On June 30, 2025, FDA issued a drug safety communication about a risk of weight loss in patients younger than 6 years of age taking extended-release stimulants for ADHD and will be revising the labeling for all these products to reflect this new safety information. Although extended-release stimulants are not approved for children younger than 6 years, health care professionals can prescribe them “off label” to treat ADHD. For additional information, see [Web] |
Methylphenidate, a piperidine-derivative, is a CNS stimulant.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 The drug is available in various dosage forms and preparations as methylphenidate or methylphenidate hydrochloride; FDA-labeled indications and patient populations vary based on the specific preparation.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Methylphenidate also has been used in the management of autism spectrum disorder (ASM)†, amphetamine-type stimulant use disorder†, and idiopathic hypersomnia†.560, 561, 562, 563, 564
Attention Deficit Hyperactivity Disorder
Methylphenidate hydrochloride immediate-release conventional tablets (e.g., Ritalin®), oral solution (e.g., Methylin®), and chewable tablets, and methylphenidate hydrochloride extended-release oral suspension (e.g., Quillivant XR®), tablets, capsules (e.g., Aptensio XR®), delayed- and extended-release capsules (e.g., Jornay PM®), and extended-release chewable tablets (e.g., Quillichew ER®) are used for the treatment of ADHD in adults and pediatric patients 6 years of age and older.114, 145, 152, 157, 158, 168, 170, 171 Methylphenidate hydrochloride extended-release trilayer core tablets (e.g., Concerta®) and bilayer core tablets (e.g., Relexxii®) are used for the treatment of ADHD in adults up to 65 years of age and pediatric patients 6 years of age and older.118, 553 Methylphenidate hydrochloride CD extended-release capsules (e.g., generic equivalent of Metadate® CD) are used for the treatment of ADHD in pediatric patients between 6-15 years of age.125 Methylphenidate hydrochloride extended-release capsules (e.g., Ritalin LA®) are used for the treatment of ADHD in pediatric patients between 6-12 years of age.129 Methylphenidate transdermal systems (e.g., Daytrana®) and methylphenidate extended-release orally disintegrating tablets (e.g., Cotempla XR-ODT®) are used for the treatment of ADHD in pediatric patients between 6-17 years of age.147, 172
Although safety and efficacy of methylphenidate in children younger than 6 years of age have not been established, the drug has been evaluated in several controlled clinical studies in preschool-aged children up to 6 years of age.140, 512, 556 AAP states that methylphenidate may be considered for the treatment of ADHD in preschool-aged children† (4 years of age to the sixth birthday) if first-line treatments (i.e., parent training in behavior management and/or behavioral classroom interventions) do not provide substantial improvement and there is continued moderate to severe disturbance in the child's functioning.500
In 2023, a Cochrane review of 212 trials involving 16,302 patients compared the efficacy of methylphenidate (at any dosage and in any formulation) to placebo or no intervention for the treatment of ADHD in children and adolescents 18 years of age and younger.556 This meta-analysis included children as young as 3 years of age, which is below the FDA-labeled age for the indication of ADHD in any of the methylphenidate formulations.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553, 556 The main efficacy outcome assessed was ADHD symptoms, which included attention, hyperactivity, and impulsivity.556 Secondary efficacy endpoints included general behavior at school and home and quality of life.556 The mean age of patients was 9.8 years; the male-to-female ratio was 3 to 1.556 The mean treatment duration of methylphenidate was 28.8 days, ranging from 1—425 days.556 The Cochrane review found that methylphenidate may improve teacher-rated ADHD symptoms and general behavior in pediatric patients with ADHD when compared to placebo or no intervention, but may not affect quality of life.556
In 2021, a Cochrane review of 10 trials involving 497 patients compared immediate-release methylphenidate formulations (at any dosage) with placebo or other pharmacologic interventions, which may have included extended-release methylphenidate, for the treatment of ADHD in adults.557 The main efficacy outcome assessed was change in ADHD symptoms.557 Secondary efficacy endpoints included in this meta-analysis included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety, and quality of life.557 Follow-up duration of included trials ranged from 6—18 weeks.557 This Cochrane review found that compared with placebo, immediate-release methylphenidate may reduce symptoms of ADHD based on investigator-rated scales but with very low-certainty evidence.557
In 2022, a Cochrane review of 21 trials involving 5066 patients compared extended-release methylphenidate formulations (at any dosage) with placebo or other ADHD medications for the treatment of ADHD in adults.558 The main efficacy outcomes included functional outcomes (i.e., academic and job adherence, measured as days of lost work or study activities) and self-rated symptoms.558 Secondary efficacy outcomes included quality of life and ADHD symptoms as rated by investigators and peers.558 The median patient age in this meta-analysis was 36 years; the median trial duration of included studies was 8 weeks.558 The review found that compared with placebo, extended-release methylphenidate improved self-rated symptoms of ADHD but had no effect on days missed at work.558 Methylphenidate was also found to improve investigator-rated ADHD symptoms, ADHD symptoms rated by peers, and self-rated quality of life.558 The level of certainty in terms of evidence was rated very low for all outcomes due to generalizability limitations, high risk of bias, and short durations of the trials included in the meta-analysis.558
The American Academy of Pediatrics (AAP) has developed guidelines for children and adolescents with ADHD.500 For pediatric patients 6-12 years of age with ADHD, FDA-labeled medications should be prescribed, in addition to parent training in behavior management (PTBM) and/or behavioral classroom interventions.500 For choice of medication, the evidence is particularly strong for stimulant drugs (e.g., methylphenidate).500 Evidence is sufficient but not as strong for atomoxetine, extended-release guanfacine, and extended-release clonidine.500 For adolescents 12-18 years of age with ADHD, FDA-labeled medications should be prescribed with the adolescent's assent.500 The provider is also encouraged to prescribe behavioral and other evidence-based training interventions if available.500 Dosages should be titrated to achieve maximum benefit with tolerable side effects.500
AAP also provides recommendations for pediatric patients with ADHD as young as 4 years of age†.500 The first lines of treatment for pediatric patients 4—6 years of age are PTBM and behavioral classroom interventions.500 AAP states that methylphenidate may be considered if these behavioral interventions do not provide significant improvement and there is moderate to severe continued disturbance in the child's functioning.500
International experts have published recommendations for the treatment of ADHD in adults.506, 559 Treatment of ADHD in adults should follow a multimodal approach that includes psychoeducation, pharmacotherapy, cognitive behavior therapy, and coaching for ADHD.506 First-line pharmacotherapy agents include long-acting stimulants such as mixed amphetamine salts, methylphenidate, and lisdexamfetamine.559 Short-acting and intermediate-acting stimulants are considered second-line and can also be adjunctive agents.559 Atomoxetine may also be used as a second-line or adjunctive agent.559
Methylphenidate hydrochloride immediate-release conventional tablets (e.g., Ritalin®), oral solution (e.g., Methylin®), chewable tablets, and methylphenidate hydrochloride extended-release tablets are also used for the treatment of narcolepsy.114, 145, 152, 158 Guidelines from the American Academy of Sleep Medicine (AASM) provide a strong recommendation for the use of several agents for the treatment of narcolepsy in adults, including modafinil, pitolisant, sodium oxybate, and solriamfetol.560 A conditional recommendation is given for armodafinil, dextroamphetamine, and methylphenidate.560 These recommendations are derived from a systematic review and meta-analysis conducted by the AASM to assess the efficacy of interventions for the treatment of central disorders of hypersomnolence, including narcolepsy.561 The conditional recommendation for the use of methylphenidate in adults with narcolepsy is based on 2 observational studies and 1 case series reviewed.561 While the quality of evidence is rated as very low, the AASM analysis had concluded that the balance between desirable and undesirable effects is likely in favor of methylphenidate.561
Methylphenidate has also been used for the symptomatic treatment of inattention, impulsivity, and hyperactivity in pediatric patients 6-18 years of age with autism spectrum disorder (ASD)†.562 563
In 2017, a Cochrane review of 4 studies involving 113 pediatric patients 5-13 years of age assessed the effect of methylphenidate (any dose or formulation) versus placebo for symptoms of ADHD (inattention, impulsivity, and hyperactivity) and ASD (impairments in social interaction and communication, and repetitive, restricted or stereotypical behaviors) in children and adolescents with ASD was published.562 The main efficacy outcomes assessed were improvement in ADHD-like symptoms, improvement in core symptoms of ASD (e.g., impaired social interaction, impaired communication, stereotypical behaviors), and improvement in overall ASD.562 All patients in the included studies had ASD and ADHD-like symptoms; studies were completed in 4-6 weeks.562 A meta-analysis found that high doses of methylphenidate (0.43 mg/kg per dose to 0.60 mg/kg per dose) had a substantial benefit on teacher and parent-rated hyperactivity but had a less substantial effect on teacher-rated inattention.562 The meta-analysis also found that there was no evidence that methylphenidate worsens or benefits the core symptoms of ASD.562
The AAP has developed guidelines for children and adolescents with ASD.563 While there are not currently any medications that correct core social and communication symptoms in patients with ASD, there are medications that may be used to help manage behavioral and psychiatric symptoms.563 Medication should only be considered after treatable medical conditions and behavioral factors are assessed and other interventions do not address the symptoms of concern; the family and patient should be included in the shared decision making process.563 For symptoms of hyperactivity, impulsivity, inattention, and distractibility, the AAP suggests the use of psychostimulants (e.g., methylphenidate, dexmethylphenidate, mixed amphetamine salts, lisdexamfetamine, dextroamphetamine) after behavioral approaches are implemented if problems persist.563 Patients should start with a low dose of the stimulant, with dosage increases as needed and tolerated.563 Stimulants may be most effective in children who do not have comorbid intellectual disability.563
Methylphenidate has also been used in the treatment of amphetamine-type stimulant use disorder†564 and idiopathic hypersomnia†.560, 561 According to guidelines from the American Society of Addiction Medicine (ASAM) and the American Academy of Addiction Psychiatry (AAAP), for amphetamine-type stimulant use disorder, a long-acting formulation of methylphenidate can be considered to promote reduced use of amphetamine-type stimulants.564 For patients with a moderate or higher frequency of use of amphetamine-type stimulants (i.e., ≥10 days per month) or for patients with co-occurring ADHD, long-acting methylphenidate can be given additional consideration.564
Guidelines from the AASM provide recommendations for the treatment of idiopathic hypersomnia†.560 Methylphenidate (versus no treatment) is suggested for the treatment of idiopathic hypersomnia in adults.560 This conditional recommendation is based on an assessment of 1 retrospective, observational study, identified as part of a systematic review, that demonstrated clinical benefit.560, 561
Dispensing and Administration Precautions
Methylphenidate hydrochloride is administered orally.114, 118, 125, 129, 145, 152, 157, 158, 168, 170, 171, 172, 553 Methylphenidate is also administered percutaneously by topical application of a transdermal system.147
Immediate-release Preparations
Immediate-release preparations of methylphenidate hydrochloride (conventional tablets, chewable tablets, oral solution) are administered daily in divided doses, generally twice daily (before breakfast and lunch) in pediatric patients and 2 or 3 times daily in adults; the manufacturers state that immediate-release preparations of the drug preferably should be administered 30-45 minutes before meals.114, 145, 152 The manufacturers state that patients who are unable to sleep if the drug is taken late in the day should receive the last daily dose before 6 p.m.114, 145, 152
Methylphenidate hydrochloride chewable tablets should be administered with a full glass (i.e., at least 240 mL [8 ounces]) of water or other fluid to avoid choking.152 Methylphenidate hydrochloride immediate release preparations (conventional tablets, chewable tablets, oral solution) should be stored from 20-25°C;114, 145, 152 the conventional and chewable tablets may be exposed to temperatures ranging from 15-30°C.114, 152 Protect oral solution and chewable tablets from moisture.145, 152
Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours.158 The extended-release tablets should be swallowed intact and should not be crushed or chewed.158 The extended-release tablets should be taken 30-45 minutes before a meal.158
Methylphenidate hydrochloride extended-release tablets should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.158 Protect from moisture.158
Extended-release Trilayer and Bilayer Core Tablets
Methylphenidate hydrochloride extended-release trilayer (e.g., Concerta®; generics) and bilayer (e.g., Relexxii®) core tablets are administered once daily in the morning without regard to meals.118, 553 The tablets should be swallowed intact and should not be crushed or chewed.118, 553 Patients receiving the extended-release trilayer core tablets should be instructed not to become concerned if they notice a tablet-like substance in their stools; this is normal since the tablet containing the drug is designed to remain intact and slowly release the drug from a nonabsorbable shell during passage through the GI tract.118, 553 The manufacturers state that it is possible that the extended-release trilayer and bilayer core tablets may be visible on abdominal radiographs under certain circumstances, particularly when digital enhancing techniques are utilized.118, 553
Methylphenidate hydrochloride extended-release trilayer (e.g., Concerta®) tablets should be stored at 25°C and bilayer (e.g., Relexxii®) core tablets should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.118, 553 Protect from moisture.118, 553
Extended-release Orally Disintegrating Tablets
Methylphenidate hydrochloride extended-release orally disintegrating tablets (Cotempla XR-ODT®) are administered once daily in the morning in a consistent manner relative to food intake.172
The extended-release orally disintegrating tablets should be administered immediately following removal from the blister package and not saved for later use.172 The tablet should be removed from the blister package with dry hands by peeling back the foil and not by pushing the tablet through the foil.172 The tablet should be placed on the patient's tongue and allowed to disintegrate in saliva without chewing or crushing.172 Administration of liquid with the tablet is not required.172
Methylphenidate hydrochloride extended-release orally disintegrating tablets (Cotempla XR-ODT®) should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.172 Following removal from the carton, blister packages containing methylphenidate hydrochloride extended-release orally disintegrating tablets should be stored in the reusable travel case provided by the manufacturer.172
Extended-release Oral Suspension
Methylphenidate hydrochloride extended-release oral suspension (Quillivant XR®) is administered once daily in the morning without regard to meals.157
Reconstitution: The extended-release oral suspension formulation of methylphenidate hydrochloride is commercially available as a powder that must be reconstituted prior to dispensing.157 The bottle should be tapped until the powder flows freely, and then the bottle cap should be removed and 53, 105, 131, or 158 mL of water should be added to a bottle labeled as containing 300, 600, 750, or 900 mg, respectively, of the drug to provide an extended-release suspension containing 25 mg/5 mL of the drug.157 The bottle adapter should be inserted into the neck of the bottle and the bottle cap replaced.157 The suspension should then be shaken vigorously with a back and forth motion for at least 10 seconds.157 The bottle should be kept tightly closed and should be vigorously shaken for at least 10 seconds before each use.157 The bottle adapter and oral dosing dispenser supplied by the manufacturer should be used to administer the oral suspension.157 The adapter should remain in place as long as the bottle is in use (up to 4 months).157 A dose is dispensed by inserting the oral dosing dispenser into the adapter in the upright bottle and then inverting the bottle and withdrawing the appropriate dose into the oral dosing dispenser.157 The manufacturer's patient information should be consulted for more detailed information on administration of the extended-release oral suspension.157
Following reconstitution, oral extended-release suspensions of methylphenidate hydrochloride should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C, and any unused suspension should be discarded after 4 months.157
Methylphenidate hydrochloride extended-release capsules (Aptensio XR®, Ritalin® LA; generics, including equivalents of Metadate® CD [methylphenidate hydrochloride CD]) are administered once daily in the morning.125, 129, 168 The manufacturer of methylphenidate hydrochloride CD extended-release capsules states that this formulation should be administered before breakfast.125 Aptensio XR® extended-release capsules may be administered without regard to meals, but should be administered in a consistent manner relative to food intake.168 The manufacturer states that administration of Ritalin® LA relative to the timing and composition of meals may need to be individually adjusted.129
The extended-release capsules may be swallowed intact or the entire contents of a capsule(s) may be sprinkled onto a small amount (e.g., one tablespoonful) of applesauce immediately prior to administration.125, 129, 168 The manufacturer of Ritalin® LA states that the capsule contents should not be mixed with warm applesauce because the release properties of the formulation could be affected.129 The sprinkle/food (applesauce or yogurt) mixture should be taken immediately and must not be stored for use at a later time.125, 129, 168 One manufacturer suggests that the patient should drink fluids immediately after swallowing the intact capsule or sprinkle/applesauce mixture.125 Subdividing the contents of a capsule is not recommended, and crushing or chewing of the extended-release capsule or the capsule contents should be avoided.125, 129, 168
Patients receiving methylphenidate hydrochloride extended-release capsules should be instructed to avoid consuming alcohol, since alcohol ingestion may result in more rapid release of the drug from these formulations.125, 129, 168
If a dose is missed, the regular schedule should be resumed the following morning; the missed dose should not be administered later in the day and an extra dose should not be administered to make up for the missed dose.168
Methylphenidate hydrochloride extended-release capsules (Aptensio XR®, Ritalin® LA; methylphenidate hydrochloride CD) should be stored at 20-25°C;125, 129, 168 but Ritalin® LA may be exposed to temperatures ranging from 15-30°C.129
Delayed- and Extended-release Capsules
Jornay PM®(methylphenidate hydrochloride) capsules exhibit both delayed-release and extended-release properties.170 These capsules are administered once daily in the evening in a consistent manner relative to food intake.170 If a dose is missed, the missed dose should be administered the same evening as soon as it is remembered; if the missed dose is not remembered until the following morning, the missed dose should be omitted and the next dose administered at the regularly scheduled time.170 Doses should not be administered in the morning.170
An initial administration time of 8:00 p.m. is recommended; the administration time should then be adjusted within the range of 6:30-9:30 p.m. to optimize tolerability and efficacy the next morning and throughout that day.170 Once the administration time has been optimized, the drug should be administered at the same time each day.170 In clinical trials in children 6-12 years of age, an administration time of 8:00 p.m. was selected for >70% of patients.170
The delayed- and extended-release capsules may be swallowed intact or the entire contents of a capsule may be sprinkled onto applesauce and administered immediately without chewing.170 The sprinkle/applesauce mixture should not be stored for later use.170
Methylphenidate hydrochloride delayed- and extended-release capsules (Jornay PM®) should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.170 Protect from humidity.170
Patients receiving transdermal methylphenidate (Daytrana®) should be carefully instructed in the proper use and disposal of the transdermal system.147
The methylphenidate transdermal system should be applied once daily in the morning, 2 hours before an effect is needed, and should be removed 9 hours after application.147 The system should be applied immediately after opening the package and removing the protective liner; the system should not be used if the package seal is broken.147 Transdermal systems should not be cut.147 After the transdermal system has been separated from the protective liner, the liner should be inspected to ensure that no adhesive (which contains the drug) has been transferred to the liner.147 The transdermal system should be discarded if adhesive transfer has occurred, if the transdermal system is torn or appears to be damaged, or if the transdermal system is difficult to separate from the liner.147 Only intact transdermal systems should be used.147 The adhesive side of the transdermal system should be placed on a clean, dry area of the hip that is not oily, damaged, or irritated; application of the transdermal system to the waistline or to areas under tight clothing should be avoided, since clothing may cause the system to rub off.147 The system should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure that there is good contact with the skin, particularly around the edges of the system.147 Application sites should be alternated daily (e.g., opposite hip) if possible.147
Topical preparations (e.g., corticosteroids or other creams; topical solutions, ointments, or emollients) should not be applied immediately prior to system application, since the effects of such preparations on system adhesion, methylphenidate absorption, or potential adverse effects of the corticosteroid are not known.147
Exposure to water during bathing, swimming, or showering can affect adherence of the transdermal system to the skin.147 Transdermal systems should not be applied or re-applied with dressings, tape, or other common adhesives.147 If a system does not fully adhere to the skin upon application or becomes partially or fully dislodged during the intended period of use, it should be replaced with a new system applied at a different site, but the total wear time should not exceed 9 hours per day regardless of the number of transdermal systems used.147
The transdermal system should be removed by slowly peeling it off the skin.147 If necessary, removal may be facilitated by gently applying an oil-based product (i.e., petroleum jelly, olive oil, mineral oil) to the edges of the transdermal system and gently working the oil underneath the edges.147 If any adhesive remains on the skin after the transdermal system has been removed, an oil-based product may be applied to the application site to gently loosen and remove any residual adhesive.147 In the unlikely event that a transdermal system remains tightly adhered to the skin despite these measures, the patient or caregiver should contact the patient's clinician or pharmacist.147 Nonmedical adhesive removers and acetone-based products (i.e., nail polish remover) should not be used to remove either the transdermal system or the adhesive.147
After removal, used systems should be folded so that the adhesive side adheres to itself and then should be flushed down the toilet or disposed of in an appropriate lidded container.147 Any unused systems that are no longer needed should be removed from their packaging, separated from the protective liner, folded so that the adhesive side adheres to itself, and then flushed down the toilet or disposed of in an appropriate lidded container.147
The manufacturer encourages parents to record on the administration chart included with each carton the time that each transdermal system was applied and removed.147 If a system was removed without the parent's or caregiver's knowledge, or if a system is missing from the tray, the parent or caregiver should be encouraged to ask the child when and how the system was removed.147
Methylphenidate transdermal systems should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C, and must not be stored unpouched.147 The transdermal systems should not be stored in a refrigerator or freezer.147 Once a sealed tray of transdermal systems has been opened, the contents should be used within 2 months.147
Dosage of oral formulations of methylphenidate hydrochloride generally is expressed in terms of the salt;114, 118, 125, 129, 145, 157, 158, 168, 170, 171 however, dosage of the extended-release orally disintegrating tablets (Cotempla XR-ODT®) is expressed in terms of methylphenidate.172 Each 8.6, 17.3, or 25.9 mg of methylphenidate is equivalent to 10, 20, or 30 mg, respectively, of methylphenidate hydrochloride.172 Dosage of methylphenidate transdermal systems is expressed in terms of methylphenidate.147
Some patients receiving longer-acting preparations may require supplemental therapy with an immediate-release formulation of the drug to increase the efficacy, particularly in the morning, or to extend the duration of therapeutic effects later in the day.137
Extended-release oral formulations may contain both immediate-release and extended-release methylphenidate in various proportions, generally ranging from 20% immediate-release and 80% extended-release drug to equal proportions of each in various delivery systems.125, 129, 157, 168, 171, 172 Differences among the commercially available methylphenidate preparations (e.g., method of drug delivery, drug release characteristics, onset and duration of activity, ease of administration) allow for individualization of therapy based on patient needs.509
Dosage of methylphenidate hydrochloride must be carefully adjusted according to individual requirements and response.152
If no improvement in symptoms is observed after dosage adjustment over a 1-month period, methylphenidate should be discontinued.114, 118, 145, 152, 158, 171
If adverse effects or paradoxical symptoms occur with methylphenidate therapy, dosage reduction, or potentially, discontinuation is recommended.114, 118, 145, 152, 158, 171
Pharmacologic treatment may be required for extended periods.118, 125, 129, 147 The long-term usefulness of the drug should be reevaluated periodically and dosage adjusted as needed.114
Attention Deficit-Hyperactivity Disorder
Methylphenidate hydrochloride dosage for the treatment of attention deficit hyperactivity disorder (ADHD) should be individualized based on patient response and tolerance.500 Dosage should be titrated from a low initial dosage to one that provides maximum benefit with minimal adverse effects.500 Because effects of CNS stimulants are achieved rapidly, dosage titration can be accomplished in a relatively short period of time.500 The manufacturers state that if improvement is not observed after appropriate dosage adjustment over a one-month period, methylphenidate should be discontinued.114 If paradoxical aggravation of symptoms or other adverse reactions occur, dosage should be reduced or, if necessary, the drug should be discontinued.114 Dosage recommendations for specific preparations are discussed below.
Immediate-release Oral Preparations (Ritalin®, Methylin®; Generics): The usual adult dosage of methylphenidate hydrochloride as conventional preparations is 20-30 mg administered in 2 or 3 divided doses daily, preferably 30-45 minutes before meals; dosage should not exceed 60 mg daily.114, 145, 152 Some patients may require dosages of 40-60 mg daily, while others may require only 10-15 mg daily.152 The average dosage is 20-30 mg daily.145, 152
Extended-release Tablets (Generics): Methylphenidate hydrochloride extended-release tablets have an intermediate duration of action (approximately 8 hours) and may be substituted for conventional methylphenidate hydrochloride tablets in adults when the 8-hour dosage of methylphenidate hydrochloride as extended-release tablets corresponds to the titrated 8-hour dosage of the drug administered as conventional tablets.158
Extended-release Chewable Tablets (QuilliChew ER®): The recommended initial dosage of methylphenidate hydrochloride as QuilliChew ER® extended-release chewable tablets in adults is 20 mg once daily in the morning.171 Clinical studies of this formulation suggest a duration of action of 8-12 hours.171, 509, 510 Dosage may be adjusted at weekly intervals in increments or decrements of 10, 15, or 20 mg daily.171 The 10 mg and 15 mg doses may be achieved by breaking the functionally-scored 20 mg and 30 mg tablets.171 Dosages exceeding 60 mg daily have not been studied and are not recommended.171
The extended-release chewable tablets should not be substituted for other methylphenidate preparations on a milligram-for-milligram basis because of different methylphenidate base compositions and pharmacokinetic profiles.171 Patients being transferred from therapy with other methylphenidate formulations to therapy with the extended-release chewable tablets should receive the same initial dosage of the extended-release chewable tablets and follow the same dosage titration schedule recommended for patients receiving this formulation as their initial methylphenidate regimen.171
Extended-release Trilayer (Concerta®; Generics) and Bilayer (Relexxii®) Core Tablets: The usual initial dosage of methylphenidate hydrochloride as extended-release trilayer (Concerta®; generics) or bilayer (Relexxii®) core tablets in adults is 18 or 36 mg once daily in the morning.118, 553 The duration of action of Concerta® is approximately 10-12 hours and the duration of action of Relexxii® is approximately 8-12 hours.554 If adequate response does not occur, dosage may be increased at weekly intervals in increments of 18 mg daily.118, 553 The maximum dosage recommended by the manufacturer is 72 mg daily.118, 553
Patients being transferred from methylphenidate hydrochloride therapy using a conventional formulation at a dosage of 5 mg 2 or 3 times daily can be switched to a dosage of 18 mg every morning as the extended-release trilayer or bilayer core tablets.118, 553 Patients receiving methylphenidate hydrochloride therapy using a conventional formulation at a dosage of 10 mg 2 or 3 times daily can be switched to 36 mg every morning as the methylphenidate hydrochloride extended-release trilayer or bilayer core tablets.118, 553 Patients receiving methylphenidate hydrochloride therapy using a conventional formulation at a dosage of 15 mg 2 or 3 times daily can be switched to 54 mg every morning as the extended-release trilayer core tablets, and those receiving a conventional formulation at a dosage of 20 mg 2 or 3 times daily can be switched to 72 mg every morning as the extended-release trilayer or bilayer core tablets.118, 553 The initial dosage of methylphenidate hydrochloride as extended-release trilayer or bilayer core tablets in patients being switched from conventional tablets should not exceed 72 mg daily.118, 553 A 27-mg extended-release trilayer core tablet also is available for patients who require a dosage in between 18 mg daily and 36 mg daily.118 Several bilayer tablet strengths (27 mg, 45 mg, and 63 mg) are also available for in-between dosages during titration.553 For other conventional tablet regimens, the nearest equivalent daily dosage can be substituted based on clinical judgment.118 Subsequent titration to higher or lower dosages may be necessary and should occur at approximately weekly intervals in increments or decrements of 18 mg daily, guided by the patient's clinical response and tolerance; however, the manufacturer states that daily dosages exceeding 72 mg daily in adults are not recommended.118, 553
In the treatment of narcolepsy, the average oral adult dosage of methylphenidate hydrochloride is 10 mg 2 or 3 times daily, given 30-45 minutes before meals.114, 145, 152 Some patients may require 40-60 mg daily; in others, 10-15 mg daily may be adequate.152 The maximum recommended daily dose is 60 mg.114, 145, 152
Attention Deficit-Hyperactivity Disorder
Immediate-release Oral Preparations (Ritalin®, Methylin®; Generics): The usual initial dosage of methylphenidate hydrochloride as conventional (immediate-release) preparations (Ritalin®, Methylin®; generics) in children ≥6 years of age is 5 mg before breakfast and lunch.114, 145, 152 Dosage may be increased gradually by 5-10 mg daily at weekly intervals; dosage should not exceed 60 mg daily.114, 145, 152 The duration of action of immediate-release formulations is approximately 3-4 hours.509
Extended-release Tablets (Generics): Methylphenidate hydrochloride extended-release tablets have an intermediate duration of action (approximately 8 hours) and may be substituted for conventional methylphenidate hydrochloride tablets in pediatric patients ≥6 years of age when the 8-hour dosage of methylphenidate hydrochloride as extended-release tablets corresponds to the titrated 8-hour dosage of the drug administered as conventional tablets.158
During long-term therapy with methylphenidate hydrochloride extended-release tablets, periodic evaluation and dosage adjustment is recommended.158
Extended-release Chewable Tablets (QuilliChew ER®): The recommended initial dosage of methylphenidate hydrochloride as QuilliChew ER® extended-release chewable tablets in pediatric patients ≥6 years of age is 20 mg once daily in the morning.171 Clinical studies of this formulation suggest a duration of action of 8-12 hours.171, 509 Dosage may be adjusted at weekly intervals in increments or decrements of 10, 15, or 20 mg daily.171 The 10 mg and 15 mg dosages can be attained by halving the functionally scored 20 mg and 30 mg tablets, respectively.171 Dosages exceeding 60 mg daily have not been studied and are not recommended.171
The extended-release chewable tablets should not be substituted for other methylphenidate preparations on a milligram-for-milligram basis because of different methylphenidate base compositions and pharmacokinetic profiles.171 Patients being transferred from therapy with other methylphenidate formulations to therapy with the extended-release chewable tablets should receive the same initial dosage of the extended-release chewable tablets and follow the same dosage titration schedule recommended for patients receiving this formulation as their initial methylphenidate regimen.171
Extended-release Trilayer (Concerta®; Generics) and Bilayer (Relexxii®) Core Tablets: The usual initial dosage of methylphenidate hydrochloride as extended-release trilayer (Concerta®; generics) or bilayer (Relexxii®) core tablets in children and adolescents 6-17 years of age is 18 mg once daily in the morning.118, 553 The duration of action of Concerta® is approximately 10-12 hours and the duration of action of Relexxii® is approximately 8-12 hours.554 If adequate response does not occur, dosage may be increased at weekly intervals in increments of 18 mg daily.118, 553 The maximum dosage recommended by the manufacturer is 54 mg daily for children 6-12 years of age and 72 mg daily (not to exceed 2 mg/kg daily) for adolescents 13-17 years of age.118, 553
Patients being transferred from methylphenidate hydrochloride therapy using a conventional formulation at a dosage of 5 mg 2 or 3 times daily can be switched to a dosage of 18 mg every morning as the extended-release trilayer or bilayer core tablets.118, 553 Patients receiving methylphenidate hydrochloride therapy using a conventional formulation at a dosage of 10 mg 2 or 3 times daily can be switched to 36 mg every morning as the methylphenidate hydrochloride extended-release trilayer or bilayer core tablets.118, 553 Patients receiving methylphenidate hydrochloride therapy using a conventional formulation at a dosage of 15 mg 2 or 3 times daily can be switched to 54 mg every morning as the extended-release trilayer or bilayer core tablets, and those receiving a conventional formulation at a dosage of 20 mg 2 or 3 times daily can be switched to 72 mg every morning as the extended-release trilayer or bilayer core tablets.118, 553 The initial dosage of methylphenidate hydrochloride as extended-release trilayer or bilayer core tablets in patients being switched from conventional tablets should not exceed 72 mg daily.118, 553 A 27-mg extended-release trilayer core tablet also is available for patients who require a dosage in between 18 mg daily and 36 mg daily.118 Several bilayer tablet strengths (27 mg, 45 mg, and 63 mg) are also available for in-between dosages during titration.553 For other conventional tablet regimens, the nearest equivalent daily dosage can be substituted based on clinical judgment.118 Subsequent titration to higher or lower dosages may be necessary and should occur at approximately weekly intervals in increments or decrements of 18 mg daily, guided by the patient's clinical response and tolerance; however, the manufacturer states that daily dosages exceeding 54 mg daily in children 6-12 years of age and 72 mg daily (not to exceed 2 mg/kg daily) in adolescents are not recommended.118, 553
Extended-release Orally Disintegrating Tablets (Cotempla XR-ODT®): The recommended initial dosage of methylphenidate as Cotempla XR-ODT® extended-release orally disintegrating tablets in pediatric patients 6-17 years of age is 17.3 mg (equivalent to 20 mg of methylphenidate hydrochloride) once daily in the morning.172 Dosage may be adjusted at weekly intervals in increments of 8.6-17.3 mg daily.172 Dosages exceeding 51.8 mg daily (equivalent to 60 mg of methylphenidate hydrochloride daily) have not been studied and are not recommended.172 Clinical studies of this formulation suggest a duration of action of approximately 12 hours.172, 509
Extended-release Oral Suspension (Quillivant XR®): The recommended initial dosage of methylphenidate hydrochloride as Quillivant XR® extended-release oral suspension (or generic equivalents) in children ≥6 years of age is 20 mg once daily in the morning.157 Dosage may be increased at weekly intervals in increments of 10-20 mg daily.157 Dosages exceeding 60 mg daily are not recommended.157 Clinical studies of this formulation suggest a duration of action of approximately 10-12 hours.157, 509
The extended-release oral suspension should not be substituted for other methylphenidate preparations on a milligram-for-milligram basis because of different methylphenidate base compositions and pharmacokinetic profiles.157 Patients being transferred from therapy with other methylphenidate formulations to therapy with the extended-release suspension should receive the same initial dosage of the extended-release oral suspension and follow the same dosage titration schedule recommended for patients receiving this formulation as their initial methylphenidate regimen.157
Extended-release Capsules (Ritalin® LA; Generics): The recommended initial dosage of methylphenidate hydrochloride as Ritalin LA® extended-release capsules (or generic equivalents) in children 6-12 years of age is 20 mg once daily; when a lower initial dosage is appropriate, therapy may be initiated at a dosage of 10 mg once daily.129 Dosage may be increased at weekly intervals in increments of 10 mg daily.129 Dosages exceeding 60 mg daily are not recommended.129 Some clinicians state that the duration of action of this formulation is approximately 6-8 hours.509
The manufacturer of Ritalin® LA extended-release capsules states that patients receiving conventional or extended-release methylphenidate hydrochloride tablets may be switched to Ritalin® LA extended-release capsules.129 Patients being transferred from methylphenidate hydrochloride therapy using a conventional tablet at a dosage of 5 mg twice daily can be switched to a dosage of 10 mg every morning as Ritalin® LA extended-release capsules.129 Patients receiving methylphenidate hydrochloride therapy using a conventional tablet at a dosage of 10 mg twice daily or a 20-mg dosage of an extended-release tablet can be switched to a dosage of 20 mg every morning as Ritalin® LA extended-release capsules.129 Patients being transferred from methylphenidate hydrochloride therapy using a conventional tablet at a dosage of 15 mg twice daily can be switched to a dosage of 30 mg every morning as Ritalin® LA extended-release capsules.129 Patients receiving methylphenidate hydrochloride therapy using a conventional tablet at a dosage of 20 mg twice daily or a 40-mg dosage of an extended-release tablet can be switched to a dosage of 40 mg every morning as Ritalin® LA extended-release capsules.129 Patients being transferred from methylphenidate hydrochloride therapy using a conventional tablet at a dosage of 30 mg twice daily or a 60-mg dosage of an extended-release tablet can be switched to a dosage of 60 mg every morning as Ritalin® LA extended-release capsules.129
Ritalin® LA extended-release capsules should not be substituted for other methylphenidate preparations on a milligram-for-milligram basis because of different methylphenidate base compositions and pharmacokinetic profiles.129 Patients being transferred from therapy with other methylphenidate formulations to therapy with this extended-release capsule formulation should receive the same initial dosage of Ritalin® LA extended-release capsules and follow the same dosage titration schedule recommended for patients receiving this extended-release capsule formulation as their initial methylphenidate regimen.129
Extended-release Capsules (Generic Equivalents of Metadate® CD): The recommended initial dosage of methylphenidate hydrochloride as methylphenidate hydrochloride CD extended-release capsules in pediatric patients ≥6 years of age is 20 mg once daily in the morning.125 Dosage may be increased at weekly intervals in increments of 10-20 mg daily.125 Dosage should not exceed 60 mg daily. Some clinicians state that the duration of action of this formulation is approximately 6-8 hours.509
Extended-release Capsules (Aptensio XR®; Generics): The recommended initial dosage of methylphenidate hydrochloride as Aptensio XR® extended-release capsules (or generic equivalent) in pediatric patients ≥6 years of age is 10 mg once daily in the morning.168 Dosage may be increased at weekly intervals in increments of 10 mg daily.168 Dosages exceeding 60 mg daily are not recommended.168 Clinical studies suggest that this formulation may have a duration of effect of 12 hours.168, 509, 510
Delayed- and Extended-release Capsules (Jornay PM®): The recommended initial dosage of methylphenidate hydrochloride as Jornay PM® delayed- and extended-release capsules in pediatric patients 6-17 years of age is 20 mg once daily in the evening .170 Following an initial delay in absorption of approximately 8-10 hours,170, 173, 510 clinical response may be observed for approximately 10-12 hours.509, 510 Dosage may be adjusted at weekly intervals in increments of 20 mg daily.170 Dosages exceeding 100 mg daily have not been studied and are not recommended.170
The delayed- and extended-release capsules should not be substituted for other methylphenidate preparations on a milligram-for-milligram basis because of different methylphenidate base compositions and pharmacokinetic profiles.170 Patients being transferred from therapy with other methylphenidate formulations to therapy with the delayed- and extended-release capsules should receive the same initial dosage of the delayed- and extended-release capsules and follow the same dosage titration schedule recommended for patients receiving this formulation as their initial methylphenidate regimen.170
Transdermal System (Daytrana®): Dosage titration, final dosage, and wear time of the transdermal system should be individualized according to the needs and response of the patient.147
In pediatric patients ≥6 years of age who are new to or are converting from another formulation of methylphenidate, the recommended initial methylphenidate transdermal regimen is 1 system delivering 10 mg/9 hours applied once daily.147 If adequate response is not achieved, dosage may be increased at weekly intervals by advancing to the next larger dosage system (i.e., a dosage system delivering 15 mg/9 hours applied once daily during week 2, followed by a dosage system delivering 20 mg/9 hours applied once daily during week 3, and then a dosage system delivering 30 mg/9 hours applied once daily during week 4).147
The methylphenidate transdermal system may be removed earlier than 9 hours if a shorter duration of effect is desired or if late-day adverse effects occur.147 If aggravation of symptoms or other adverse events occur, the dosage or wear time should be reduced, or, if necessary, the drug should be discontinued.147
The manufacturers make no specific dosage recommendations in patients with hepatic impairment.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
The manufacturers make no specific dosage recommendations in patients with renal impairment.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Methylphenidate hydrochloride has not been studied in patients ≥65 years of age and the manufacturers make no specific dosage recommendations in geriatric patients.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Generally, dosage selection for geriatric patients should start at the lower end of the dosage range, reflecting the greater frequency of reduced hepatic, renal, or cardiac function and of concomitant diseases and drug therapy in geriatric patients.168
A boxed warning is included in the prescribing information for methylphenidate hydrochloride regarding the high potential for abuse and misuse with the drug.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 In addition, the drug can be diverted for nonmedical use into illicit channels or distribution. 114, 118, 125, 129, 145, 147, 152, 157, 168, 170, 171, 172, 553 The use of methylphenidate hydrochloride exposes patients to the risks of abuse and misuse, which can lead to the development of substance use disorder (including addiction).114, 118, 147, 152 Misuse and abuse of CNS stimulants such as methylphenidate hydrochloride can result in overdose or death.114, 118, 147, 152 This risk is further increased with higher dosages or unapproved routes of administration (i.e., snorting, injection).114, 118, 147, 152 Because CNS stimulants, including methylphenidate, have a high potential for abuse and dependence, the risk of abuse, misuse, and addiction should be assessed prior to initiation and frequently for the duration of therapy.114, 118, 147, 152 Patients receiving stimulants should be also monitored for signs of abuse, misuse, and addiction.114, 118, 147, 152 In addition, tolerance can develop during CNS stimulant therapy.147 In patients who are physically dependent on CNS stimulants, abrupt cessation of therapy, rapid dosage reduction, or administration of an antagonist may result in a withdrawal syndrome characterized by dysphoric mood, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.147
Patients and/or their caregivers should be advised that methylphenidate can be abused and can result in dependence; they should be advised that methylphenidate should not be shared with others and should be stored in a safe (preferably locked) location to prevent misuse and abuse.114, 118, 152 Methylphenidate should be disposed of by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site when it is no longer needed.114, 118, 152 If there is no take-back program or authorized DEA collection site available, the drug can be mixed with an undesirable, nontoxic substance, such as dirt, cat litter, or used coffee grounds, and disposed of in a sealed plastic bag in the household trash.114, 118, 145, 152
Other Warnings and Precautions
Risks to Patients with Serious Cardiac Disease
Although a causal relationship to stimulants has not been established, sudden unexplained death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease receiving usual dosages of stimulants for the treatment of attention deficit hyperactivity disorder (ADHD).114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Children, adolescents, and adults who are being considered for stimulant therapy should undergo a thorough medical history review (including evaluation for a family history of sudden death or ventricular arrhythmia) and physical examination to detect the presence of cardiac disease.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 In general, CNS stimulants should not be used in children, adolescents, or adults with known serious structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Patients or caregivers should inform clinicians immediately if adverse cardiovascular effects (e.g., exertional chest pain, unexplained syncope, other symptoms suggestive of cardiac disease) occur during stimulant therapy.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Increased Blood Pressure and Heart Rate
Stimulants, including methylphenidate, can cause increases in average blood pressure by about 2-4 mm Hg and heart rate by about 3-6 beats/minute; larger increases may occur in some patients.114, 118, 147, 152, 168 All patients should be monitored for hypertension and tachycardia.114, 118, 147, 152, 168
Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, mania) have been reported in patients without a history of psychotic illness or mania who received usual dosages of stimulants.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% of patients receiving stimulants compared with 0% of those receiving placebo.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 If psychotic or manic symptoms occur during stimulant therapy, discontinuance of therapy should be considered.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Stimulants have the potential to precipitate mixed or manic episodes in patients with comorbid bipolar disorder.114, 118, 147, 157, 168 Prior to initiating stimulant therapy, patients with ADHD should be carefully screened to determine if they are at risk for developing a manic episode; such screening should include a detailed psychiatric history (e.g., current or prior depressive symptoms; family history of suicide, bipolar disorder, or depression).114, 118, 147, 168
Stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.114, 118, 147, 152, 157, 168
Patients or caregivers should be instructed to inform clinicians of preexisting illnesses or conditions, including suicidal ideation or behaviors or mental or psychiatric disorders, and any family history of such conditions.114, 118, 125, 147 They also should be instructed to inform clinicians immediately if new or worsening psychiatric effects (e.g., hallucinations, delusional thinking, bipolar disorder, behavioral disorders, aggressive behavior or hostility) occur during stimulant therapy.114, 118, 125, 147
Some evidence suggests that stimulants may lower the seizure threshold in patients with a history of seizures, in those with prior electroencephalography (EEG) abnormalities without seizures, and rarely, in patients without prior seizures or EEG abnormalities.118, 147, 152 If seizures occur in a patient receiving methylphenidate, the drug should be discontinued.118, 147, 152
Methylphenidate may, in rare instances, cause prolonged and sometimes painful erections in both adult and pediatric male patients.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Although not reported during initiation, priapism was reported after continued therapy with methylphenidate, typically after dosage increases; priapism also occurred during withdrawal, such as drug holidays or discontinuation.114, 118, 147, 152 Patients who develop abnormally sustained, frequent, or painful erections during methylphenidate therapy should seek immediate medical attention.114, 118, 147, 152
Peripheral Vasculopathy, including Raynaud's Phenomenon
Because stimulants used to treat ADHD, including methylphenidate, are associated with peripheral vascular disorders, including Raynaud's phenomenon, careful observation for digital changes is warranted during stimulant therapy, and further clinical evaluation (e.g., referral to a rheumatologist) may be appropriate for certain patients.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in postmarketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 The manifestations generally improved after dosage reduction or discontinuance of the stimulant.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Patients should be informed about the risk of peripheral vascular disorders, including Raynaud's phenomenon, and the associated signs and symptoms (e.g., feelings of numbness, coolness, or pain in fingers or toes; changes in color from pale to blue to red).114, 118, 147, 152 Patients should be advised to report any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes to their clinician and to immediately contact their clinician if any signs of unexplained wounds appear on fingers or toes.114, 118, 147, 152
Long-Term Suppression of Growth in Pediatric Patients
Therapy with CNS stimulants has been associated with weight loss and a slowing of growth in pediatric patients.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Results of an analysis of weight and height patterns in children 7-13 years of age suggested that treatment with methylphenidate for up to 3 years was associated with a slowing in growth rate (on average, height gain was suppressed by about 2 cm and weight gain was suppressed by 2.7 kg over 3 years), without evidence of growth rebound during this period of development.114, 118, 147, 152 Therefore, the manufacturers of stimulant preparations state that growth should be closely monitored during therapy with stimulants, and children who are not growing or gaining height or weight as expected may require temporary discontinuance of therapy.114, 118, 147, 152
Potential for Gastrointestinal Obstruction
Methylphenidate hydrochloride extended-release trilayer and bilayer core tablets (e.g., Concerta®, generics; Relexxii®) are nondeformable and do not appreciably change shape in the GI tract, these preparations should not usually be administered in patients with preexisting severe pathologic or iatrogenic GI narrowing conditions (e.g., esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, or a past history or peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum).118, 553 Obstructive symptoms have rarely been reported in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations.118, 553
Due to the controlled-release design of the tablets, these preparations should only be used in patients who can swallow tablets whole.118, 553
Periodic monitoring of CBC, differential, and platelet counts are recommended during prolonged methylphenidate therapy.118, 147, 152
Angle closure glaucoma has been reported in patients receiving methylphenidate therapy.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Although the mechanism has not been fully elucidated, patients receiving methylphenidate therapy who are at increased risk for acute angle closure glaucoma (e.g., with significant hyperopia) should undergo evaluation by an ophthalmologist.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Increased Intraocular Pressure and Glaucoma
Elevations in intraocular pressure (IOP) have been reported in patients receiving methylphenidate therapy.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
The manufacturers recommend prescribing methylphenidate therapy in patients with open-angle glaucoma or abnormally increased IOP only when the benefits outweigh the risks of treatment.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Patients with a history of abnormally increased IOP or open angle glaucoma receiving methylphenidate should be monitored for ophthalmologic changes.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Motor and Verbal Tics and Worsening of Tourette's Syndrome
Onset or exacerbation of motor or verbal tics and worsening of Tourette's syndrome have been reported with CNS stimulants, including methylphenidate.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Prior to initiation of therapy, patients should be screened for a family history and clinically evaluated for motor or verbal tics or Tourette's syndrome.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Patients receiving methylphenidate therapy should be routinely monitored for the emergence or worsening of tics or Tourette's syndrome, and treatment discontinued if clinically needed.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Risks in Patients with Phenylketonuria
Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that some oral formulations of methylphenidate hydrochloride may contain aspartame, which is metabolized in the GI tract to provide phenylalanine.171 Each 20-, 30-, or 40-mg extended-release chewable tablet (QuilliChew ER®) provides 3, 4.5, or 6 mg of phenylalanine, respectively.171
External Heat with the Transdermal System
Patients receiving the methylphenidate transdermal system should be advised to avoid exposing the application site to direct external heat sources (e.g., hair dryers, heating pads, electric blankets, heated water beds) while wearing the transdermal system.147 Release of methylphenidate from the transdermal system is temperature dependent; release may increase more than twofold when the system is exposed to heat, and this may result in overdosage of the drug.147
Contact Sensitization with the Transdermal System
Use of the methylphenidate transdermal system may result in contact sensitization.147 Transdermal methylphenidate should be discontinued if contact sensitization is suspected (i.e., if erythema develops and is accompanied by evidence of a more intense local reaction [e.g., edema, papules, vesicles] that does not improve substantially within 48 hours or that spreads beyond the application site).147 Diagnosis of allergic contact dermatitis should be confirmed by appropriate diagnostic testing.147 Patients sensitized from use of the methylphenidate transdermal system may develop systemic sensitization or other systemic reactions if methylphenidate-containing products are administered via other routes (e.g., orally).147 Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive patch test sites, or generalized skin eruptions in previously unaffected skin.147 Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting.147 Patients who develop contact sensitization to the methylphenidate transdermal system should be under close medical supervision if oral methylphenidate therapy is initiated.147 Some patients sensitized to methylphenidate by exposure to the methylphenidate transdermal system may not be able to receive methylphenidate in any form.147
Chemical Leukoderma with the Transdermal System
Use of the methylphenidate transdermal system may result in a persistent loss of skin pigmentation at and around the application site.147, 163 In some cases, loss of pigmentation has been reported at other sites that are distant from the application site.147, 163 Time to onset has ranged from 2 months to 4 years; affected areas up to 8 inches in diameter reported.163 Chemical leukoderma can mimic the appearance of vitiligo, particularly when the loss of skin pigmentation involves areas distant from the application site.147 Individuals with a history of vitiligo and/or a family history of vitiligo may be more at risk.147 Discontinue use of the methylphenidate transdermal system in patients with chemical leukoderma; however, skin depigmentation may persist even after use of the methylphenidate transdermal system is discontinued.147
Patients receiving the methylphenidate transdermal system should be monitored for loss of skin pigmentation, especially at application sites.163 Patients should be advised to immediately report changes in skin color to their clinician.163
Risk of Choking with Chewable Tablets
Administration of methylphenidate hydrochloride chewable tablets without adequate fluid may cause tablet contents to swell, resulting in blockage of the throat or esophagus and, possibly, choking.152 Therefore, chewable tablets should be taken with a full glass (i.e., at least 240 mL [8 ounces]) of water or other fluid and should not be administered in patients with difficulty swallowing.152 Patients should be advised to immediately seek medical attention if they experience chest pain, vomiting, or difficulty in swallowing or breathing following administration of the chewable tablets.152
Available data on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, spontaneous abortion, or adverse maternal or fetal outcomes; however, there may be fetal risks associated with use of CNS stimulants during pregnancy.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170 CNS stimulants, such as methylphenidate, can cause vasoconstriction and thereby decrease placental perfusion.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170 While no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic dosages of methylphenidate during pregnancy, premature delivery and low birth-weight infants have been reported in amphetamine-dependent women.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170
In embryofetal development studies in rats and rabbits, no effects on morphologic development were observed following oral administration of methylphenidate during organogenesis at dosages up to 10 and 15 times, respectively, an adolescent dosage of 60 mg daily (based on body surface area); however, spina bifida was observed in rabbits at a dosage of 52 times this human dosage.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170 In a pre- and postnatal development study in rats, oral administration of methylphenidate throughout pregnancy and lactation at dosages of 6 times an adolescent dosage of 60 mg daily was associated with a decrease in pup body weight.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170
The National Pregnancy Registry for ADHD Medications monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170 Clinicians are encouraged to register women who become pregnant while receiving methylphenidate by calling 866-961-2388 or visiting [Web] .114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170
Limited data suggest that breast-fed infants receive 0.2-0.7% of the maternal weight-adjusted dosage of methylphenidate; in 5 case reports, the milk-to-plasma ratio of the drug ranged from 1.1-2.7.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170 Adverse effects on the breast-fed infant or on milk production have not been reported to date; however, any long-term neurodevelopmental effects are unknown.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170
The developmental and health benefits of breast-feeding should be considered along with the importance of methylphenidate to the woman and any potential adverse effects on the breast-fed infant from either the drug or the underlying maternal condition.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170 If a woman receiving methylphenidate breast-feeds, the infant should be monitored for adverse effects (e.g., agitation, insomnia, anorexia, reduced weight gain).114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170
Although safety and efficacy of methylphenidate in children <6 years of age have not been established, the drug has been used in several controlled clinical studies in preschool-aged children up to 6 years of age.140, 512, 556 AAP states that methylphenidate may be considered for treatment of ADHD in preschool-aged children† (4 years of age to the sixth birthday) if first-line treatments (i.e., parent training in behavior management and/or behavioral classroom interventions) do not provide substantial improvement and there is continued, moderate to severe disturbance in the child's functioning.500 Some studies have reported higher rates of adverse effects in preschool-aged children up to 6 years of age, particularly with higher dosages, than had previously been reported in children 6 years of age and older and the adverse effects reported in preschool-aged children may be different than those reported in older children with ADHD.140, 512 Some behaviors reported as adverse stimulant effects in clinical studies in preschool-aged children receiving methylphenidate also were reported in those receiving placebo; some of these behaviors may actually improve in preschool-aged children receiving methylphenidate therapy.140 In placebo-controlled and 12-month open-label extension studies of methylphenidate hydrochloride extended-release capsules (Aptensio XR®) in children 4 to less than 6 years of age with ADHD, high rates of adverse effects, particularly weight loss, were observed.168 Systemic exposure to the drug in these preschool-aged children was approximately twofold to threefold higher than that observed in older children and adolescents receiving the same methylphenidate hydrochloride dosage.168 Because some data suggest that the rate of methylphenidate metabolism may be slower in children 4-5 years of age, therapy with the drug should be initiated at a low dosage and increased in smaller increments; maximum dosages have not been adequately studied in preschool-aged children.500 Additional study and experience are required to elucidate further the safety and efficacy of the drug in this age group.512
Long-term administration of CNS stimulants has been associated with at least a temporary suppression of normal weight and/or height patterns in children.114, 118, 147, 152 Therefore, the manufacturers state that patients requiring long-term therapy with methylphenidate should be carefully monitored, and children who are not growing or gaining height or weight as expected may require temporary discontinuance of therapy.114, 118, 147
In juvenile animal toxicity studies, rats receiving methylphenidate beginning early in the postnatal period and continuing through sexual maturation at a dosage of 4 or more times the usual maximum recommended pediatric dosage of 60 mg daily exhibited decreased spontaneous locomotor activity in adulthood; in addition, female rats exhibited a deficit in acquisition of a specific learning task at a dosage of 8 times the usual maximum recommended pediatric dosage.114 The no-effect level for juvenile neurobehavioral development in rats was approximately 0.5 times the usual maximum recommended pediatric dosage.114 The clinical relevance of these long-term behavioral effects observed in rats is unknown.114
Methylphenidate hydrochloride has not been studied in patients ≥65 years of age.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Although methylphenidate hydrochloride has not been studied in patients with hepatic impairment,114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 hepatic impairment is expected to have minimal effects on the drug's pharmacokinetics.114, 125, 129, 145, 158
Methylphenidate hydrochloride has not been studied in patients with renal impairment.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 Renal impairment is expected to have little effect on the pharmacokinetics of methylphenidate.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553
Common adverse effects reported in patients receiving immediate-release methylphenidate preparations (e.g., conventional tablets, oral solution) include tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain.114, 145
Nervousness and insomnia were the most commonly reported adverse effects with immediate-release methylphenidate chewable tablets, although the manufacturer states that these effects can usually be minimized with dosage reduction and omitting administration in the afternoon or evening.152
The most common adverse effect reported in >5% of children and adolescents receiving extended-release methylphenidate trilayer (e.g., Concerta®; generics) and bilayer (e.g., Relexxii®) core tablets was abdominal pain; in studies conducted in adults, the most common adverse effects reported in >5% of patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight loss, irritability, and hyperhidrosis.118, 553
The most common adverse effects reported in >5% of patients receiving methylphenidate hydrochloride extended-release capsules (Ritalin® LA) were headache, insomnia, upper abdominal pain, decreased appetite, and anorexia.129 The most common adverse effects reported in ≥5% of patients and twice the rate of placebo in patients receiving methylphenidate hydrochloride CD extended-release capsules include anorexia and insomnia.125
The most common adverse effects reported in ≥5% of pediatric patients 6-12 years of age receiving the methylphenidate transdermal patch (Daytrana®) and twice the rate of placebo include a decreased appetite, insomnia, nausea, vomiting, weight loss, tics, affect lability, and anorexia.147 In adolescents 13-17 years of age receiving the methylphenidate transdermal patch (Daytrana®), the most common adverse effects reported in ≥5% of patients and twice the rate of placebo were decreased appetite, nausea, insomnia, weight loss, dizziness, abdominal pain, and anorexia.147 Most of these patients also had erythema at the application site.147
The most common adverse effects reported in ≥5% of pediatric patients 6-17 years of age receiving methylphenidate hydrochloride extended-release capsules (Aptensio XR®) were abdominal pain, decreased appetite, and insomnia.168
Common adverse effects in patients receiving delayed- and extended-release capsules (Jornay PM®) not based on accumulated data from other methylphenidate products and occurring in ≥5% of pediatric patients 6-12 years of age and twice the rate of placebo, include headache, psychomotor hyperactivity, and mood swings.170
Methylphenidate is not metabolized by cytochrome P-450 (CYP) isoenzymes in vitro.125 Methylphenidate has not been shown to inhibit CYP isoenzymes at clinically relevant plasma concentrations.125
Alcohol ingestion may result in more rapid release of methylphenidate hydrochloride from extended-release capsules, delayed- and extended-release capsules, extended-release orally disintegrating tablets, or extended-release chewable tablets; patients receiving these formulations should be instructed to avoid consuming alcohol.125, 129, 168, 170, 171, 172
Concomitant use of methylphenidate with halogenated anesthetic agents (e.g., desflurane, enflurane, halothane, isoflurane, sevoflurane) may increase the risk of sudden increases in blood pressure and heart rate during surgery.114 Use of methylphenidate should be avoided on the day of surgery in patients receiving anesthetic agents.114
Some manufacturers state that the metabolism of tricyclic antidepressants and selective serotonin-reuptake inhibitors (SSRIs) may be inhibited when methylphenidate is used concomitantly and that dosage reduction of tricyclic antidepressants and SSRIs may be required in patients receiving concomitant methylphenidate therapy.118, 145, 147, 152
Methylphenidate should be used with caution in patients receiving pressor agents.118, 145, 147, 152
Methylphenidate may decrease the efficacy of antihypertensive agents.114 Blood pressure should be monitored and dosage of the antihypertensive agent adjusted as necessary.114
Drugs that alter gastric pH (e.g., esomeprazole, famotidine, omeprazole, pantoprazole, sodium bicarbonate) may affect the release of methylphenidate from certain extended-release formulations (e.g., Cotempla XR-ODT®) and thereby alter the pharmacokinetic and pharmacodynamic profiles of these formulations. 172 The manufacturer states that concomitant use of Cotempla XR-ODT® with a histamine H2-receptor antagonist or proton-pump inhibitor is not recommended.172
Concomitant use of MAO inhibitors (e.g., isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, tranylcypromine) and CNS stimulants, including methylphenidate, can cause hypertensive crisis, possibly resulting in death, stroke, myocardial infarction, aortic dissection, ophthalmologic complications, eclampsia, pulmonary edema, and renal failure.114
Methylphenidate is contraindicated in patients currently receiving, or having recently received (i.e., within 14 days), MAO inhibitor therapy.114, 118, 125, 129, 145, 147, 152, 157, 158, 168
In patients receiving concomitant therapy with methylphenidate and risperidone, a change (either increase or decrease) in dosage of one or both drugs may be associated with an increased risk of extrapyramidal symptoms.114 Patients receiving such concomitant therapy should be monitored for extrapyramidal symptoms.114
The metabolism of coumarin anticoagulants and anticonvulsants (e.g., phenobarbital, phenytoin, primidone) has been reported to be inhibited when these drugs are administered in patients receiving methylphenidate.118, 147, 152 Some manufacturers state that dosage reduction of coumarin anticoagulants or anticonvulsants may be required in patients receiving concomitant methylphenidate therapy118, 147, 152 and that it may be necessary to monitor plasma drug concentrations (or, in the case of coumarin anticoagulants, prothrombin time [PT]) when methylphenidate is initiated or discontinued.118, 147
Methylphenidate is a piperidine-derivative CNS stimulant.114, 118, 125, 129, 145, 147, 152, 157, 158, 168, 170, 171, 172, 553 The pharmacologic action of the CNS stimulant effects involved in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy has not been fully elucidated, but is thought to be related to the blockade of norepinephrine and dopamine reuptake into presynaptic neurons and the increased release of norepinephrine and dopamine into the extraneuronal space.114 Methylphenidate is a racemic mixture of the d- and l-threo enantiomers.114 The d-threo enantiomer exhibits more pharmacologic activity than the l-threo enantiomer.114
Methylphenidate hydrochloride is commercially available as conventional tablets, chewable tablets, and an oral solution formulated for immediate release of the drug; extended-release tablets and extended-release capsules (Ritalin® LA; generics) with an intermediate duration of action; longer-acting, extended-release capsules (Aptensio XR®; generics), extended-release trilayer core tablets (e.g., Concerta®; generics), extended-release bilayer core tablets (e.g., Relexxii®), extended-release orally disintegrating tablets (Cotempla XR-ODT®), extended-release chewable tablets (QuilliChew ER®), and a powder for oral suspension formulated for extended release of the drug (Quillivant ER®; generics); and delayed- and extended-release capsules (Jornay PM®), which have delayed-release and extended-release properties, with a longer duration of action following an initial release of not more than 5% of the total drug within the first 10 hours.114, 118, 125, 129, 145, 152, 157, 158, 168, 170, 171, 172, 553 Methylphenidate is commercially available as a transdermal system.147
Various formulations of methylphenidate hydrochloride extended-release capsules are commercially available.125, 129, 168 Some methylphenidate hydrochloride extended-release capsules (methylphenidate hydrochloride CD) contain 30% of the dose in immediate-release beads and 70% of the dose in extended-release beads that slowly release methylphenidate,125 and some (e.g., Ritalin® LA) contain the drug in equal amounts in immediate- and extended-release beads.129 Other extended-release capsules (e.g., Aptensio XR®) contain multilayered beads that are composed of an immediate-release layer containing approximately 40% of the dose and an extended-release layer containing approximately 60% of the dose.168
Extended-release trilayer (Concerta®; generics) and bilayer (Relexxii®) core tablets of methylphenidate hydrochloride contain the drug in an oral osmotic delivery system formulation.118, 553 The Concerta® osmotic delivery system consists of an osmotically active trilayer core (comprised of two layers containing the drug and a push layer containing osmotically active components) surrounded by a semipermeable membrane with an immediate-release drug overcoat and a laser-drilled delivery orifice.118 The Relexxi® osmotic delivery system consists of an osmotically active bilayer core (comprised of one layer of the drug and excipients, and a push layer containing osmotically active components) surrounded by a semipermeable membrane with an immediate-release drug overcoat and a laser-drilled delivery orifice.553 When exposed to water in the GI tract, the drug overcoat is solubilized providing an initial dose of methylphenidate; as water enters the formulation, the osmotic layer expands and the drug is pushed out the delivery orifice of the membrane into the GI tract at a controlled rate.118, 553 The inert tablet ingredients remain intact and are eliminated in feces.118, 553
Methylphenidate hydrochloride extended-release orally disintegrating tablets (Cotempla XR-ODT®) contain approximately 25% immediate-release and 75% extended-release methylphenidate hydrochloride.172
Methylphenidate hydrochloride extended-release chewable tablets (QuilliChew ER®) contain approximately 30% immediate-release and 70% extended-release methylphenidate.171 Although dosage strength is expressed in terms of methylphenidate hydrochloride equivalents, only about 15% of the drug contained in the formulation is present as the hydrochloride salt with the remainder present as methylphenidate ionically bound to the sulfonate groups of sodium polystyrene sulfonate particles.171
Methylphenidate hydrochloride delayed- and extended-release capsules (Jornay PM®) contain beads with 2 functional coatings (an outer delayed-release film coating designed to dissolve at pH exceeding 7 and an inner extended-release coating) surrounding a drug-containing core.170, 173 The outer coating delays the initial release of methylphenidate, while the inner coating controls release of the drug throughout the day.170
The powder for extended-release oral suspension contains approximately 20% immediate-release and 80% extended-release methylphenidate hydrochloride.157
Methylphenidate transdermal system consists of a laminate film backing layer, an adhesive layer containing the drug, and a protective liner, which must be removed prior to application, that is attached to the adhesive surface.147 The methylphenidate dosage delivered is dependent on the size of the transdermal system and the length of time the system is worn.147
Methylphenidate hydrochloride appears to be well absorbed from the GI tract;114, 152 however, oral bioavailability of the drug is low (about 30%; range: 10-52%), which suggests substantial first-pass metabolism.129, 147 Because of substantially greater first-pass metabolism following oral compared with transdermal administration, a lower transdermal dose of methylphenidate may result in greater systemic exposure to d -methylphenidate (the more pharmacologically active isomer) than a higher (on a mg/kg basis) oral dose of the drug.147 Following repeated transdermal administration of methylphenidate, l -methylphenidate is systemically available; on average, systemic exposure to l -methylphenidate is 27-45% less than exposure to d -methylphenidate.147 Little, if any, l -methylphenidate is systemically available following oral administration of the drug.147
While exposure to the drug may be higher in children than in adults following oral administration of equivalent dosages, the pharmacokinetic profile of methylphenidate in pediatric patients and adults generally is similar following adjustment for differences in body weight.129, 157, 168, 170, 171, 172
Following oral administration of methylphenidate hydrochloride as conventional tablets, oral solution, or chewable tablets (immediate-release formulations [Ritalin®, Methylin®]), peak plasma concentrations were attained at approximately 1-2 hours.114, 145, 152 The oral solution and chewable tablets are bioequivalent to the conventional tablets.145, 152 Effects persist for approximately 3-4 hours after oral administration of immediate-release preparations of methylphenidate hydrochloride.509, 510 In adults, administration of methylphenidate hydrochloride 20 mg as an oral solution with a high-fat meal delayed the peak plasma concentration by approximately 1 hour and increased the average peak plasma concentration and AUC for methylphenidate by 13 and 25%, respectively; the magnitude of increase in peak plasma concentration and AUC is similar between methylphenidate hydrochloride oral solution and conventional tablets.145 Administration of methylphenidate hydrochloride 20 mg as chewable tablets with a high-fat meal in adults delayed the time to peak plasma concentration by approximately 1 hour and increased the AUC by about 20%; the magnitude of food effect is comparable to that observed with conventional tablets.152
Extended-release methylphenidate hydrochloride tablets are absorbed more slowly but to the same extent as the conventional tablets.158 Following oral administration of the extended-release tablets in children, peak plasma concentrations were attained at 4.7 hours.158 Effects persist for about 8 hours after oral administration of the extended-release tablets.158
Following oral administration of a single 40-mg dose of methylphenidate hydrochloride as extended-release chewable tablets (QuilliChew ER®) in the fasted state, peak plasma concentrations were achieved at a median of 5 hours.171 Peak concentrations and AUC achieved following a single 40-mg dose as extended-release chewable tablets were about 20 and 11% lower, respectively, than values achieved following oral administration of an equivalent dosage of an immediate-release chewable tablet (two 20-mg doses given 6 hours apart).171 Effects persist for about 8-12 hours after oral administration of the extended-release chewable tablets.171, 509, 510 Administration of the extended-release chewable tablets (single 40-mg dose) with a high-fat meal had no effect on the time to peak concentration, and increased the peak concentration and AUC by about 20% and 4%, respectively.171 In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that about 90% of the drug was released from the 40-mg extended-release chewable tablets within the first half hour at an alcohol concentration of 40%; the manufacturer states that these results are representative for the available strengths of this preparation.171
In adults, the relative bioavailability of the extended-release trilayer (Concerta®) and bilayer (Relexxii®) core tablets of methylphenidate hydrochloride administered once daily are comparable to that of the conventional tablets administered 3 times daily.118, 553 Following oral administration of a single 18-mg dose of the extended-release trilayer core tablets (Concerta®) of methylphenidate hydrochloride in healthy adults, an initial peak plasma concentration was attained within 1 hour while peak plasma concentrations of about 3.7 ng/mL were achieved at approximately 7 hours.118 Following oral administration of the extended-release bilayer core tablets (Relexxii®), an initial peak plasma concentration was attained in about 1.5 hours, with peak plasma concentrations achieved after a mean of 5.5 hours.553 No substantial accumulation is observed with repeated once-daily administration of extended-release trilayer or bilayer tablets over the dose range of 18-144 mg.118 Effects persist for about 10-12 hours after oral administration of the extended-release trilayer core tablets (Concerta®).118, 509 The duration of action of extended-release bilayer core tablets (Relexxii®) is approximately 8-12 hours.554 Administration of the extended-release trilayer or bilayer core tablets with a high-fat meal does not alter pharmacokinetics or pharmacodynamics of this preparation of methylphenidate hydrochloride.118, 553 In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated no increase in the amount of drug released from the 18-mg extended-release trilayer core tablet (Concerta®) within the first hour at an alcohol concentration of up to 40%; the manufacturer states that these results are representative for the available strengths of this preparation.118 No increase in the amount of drug released from extended-release bilayer core tablets (Relexxii®) was observed within the first 2 hours at alcohol concentrations of up to 40%.553
Following oral administration of a single 51.8-mg dose of methylphenidate (equivalent to 60 mg of methylphenidate hydrochloride) given as two 25.9-mg extended-release orally disintegrating tablets (Cotempla XR-ODT®) under fasted conditions in healthy adults, peak concentrations were achieved at a median of 5 hours; peak concentration and AUC were about 26 and 6% higher, respectively, with the extended-release orally disintegrating tablets than with a 60-mg extended-release capsule formulation of methylphenidate hydrochloride.172 Effects persist for approximately 12 hours after oral administration of the extended-release orally disintegrating tablets.172, 509 Administration of the extended-release orally disintegrating tablets with a high-fat meal decreased peak concentration by approximately 24%, increased AUC by approximately 16%, and decreased the time to peak concentration by about 30 minutes (from 5 hours in the fasted state to 4.5 hours in the fed state).172 In vitro studies evaluating the effect of alcohol on the release of methylphenidate indicated the potential for increased drug release in the presence of 40% alcohol but not at lower alcohol concentrations.172
Following oral administration of a single 60-mg dose of methylphenidate hydrochloride as extended-release oral suspension (Quillivant XR®) in the fasted state in healthy adults, peak plasma concentrations of d -methylphenidate (the more pharmacologically active isomer of the drug) were achieved at a median of 5 hours; bioavailability of the extended-release oral suspension (single 60-mg dose) relative to that of an immediate-release oral solution (given as two 30-mg doses 6 hours apart) was 95%.157 Effects persist for about 10-12 hours after oral administration of the extended-release oral suspension.157, 509, 510 Administration of the extended-release oral suspension (60-mg dose) with a high-fat meal in adults reduced the time to peak concentration of the drug by approximately 1 hour; peak plasma concentration and AUC were increased by approximately 28 and 19%, respectively, but these effects were not considered clinically important.157 In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated no increase in the amount of drug released from the extended-release oral suspension at an alcohol concentration of 5 or 10%; at an alcohol concentration of 20%, drug exposure was increased, on average, by 20%.157
Following oral administration of a single 20-mg dose of methylphenidate extended-release capsules (Ritalin® LA) in children or adults, peak plasma concentrations of the drug are attained at 2 hours and again at 5.5-6.6 hours after a dose.129 The relative bioavailability of Ritalin® LA extended-release capsules administered once daily is comparable to that of the conventional tablets administered twice daily 4 hours apart.129 The initial rate of absorption of methylphenidate hydrochloride and the time to first and second peak plasma concentrations were similar following administration of 40 mg of the drug once daily as the extended-release capsules or 20 mg twice daily (given 4 hours apart) as conventional tablets, but greater interindividual variability and a smaller difference between peak and trough plasma concentrations (resulting from a lower second peak concentration and a higher minimum concentration between the 2 peak concentrations) were observed with the extended-release capsules.129 Effects persist for about 6-8 hours after oral administration of Ritalin® LA extended-release capsules.509 In a single-dose study in healthy adults, administration of Ritalin® LA extended-release capsules with a high-fat breakfast delayed the first and second peak plasma concentrations and decreased the second mean peak plasma concentration by 25% compared with administration in the fasting state.129 The bioavailability of the extended-release capsules was not affected by opening the capsules and sprinkling the contents onto applesauce.129 In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that 98% of the drug was released from Ritalin® LA 40-mg extended-release capsules within the first hour at an alcohol concentration of 40%; the manufacturer states that these results are representative for the available strengths of this preparation.129
After oral administration of methylphenidate hydrochloride 20 or 40 mg as methylphenidate hydrochloride CD extended-release capsules (generic equivalents of Metadate® CD) in children, peak plasma concentrations were attained at 1.5 hours and again at 4.5 hours after a dose.125 In children, the mean peak plasma concentration and AUC for methylphenidate were slightly lower following administration of 20 mg of the drug once daily as the extended-release capsules than following administration of 10 mg twice daily as conventional tablets.125 Effects persist for about 6-8 hours after oral administration of methylphenidate hydrochloride CD extended-release capsules.509 Administration of methylphenidate hydrochloride CD extended-release capsules (40-mg dose) with a high-fat meal in adults delayed the first peak plasma concentration by approximately 1 hour and increased the average peak plasma concentration and AUC for methylphenidate by 30 and 17%, respectively.125 The bioavailability was not affected by opening the capsules and sprinkling the contents onto applesauce.125 In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that 84% of the drug was released from methylphenidate hydrochloride CD 60 mg extended-release capsules within the first hour at an alcohol concentration of 40%; the manufacturer states that these results are representative for the available strengths of this preparation.125
Following oral administration of methylphenidate extended-release capsules (Aptensio XR®) in adults, peak plasma methylphenidate concentrations were attained at approximately 2 hours and again at approximately 8 hours after a dose.168 In adults, the relative bioavailability of Aptensio XR® extended-release capsules administered once daily is comparable to that of the conventional tablets administered 3 times daily.168 Effects persist for about 12 hours after oral administration of Aptensio XR® extended-release capsules.168, 509, 510 Administration of Aptensio XR® extended-release capsules with a high-fat meal decreased the second peak plasma concentration, increased the average peak concentration by about 28%, and increased AUC by about 19%; in clinical trials, this formulation of the drug was administered without regard to meals.168 The bioavailability was not affected by opening the capsules and sprinkling the contents onto applesauce.168 In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that 96% of the drug was released from Aptensio XR® 80 mg extended-release capsules within 2 hours at an alcohol concentration of up to 40%.168 The manufacturer states that these results are representative for the available strengths of this preparation.168
Following nighttime (9 p.m.) oral administration of methylphenidate delayed- and extended-release capsules (Jornay PM®) in adults, no more than 5% of the total dose is available within the first 10 hours; a single peak concentration occurs at a median of 14 hours following administration, followed by gradual decline in concentrations throughout the rest of the day.170 The relative bioavailability of the delayed- and extended-release capsules administered once daily is approximately 74% that of an immediate-release formulation administered in 3 divided doses daily.170 Following an initial delay in absorption of approximately 8-10 hours,170, 173, 510 effects persist for approximately 10-12 hours.509, 510 Administration of the delayed- and extended-release capsules at night with a high-fat meal decreased the mean peak concentration by 14% compared with administration in the fasted state and delayed the peak concentration by approximately 2.5 hours, but did not alter the extent of absorption.170 Following administration of the drug at night, a morning meal had no effect on the pharmacokinetics.170 The pharmacokinetic parameters are not affected by opening the capsules and sprinkling the contents onto applesauce.170 In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that 97% of the drug was released from the delayed- and extended-release capsules within 2 hours at an alcohol concentration of 40%; increased release of the drug was not observed at alcohol concentrations of 5-20%.170
Systemic absorption of methylphenidate from transdermal systems (Daytrana®) is a function of both the length of time the system is worn and the size of the system.147 In patients with ADHD, peak plasma concentrations of methylphenidate are achieved about 10 hours after single-dose transdermal application and 8 hours after repeated applications of transdermal systems worn for up to 9 hours.147 Following single-dose transdermal application in children and adolescents, there was an average delay of 2 hours before d -methylphenidate was detectable in the circulation; with repeated administration, low concentrations of the drug were detected earlier after application because of a carry-over effect.147 Application of the transdermal system to inflamed skin results in shorter time to peak plasma concentration (4 hours) and a threefold increase in peak plasma concentration and AUC compared with application to intact skin.147 When heat is applied to the transdermal system after application, time to peak plasma concentration occurs 0.5 hour earlier, and median peak plasma concentration and AUC are twofold and 2.5-fold higher, respectively, than those observed following application without heat.147 Application sites other than the hip can have different absorption characteristics and have not been adequately studied.147 Some data suggest that transdermal absorption of methylphenidate may be increased with repeated administration; on average, steady state is likely to be achieved by approximately day 14 of dosing.147
Methylphenidate is about 10-33% bound to plasma proteins.129 Methylphenidate is metabolized primarily by de-esterification by carboxylesterase 1A1 to form α-phenylpiperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.118, 125, 129, 145, 147, 152 Some data indicate that clearance of methylphenidate increases with increasing weight, suggesting that patients with higher body weight may have lower exposures to total methylphenidate at similar doses.118
Following oral administration of methylphenidate hydrochloride conventional tablets in adults or children, the mean terminal elimination half-life was reported to be 3.5 or 2.5 hours, respectively.129 The mean terminal elimination half-life following oral administration of methylphenidate hydrochloride as an oral solution in adults is similar to that following administration of conventional tablets.145 The mean terminal half-life following oral administration of methylphenidate hydrochloride 20 mg as chewable tablets in adults is 3 hours, which is comparable to that following administration of conventional tablets.152 Following oral administration of methylphenidate hydrochloride conventional (5 mg 3 times daily) or extended-release trilayer core tablets (Concerta®) (18 mg once daily) in adults, the plasma elimination half-life reportedly is 3 or 3.5 hours, respectively.118
Following oral administration of a single 60-mg dose of methylphenidate hydrochloride as an extended-release oral suspension (Quillivant XR®), the mean terminal elimination half-life of d -methylphenidate was 5.6 hours in healthy adults.157 Following oral administration of a single 40-mg dose of extended-release chewable tablets (QuilliChew ER®) in healthy individuals, the mean terminal elimination half-life of methylphenidate was about 5.2 hours.171 Following a single methylphenidate dose of 51.8 mg as extended-release orally disintegrating tablets (Cotempla XR-ODT®) in healthy individuals, the mean terminal elimination half-life of methylphenidate was about 4 hours.172
The mean half-life of methylphenidate following oral administration as Ritalin® LA extended-release capsules was 2.5 hours in children and 3.5 hours in adults.129 Following oral administration of a single 20-mg dose of methylphenidate hydrochloride CD extended-release capsules in adults, the mean terminal half-life of the drug was reported to be 6.8 hours.125 Following oral administration of a single 80-mg dose of methylphenidate hydrochloride as Aptensio XR® extended release-capsules in adults, the half-life was 5 hours.168 Following oral administration of methylphenidate hydrochloride delayed- and extended-release capsules (Jornay PM®) in adults, the apparent half-life of methylphenidate was approximately 5.9 hours.170 Following oral administration of extended-release trilayer and bilayer core tablets of methylphenidate hydrochloride in adults and adolescents, the elimination half-life of methylphenidate was approximately 3.5 hours.118, 553 The mean elimination half-life of methylphenidate following removal of the transdermal system in children and adolescents 6-17 years of age was approximately 4-5 hours for d -methylphenidate and 1.4-2.9 hours for l -methylphenidate.147
Following oral administration of methylphenidate hydrochloride as conventional tablets, 78<97% of the dose is excreted in the urine and 1<3% as metabolites in feces within 48<96 hours.114
Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since <1% of a radiolabeled dose of the drug is excreted in urine as unchanged drug and the major metabolite (ritalinic acid) has little or no pharmacologic activity.114 Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since the main metabolic pathway involves de-esterification by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.114
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Methylphenidate hydrochloride is subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Transdermal System | 10 mg/9 hours (27.5 mg/12.5 cm2) | Daytrana® (C-II) | Noven |
15 mg/9 hours (41.3 mg/18.75 cm2) | Daytrana® (C-II) | Noven | ||
20 mg/9 hours (55 mg/25 cm2) | Daytrana® (C-II) | Noven | ||
30 mg/9 hours (82.5 mg/37.5 cm2) | Daytrana® (C-II) | Noven |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules, delayed- and extended-release (containing coated beads) | 20 mg | Jornay PM® (C-II) | Ironshore |
40 mg | Jornay PM® (C-II) | Ironshore | ||
60 mg | Jornay PM® (C-II) | Ironshore | ||
80 mg | Jornay PM® (C-II) | Ironshore | ||
100 mg | Jornay PM® (C-II) | Ironshore | ||
Capsules, extended-release (containing beads) | 10 mg (beads, extended-release 5 mg with 5 mg immediate-release)* | Methylphenidate Hydrochloride Extended-release Capsules (C-II) | ||
Ritalin® LA (C-II) | Novartis | |||
10 mg (beads, extended-release 6 mg with 4 mg immediate-release)* | Aptensio XR® (C-II) | Rhodes | ||
Methylphenidate Hydrochloride Extended-release Capsules (C-II) | ||||
10 mg (beads, extended-release 7 mg with 3 mg immediate-release)* | Methylphenidate Hydrochloride CD Extended-release Capsules (C-II) | |||
15 mg (beads, extended-release 9 mg with 6 mg immediate-release)* | Aptensio XR® (C-II) | Rhodes | ||
Methylphenidate Hydrochloride Extended-release Capsules (C-II) | ||||
20 mg (beads, extended-release 10 mg with 10 mg immediate-release)* | Methylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
Ritalin® LA (C-II) | Novartis | |||
20 mg (beads, extended-release 12 mg with 8 mg immediate-release)* | Aptensio XR® (C-II) | Rhodes | ||
Methylphenidate Hydrochloride Extended-release Capsules (C-II) | ||||
20 mg (beads, extended-release 14 mg with 6 mg immediate-release)* | Methylphenidate Hydrochloride CD Extended-release Capsules (C-II) | |||
30 mg (beads, extended-release 15 mg with 15 mg immediate-release)* | Methylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
Ritalin® LA (C-II) | Novartis | |||
30 mg (beads, extended-release 18 mg with 12 mg immediate-release)* | Aptensio XR® (C-II) | Rhodes | ||
Methylphenidate Hydrochloride Extended-release Capsules (C-II) | ||||
30 mg (beads, extended-release 21 mg with 9 mg immediate-release)* | Methylphenidate Hydrochloride CD Extended-release Capsules (C-II) | |||
40 mg (beads, extended-release 20 mg with 20 mg immediate-release)* | Methylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
Ritalin® LA (C-II) | Novartis | |||
40 mg (beads, extended-release 24 mg with 16 mg immediate-release)* | Aptensio XR® (C-II) | Rhodes | ||
Methylphenidate Hydrochloride Extended-release Capsules (C-II) | ||||
40 mg (beads, extended-release 28 mg with 12 mg immediate-release)* | Methylphenidate Hydrochloride CD Extended-release Capsules (C-II) | |||
50 mg (beads, extended-release 35 mg with 15 mg immediate-release)* | Methylphenidate Hydrochloride CD Extended-release Capsules (C-II) | |||
60 mg (beads, extended-release 30 mg with 30 mg immediate-release)* | Methylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
60 mg (beads, extended-release 36 mg with 24 mg immediate-release)* | Aptensio XR® (C-II) | Rhodes | ||
Methylphenidate Hydrochloride Extended-release Capsules (C-II) | ||||
60 mg (beads, extended-release 42 mg with 18 mg immediate-release)* | Methylphenidate Hydrochloride CD Extended-release Capsules (C-II) | |||
For suspension, extended-release | 25 mg (extended-release 20 mg with 5 mg immediate-release) per 5 mL | Quillivant XR® (C-II) | Tris | |
Solution | 5 mg/5 mL* | Methylin® (C-II) | Shionogi | |
Methylphenidate Hydrochloride Oral Solution (C-II) | ||||
10 mg/5 mL* | Methylin® (C-II) | Shionogi | ||
Methylphenidate Hydrochloride Oral Solution (C-II) | ||||
Tablets | 5 mg* | Methylphenidate Hydrochloride Tablets (C-II) | ||
Ritalin® Hydrochloride (C-II) | Novartis | |||
10 mg* | Methylphenidate Hydrochloride Tablets (C-II) | |||
Ritalin® Hydrochloride (C-II; scored) | Novartis | |||
20 mg* | Methylphenidate Hydrochloride Tablets (C-II) | |||
Ritalin® Hydrochloride (C-II; scored) | Novartis | |||
Tablets, chewable | 2.5 mg* | Methylphenidate Hydrochloride Chewable Tablets (C-II) | ||
5 mg* | Methylphenidate Hydrochloride Chewable Tablets (C-II) | |||
10 mg* | Methylphenidate Hydrochloride Chewable Tablets (C-II) | |||
Tablets, extended-release | 10 mg* | Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||
20 mg* | Methylphenidate Hydrochloride Extended-release Tablets (C-II) | |||
Tablets, extended-release, chewable | 20 mg (extended-release 14 mg with 6 mg immediate-release) | QuilliChew ER® (C-II; scored) | Pfizer | |
30 mg (extended-release 21 mg with 9 mg immediate-release) | QuilliChew ER® (C-II; scored) | Pfizer | ||
40 mg (extended-release 28 mg with 12 mg immediate-release) | QuilliChew ER® (C-II) | Pfizer | ||
Tablets, extended-release core | 18 mg (core 14 mg with 4 mg immediate-release)* | Concerta® (C-II) | Janssen | |
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
18 mg (core 15 mg with 3 mg immediate-release)* | Relexxii® (C-II) | |||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
27 mg (core 21 mg with 6 mg immediate-release)* | Concerta® (C-II) | Janssen | ||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
27 mg (core 22 mg with 5 mg immediate-release)* | Relexxii® (C-II) | |||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
36 mg (core 28 mg with 8 mg immediate-release)* | Concerta® (C-II) | Janssen | ||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
36 mg (core 29.5 mg with 6.5 mg immediate-release)* | Relexxii® (C-II) | |||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
45 mg (core 37 mg with 8 mg immediate-release)* | Relexxii® (C-II) | |||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
54 mg (core 42 mg with 12 mg immediate-release)* | Concerta® (C-II) | Janssen | ||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
54 mg (core 44 mg with 10 mg immediate-release)* | Relexxii® (C-II) | |||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
63 mg (core 52 mg with 11 mg immediate-release)* | Relexxii® (C-II) | |||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
72 mg (core 59 mg with 13 mg immediate-release)* | Relexxii® (C-II) | |||
Methylphenidate Hydrochloride Extended-release Tablets (C-II) | ||||
Tablets, extended-release, orally disintegrating | 8.6 mg (of methylphenidate [approximately 6.4 mg extended-release with 2.2 mg immediate-release]) (equivalent to 10 mg methylphenidate hydrochloride) | Cotempla XR-ODT® (C-II) | Neos | |
17.3 mg (of methylphenidate [approximately 13 mg extended-release with 4.3 mg immediate-release]) (equivalent to 20 mg methylphenidate hydrochloride) | Cotempla XR-ODT® (C-II) | Neos | ||
25.9 mg (of methylphenidate [approximately 19.4 mg extended-release with 6.5 mg immediate-release]) (equivalent to 30 mg methylphenidate hydrochloride) | Cotempla XR-ODT® (C-II) | Neos |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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