 mg/9 hours.

Pricing: US

Capsule ER 24 Hour Therapy Pack (Adhansia XR Oral)

25 mg (per each): $13.83

35 mg (per each): $13.83

45 mg (per each): $13.83

55 mg (per each): $13.83

70 mg (per each): $13.83

85 mg (per each): $13.83

Capsule ER 24 Hour Therapy Pack (Aptensio XR Oral)

10 mg (per each): $10.00

15 mg (per each): $10.10

20 mg (per each): $10.00

30 mg (per each): $10.00

40 mg (per each): $10.00

50 mg (per each): $10.00

60 mg (per each): $10.00

Capsule ER 24 Hour Therapy Pack (Jornay PM Oral)

20 mg (per each): $16.17

40 mg (per each): $16.17

60 mg (per each): $16.17

80 mg (per each): $16.17

100 mg (per each): $16.17

Capsule ER 24 Hour Therapy Pack (Methylphenidate HCl ER (LA) Oral)

10 mg (per each): $10.27 - $12.33

20 mg (per each): $5.67 - $12.98

30 mg (per each): $5.80 - $13.27

40 mg (per each): $5.96 - $13.64

60 mg (per each): $12.37 - $14.84

Capsule ER 24 Hour Therapy Pack (Methylphenidate HCl ER (XR) Oral)

10 mg (per each): $8.50 - $9.50

15 mg (per each): $8.50 - $9.50

20 mg (per each): $8.50 - $9.50

30 mg (per each): $8.50 - $9.50

40 mg (per each): $8.50 - $9.50

50 mg (per each): $8.50 - $9.50

60 mg (per each): $8.50 - $9.50

Capsule ER 24 Hour Therapy Pack (Ritalin LA Oral)

10 mg (per each): $11.94

20 mg (per each): $11.94

30 mg (per each): $12.21

40 mg (per each): $12.55

Capsule, controlled release (Methylphenidate HCl ER (CD) Oral)

10 mg (per each): $5.60 - $8.42

20 mg (per each): $5.60 - $8.42

30 mg (per each): $5.60 - $8.42

40 mg (per each): $7.12 - $11.55

50 mg (per each): $9.44 - $14.19

60 mg (per each): $9.44 - $14.19

Chewable (Methylphenidate HCl Oral)

2.5 mg (per each): $1.92 - $3.16

5 mg (per each): $2.23 - $4.51

10 mg (per each): $2.54 - $6.43

Patch (Daytrana Transdermal)

10 mg/9 hrs (per each): $17.64

15 mg/9 hrs (per each): $17.64

20 mg/9 hrs (per each): $17.64

30 mg/9 hrs (per each): $17.64

Solution (Methylin Oral)

5 mg/5 mL (per mL): $0.17

10 mg/5 mL (per mL): $0.24

Solution (Methylphenidate HCl Oral)

5 mg/5 mL (per mL): $0.25 - $0.90

10 mg/5 mL (per mL): $0.38 - $1.29

Suspension Reconstituted ER (Quillivant XR Oral)

25 mg/5 mL (per mL): $3.39

Tablet Chewable Extended Release (QuilliChew ER Oral)

20 mg (per each): $14.91

30 mg (per each): $14.91

40 mg (per each): $14.91

Tablet Extended Release Dispersible (Cotempla XR-ODT Oral)

8.6 mg (per each): $17.81

17.3 mg (per each): $17.81

25.9 mg (per each): $17.81

Tablet, 24-hour (Methylphenidate HCl ER Oral)

18 mg (per each): $6.22

27 mg (per each): $6.38

36 mg (per each): $6.58

54 mg (per each): $7.16

Tablet, controlled release (Concerta Oral)

18 mg (per each): $15.18

27 mg (per each): $15.56

36 mg (per each): $16.05

54 mg (per each): $17.46

Tablet, controlled release (Methylphenidate HCl ER Oral)

10 mg (per each): $7.50 - $8.00

18 mg (per each): $0.89 - $13.21

20 mg (per each): $7.75 - $8.25

27 mg (per each): $0.89 - $13.54

36 mg (per each): $1.06 - $13.97

54 mg (per each): $1.06 - $15.20

72 mg (per each): $22.81

Tablet, controlled release (Relexxii Oral)

72 mg (per each): $25.34

Tablets (Methylphenidate HCl Oral)

5 mg (per each): $0.61 - $0.74

10 mg (per each): $0.36 - $1.05

20 mg (per each): $0.34 - $1.51

Tablets (Ritalin Oral)

5 mg (per each): $0.79

10 mg (per each): $1.12

20 mg (per each): $1.62

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Adaphen (ZA);
  • Adaphen XL (ZA);
  • Addwize (IN);
  • Aradix Retard (CL, PE, PY);
  • Attenta (AU);
  • Aurium (PY);
  • Cognil (PY);
  • Comcerta (VE);
  • Concentra (BD);
  • Concentra SR (BD);
  • Concerta (AE, AR, AT, AU, BB, BE, BG, BH, BM, BR, BS, BZ, CH, CL, CN, CO, CR, CY, DE, DK, DO, EC, EE, EG, ES, FI, GR, GT, GY, HK, HN, HR, ID, IE, IL, IS, JM, JP, KW, LB, LT, LU, MT, MX, MY, NI, NL, NO, NZ, PA, PE, PH, PL, PR, PT, QA, RO, SA, SE, SG, SI, SK, SR, SV, TH, TR, TT, TW, UY, VN, ZA, ZW);
  • Concerta LP (FR);
  • Concerta Oros (KR);
  • Concerta XL (GB);
  • Contramyl (ZA);
  • Delmosart (NO);
  • Equasym (BE, CH, ES, IE, IT);
  • Equasym Depot (DK, NO, SE);
  • Equasym Retard (DE);
  • Equasym XL (GB);
  • Inspiral (IN);
  • Matoride XL (GB);
  • Medikinet (AT, BE, CH, DE, DK, EE, GB, IE, NO, PL, SE);
  • Medikinet CR (DE);
  • Medikinet MR (IL, SG);
  • Medikinet Retard (KR);
  • Medikinet XL (EE, GB);
  • Menidated (EG);
  • Metadate CD SR (KR);
  • Methylin (AR);
  • Methylphen (BD);
  • MFD (AR);
  • Nebapul (CL);
  • Neucon (ZA);
  • Penid (KR);
  • Phenida (PK);
  • Prohiper (ID);
  • Quasym LP (FR);
  • Rephenidate (IL);
  • Rilatine (LU);
  • Ritalin (AE, AT, AU, BB, BF, BH, BJ, CH, CI, CL, CO, CY, CZ, DE, DK, ET, GB, GH, GM, GN, HK, ID, IE, IL, IQ, IR, IS, IT, JO, JP, KE, KW, LB, LK, LR, LY, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NO, NZ, OM, PE, PK, SA, SC, SD, SE, SG, SI, SL, SN, SY, TN, TW, TZ, UG, VE, YE, ZA, ZM, ZW);
  • Ritalin LA (AU, BB, CO, HK, ID, IL, MY, PE, PT, TR);
  • Ritalin LP (VE);
  • Ritalin SR (NO, VE);
  • Ritalin-SR (CH, HK, ID, MY, NZ, SG);
  • Ritalina (AR, BR, PY, UY);
  • Ritalina LA (UY);
  • Ritaline (BE, FR, GR);
  • Ritaline LP (FR);
  • Rubifen (AR, ES, LK, NZ, PT, SG, TH, UY);
  • Rubifen SR (NZ);
  • Tradea (CR, DO, GT, HN, MX, NI, PA, SV);
  • Tradea LP (CR, DO, GT, HN, NI, PA, SV);
  • Xenidate XL (GB)


For country abbreviations used in Lexicomp (show table)

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