VA Class:CN802

AHFS Class:

• Respiratory and CNS Stimulants 28:20.32

Generic Name(s):

• Methylphenidate Hydrochloride

Methylphenidate is a piperidine-derivative CNS stimulant that has pharmacologic actions that are qualitatively similar to those of amphetamines.

Methylphenidate is used in the treatment of attention deficit hyperactivity disorder (ADHD).101,102,103,107,114,115,116,117,118,125,129,132,145,147,152,157,158,168 Methylphenidate also is used in the symptomatic treatment of narcolepsy.

Attention Deficit Hyperactivity Disorder

Methylphenidate is used in the treatment of ADHD in children 6 years of age and older, adolescents, and adults.101,102,103,107,114,115,116,117,118,125,129,132,145,147,152,157,158,168 Multimodal, multidisciplinary treatment approaches that may include pharmacotherapy, behavioral treatment, and psychological, educational, social, and other measures are recommended in the treatment of ADHD.500,504,506 Most evidence and experience on the treatment of ADHD has been in adolescents and children 6 years of age and older.101,132,512

Diagnostic Considerations

ADHD is one of the most commonly diagnosed neurobehavioral disorders of childhood,101,115,500 generally estimated as occurring in about 3-5% of children,100,504,506 although wider ranges of prevalence have been reported.101,102,103,500 ADHD has been reported more frequently in boys than in girls (ratio of about 2:1),100 possibly because hyperactive behaviors, which are more easily observed and potentially disruptive, occur more frequently in boys.102,500,506

The diagnosis of ADHD should be made using well-tested diagnostic interview methods.100,101,102,103,506,511 To help ensure an accurate diagnosis and decrease the variation in how the diagnosis is made, clinicians should employ Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria in the context of their clinical assessment to diagnose ADHD.500,506 According to DSM-5 criteria, there are 3 presentations of ADHD: predominantly inattentive, predominantly hyperactive-impulsive, and combined inattentive and hyperactive-impulsive.100 The DSM-5 diagnostic criteria for ADHD require individuals to exhibit symptoms in more than one setting (e.g., social, home, academic, occupational) and to experience the onset of symptoms before the age of 12 years.100,500,506 The criteria define ADHD in pediatric patients younger than 17 years of age as the presence of 6 or more symptoms in either the inattention or hyperactivity-impulsivity domain, or, for the combined presentation, in both domains.100 In older adolescents and adults, only 5 symptoms are required.100 Patients who previously have met full DSM-5 criteria for ADHD but subsequently meet fewer than the full criteria for a period of 6 months but still have symptoms resulting in impairment in social, academic, or occupational functioning are considered to be in partial remission.100

In pediatric patients, information is obtained mainly from parents or guardians, teachers, other school personnel, and mental health clinicians caring for the child or adolescent.500 Confirmation of ADHD in previously undiagnosed adults may present challenges such as difficulty in obtaining a longitudinal history, poor insight and underestimation by the adult patient of the severity of symptoms and resulting impairment, development of adaptive or compensatory skills, and differentiation of ADHD from other psychiatric conditions.100,132,141,142,506 Evaluations should include screening for common comorbid conditions, such as oppositional defiant disorder, conduct disorder, mood disorders, anxiety disorders, antisocial and other personality disorders, substance use disorder, autism spectrum disorder, obsessive-compulsive disorder, learning and language disorders, tic disorders, and sleep apnea.100,500,506,513,514

ADHD is characterized by developmentally inappropriate symptoms (e.g., wandering off task; lack of persistence; difficulty in sustaining focus; disorganization; excessive motor activity, fidgeting, or talkativeness; social intrusiveness; engaging in hasty actions with a high potential for harm; making important decisions without regard to long-term consequences) that negatively affect social and academic or occupational activities.100,101,102,103,114,115,116,145 The essential feature of ADHD is a persistent pattern of inattention and/or hyperactivity/impulsivity that is more frequent and severe than is observed in individuals with a comparable developmental level.100,103 During preschool, the main manifestation is hyperactivity; inattention becomes more evident during elementary school.100 Symptoms of motor hyperactivity often become less pronounced during adolescence and adulthood, but restlessness, inattention, poor planning, emotional dysregulation, and impulsivity may persist.100,500,506 Physical symptoms of hyperactivity in children may be replaced in adults with fidgetiness or an inner feeling of restlessness, difficulty relaxing, and a feeling of being chronically “on edge”.100,141,506

ADHD represents a major public health problem with profound impact on individuals, families, schools, and society.504,506,513 In most patients, at least some symptoms of ADHD persist from childhood into adulthood, resulting in continued impairment in social, academic, and occupational functioning.100,500,506 Thus, many experts consider ADHD to be a chronic condition.500,504,506,511 ADHD is estimated to occur in about 2.5% of adults.100,504,506,513 Patients with ADHD may exhibit pronounced difficulties and impairment resulting from the disorder across their lifespan; interpersonal relationships, academic and occupational performance, and financial status may be adversely affected, and individuals with ADHD may experience higher rates of substance use and other psychiatric disorders, accidents, injuries, incarceration, premature death, and other adverse consequences of risk-taking behaviors as compared with individuals without ADHD.100,506,513,517

Therapeutic Considerations

Considerations in Choosing a Therapy

Multimodal, age-appropriate, multidisciplinary treatment approaches that may include pharmacotherapy, behavioral treatment, and psychological, educational, social, and other measures are recommended in the treatment of ADHD.500,504,506 The choice of therapeutic intervention(s) for ADHD will depend on the patient's age, comorbid conditions, specific target symptoms, and the strengths and weaknesses of the patient, family, school, and community.500,504 Establishment of treatment goals for children with ADHD should be a collaborative effort involving parents, school personnel, and patients.500 In adults with ADHD, the treatment plan ideally should include the adult's partner, family, or close relationships.506 Low adherence rates may undermine the effectiveness of ADHD treatments.504,510,513

A wide variety of treatments have been employed for the management of ADHD, including drug therapy with stimulants (e.g., amphetamines, methylphenidate, dexmethylphenidate), psychotropic drugs (e.g., antidepressants), and other drugs (e.g., atomoxetine, clonidine, guanfacine, viloxazine); psychosocial treatment (e.g., behavioral or cognitive behavioral therapy, training interventions); and other measures.101,102,103,105,106,107,115,116,500,505,506,511,516 Drug therapy, particularly stimulant therapy, and psychosocial interventions have been the focus of most research to date.101,102,103,107,115,116 Most randomized trials have been of short duration (usually not exceeding 3 months),101,115 although the Multimodal Treatment Study of Children with ADHD (MTA) was a large, multicenter study with a treatment duration of 14 months and longitudinal follow-up over many years.115,116,515 Current evidence from these studies supports the short-term efficacy of stimulants and psychosocial treatment.101,103,107,115,116

Most studies comparing behavioral therapy versus stimulants for treatment of ADHD in children have shown a stronger immediate effect on core ADHD symptoms from stimulants, but the children's parents have been more satisfied with the effect of behavioral therapy, which addresses symptoms and functions in addition to the core ADHD symptoms.500 The beneficial effects of behavioral therapies tend to persist, whereas effects of drug therapy cease when the drug is discontinued.500 Optimal care is more likely to occur when both therapies are used.500,504,515

The American Academy of Pediatrics (AAP) states that pharmacologic therapy is not appropriate for children whose symptoms do not meet DSM-5 criteria for ADHD.500

In adults with ADHD, treatment may include psychoeducation, pharmacologic therapy, cognitive behavior therapy, and coaching.506

The clinical utility of pharmacogenomic tools or other pharmacoepidemiologic approaches for tailoring drug therapy in individual patients (e.g., for selecting drug or dosage) has not been established, and pharmacogenomic testing currently is not recommended.500,505

Stimulants

Stimulants (e.g., methylphenidate, dexmethylphenidate, amphetamines) remain the most effective and most commonly used first-line drugs for the management of ADHD in pediatric patients and adults.101,102,103,105,106,107,110,115,116,122,504,510,511,518 Meta-analyses of clinical trial data indicate that methylphenidate and amphetamines are associated with moderate to large improvements in ADHD symptoms in children and adolescents and moderate improvements in adults.504,517 A meta-analysis evaluating the comparative efficacy and tolerability of pharmacologic therapies for ADHD, based on short-term (approximately 12 weeks) outcome data from 133 randomized, controlled, double-blind studies, suggested that methylphenidate might be preferred for initial therapy in children and adolescents and amphetamines might be preferred in adults based on the totality of outcome measures analyzed in the meta-analysis (i.e., change in severity of core ADHD symptoms, global clinical functioning, effects on weight and blood pressure, study drop-out rates due to adverse effects or for any reason).523 However, an individual's response to methylphenidate versus amphetamines is idiosyncratic, with approximately 40% of individuals responding equally well to methylphenidate or amphetamines and approximately 40% responding preferentially to one stimulant versus the other.500,505,510 The subtype (presentation) of ADHD does not appear to be a predictor of response to a specific drug.500

Short-term and longer-term (up to 14 months' duration) studies have shown unequivocal beneficial effects of the stimulants on the defining core symptoms of ADHD (attention and concentration, activity, distractability, impulsivity) and associated aggressiveness during continued therapy with the drugs.101,103,107,115,116,500,504,506,517 Other data suggest promising effects of stimulants on certain functional outcomes (e.g., occurrence of criminal behavior, accidents, and injuries), but additional study of the effects of treatment on long-term functioning is needed.504,517,518 The acute response rate for stimulant therapy in ADHD is about 70%, but can increase to approximately 90% with sequential trials of different stimulants and stimulant formulations if therapy is managed and titrated carefully.103,115,500,510,511,518 Patients who fail to show positive therapeutic effects or who experience intolerable adverse effects with one stimulant should be tried on an alternative stimulant before concluding that stimulant therapy is unsuccessful.510

Although the abuse potential of CNS stimulants such as amphetamines and methylphenidate is well established,101,103,107 some evidence, including findings of registry and longitudinal studies and meta-analyses, indicates that stimulant use does not lead to an increased risk of substance abuse, and effective stimulant therapy for ADHD actually may reduce the risk for subsequent substance use disorders.133,134,504,513,525,526,527 However, there is evidence that diversion of stimulants for nonmedical uses has increased in recent decades, and is a particular concern among adolescents and young adults seeking enhanced academic or work performance.500,506,528 Most of the data to date on diversion for nonmedical use involves college students.528 Clinicians must remain alert to the potential for abuse or diversion.526 Care must be taken to ensure that individuals are diagnosed and treated for ADHD when appropriate while limiting the risk of diversion and misuse.500,506,513,528 (See Therapeutic Considerations for Patients with Comorbid Conditions under Uses.)

Nonstimulants

Selective norepinephrine-reuptake inhibitors (e.g., atomoxetine, viloxazine) and central α₂-adrenergic agonists (e.g., clonidine, guanfacine) have been shown to be effective in reducing core symptoms of ADHD;500,516 however, experience with such drug therapy is less extensive than that with stimulants, and meta-analyses suggest that the effect size of nonstimulants may be smaller than that of stimulants.500,504,522,523,524 Therefore, some clinicians prefer to reserve these drugs for second-line therapy (after stimulants).504 These drugs also may have a role in patients with certain comorbid disorders.506,511 (See Therapeutic Considerations for Patients with Comorbid Conditions under Uses.) In addition, use of these nonstimulant drugs as adjuncts to stimulants may be considered if stimulant therapy is not fully effective or is limited by adverse effects.500,504,511

Antidepressants (e.g., bupropion, venlafaxine, tricyclic antidepressants [mainly desipramine]) also have shown some benefit in improving symptoms of ADHD, although evidence of their efficacy generally is limited.506,513,518,519,520,521 Some clinicians state that bupropion may be an alternative for patients who are unresponsive or intolerant to, or are unwilling to take, other therapies (e.g., stimulants) and may have a role in patients with certain comorbid conditions.506,511,519 (See Therapeutic Considerations for Patients with Comorbid Conditions under Uses.) Tricyclic antidepressants are associated with a narrower margin of safety.122 In addition, although a causal relationship has not been established, several cases of sudden death in children receiving desipramine have raised concerns about the use of this tricyclic antidepressant.107,111,112,113,122,520 (See Cautions: Pediatric Precautions, in Desipramine 28:16.04.28.) Therefore, some experts no longer recommend use of desipramine for the treatment of ADHD in children.122,529

Therapeutic Considerations for Patients with Comorbid Conditions

Many patients with ADHD, including up to 80% of adults with ADHD, may have at least one coexisting psychiatric disorder.506,513,514 The effect of comorbid conditions on ADHD treatment is variable.500 In some cases, treatment of ADHD may alleviate the comorbid condition; in other cases, the comorbid condition may require treatment in addition to the ADHD treatment.500,513 In general, the condition that is most severe, destabilizing, or causing the greatest functional impairment should be treated first, with other conditions or remaining symptoms subsequently treated in a step-wise manner once the patient's condition has been stabilized.513 Stabilization of bipolar disorder or substance use disorders generally is necessary before effective treatment of ADHD can be achieved.513

Nonstimulant drug therapies may be used alone or in combination with stimulants in patients with ADHD and comorbid conditions (e.g., aggression, anxiety, depression, tic disorders).107,122,511,513 Although current evidence indicates that stimulants do not worsen tics in most patients with comorbid tic disorders, some patients receiving stimulants may experience worsening of tics, and central α₂-adrenergic agonists (e.g., clonidine, guanfacine) or atomoxetine may be alternative treatment options for those patients.505,511,529 Although there is a risk that stimulants may precipitate manic episodes in patients with comorbid bipolar disorder, the risk may be reduced if a mood stabilizing agent is initiated prior to the stimulant.506,511,513 When substance abuse is a concern, immediate-release formulations of stimulants should be avoided and drugs with a lower abuse potential (e.g., central α₂-adrenergic agonists, atomoxetine, bupropion) may be considered;500,506,513,518,528 alternatively, since some evidence indicates reduced substance use during periods of ADHD stimulant therapy, if stimulants are required for their potentially greater and more rapid onset of effect, stimulant formulations that are less readily abused (e.g., extended-release formulations, the prodrug lisdexamphetamine) may be considered.506,511,513,527,528

Preschool-aged Children

AAP states that methylphenidate therapy 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 If evidence-based behavioral treatments are not available, the risks of initiating medication before the age of 6 years must be weighed against the harm of delaying treatment.500 Available data suggest that methylphenidate may be slightly less effective and less well tolerated in preschool-aged children than in school-aged children;512 preschool-aged children may experience increased mood lability and dysphoria with stimulant therapy.500 (See Pediatric Precautions under Cautions.) Although some amphetamine preparations are FDA-labeled for use in children younger than 6 years of age, this authorization was issued at a time when approval criteria were less stringent than current requirements,500,512 and AAP states that nonstimulants and stimulants other than methylphenidate have not been adequately studied in this age group.500

Elementary and Middle School-aged Children

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

Adolescents

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

Adults

Some clinicians recommend long-acting stimulants as first-line pharmacologic therapy for adult ADHD, with long-acting nonstimulants (e.g., atomoxetine) and short- or intermediate-acting stimulants used as second-line or adjunctive therapy.505,518 Nonpharmacologic therapies (e.g., cognitive behavioral therapy, psychoeducation) also play an essential role in treatment.506,513,518 Because of the high frequency of comorbid disorders in adults with ADHD, potential effects on comorbid psychiatric symptoms are an important consideration.506,513 Clinical trials of drug therapies for adult ADHD have mainly included young and middle-aged adults.518

Narcolepsy

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

Administration

Methylphenidate hydrochloride is administered orally.114,118,125,129,145,157,158,168,169,170,171,172 Methylphenidate is administered percutaneously by topical application of a transdermal system.147

Oral Administration

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 To avoid insomnia, the last daily dose of immediate-release preparations should be given several hours before retiring. 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 (See Precautions and Contraindications Associated with Specific Methylphenidate Formulations under Cautions.)

Extended-release Tablets

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

Extended-release Trilayer Core Tablets

Methylphenidate hydrochloride extended-release trilayer core tablets (e.g., Concerta^®; generics) are administered once daily in the morning without regard to meals.118 The tablets should be swallowed intact and should not be crushed or chewed.118 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 The manufacturer states that it is possible that the extended-release trilayer core tablets may be visible on abdominal radiographs under certain circumstances, particularly when digital enhancing techniques are utilized.118

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

Extended-release Oral Suspension

Methylphenidate hydrochloride extended-release oral suspension (Quillivant XR^®) is administered once daily in the morning without regard to meals.157

This formulation of methylphenidate hydrochloride is commercially available as a powder for extended-release oral suspension 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.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

Extended-release Capsules

Methylphenidate hydrochloride extended-release capsules (Adhansia XR^®, Aptensio XR^®, Ritalin^® LA; generics, including equivalents of Metadate^® CD [methylphenidate hydrochloride CD]) are administered once daily in the morning.125,129,168,169 The manufacturers state that methylphenidate hydrochloride CD extended-release capsules should be administered before breakfast125 and that Adhansia XR^® and Aptensio XR^® extended-release capsules may be administered without regard to meals, although Aptensio XR^® should be administered in a consistent manner relative to food intake.168,169 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.125,129,168,169 The contents of Adhansia XR^® capsules also may be sprinkled on a tablespoonful of yogurt.169 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 (or within 10 minutes for Adhansia XR^®) and must not be stored for use at a later time.125,129,168,169 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.125,129,168,169

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.125,129,168,169 (See Absorption under Pharmacokinetics.)

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.168,169

Delayed- and Extended-release Capsules

Methylphenidate hydrochloride delayed- and extended-release capsules (Jornay PM^®) 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

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 more than 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 stored for later use.170

Transdermal Administration

Patients receiving transdermal methylphenidate 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

Dosage

Dosage of methylphenidate hydrochloride must be carefully adjusted according to individual requirements and response. Prior to initiation of therapy, pediatric patients and adults should be evaluated for the presence of cardiac disease through careful medical history, physical examination, and screening for family history of sudden death or ventricular arrhythmias.114 In addition, patients should be evaluated for risk of abuse prior to initiation of therapy and monitored for signs of abuse and dependence during therapy.114

Dosage of oral formulations of methylphenidate hydrochloride generally is expressed in terms of the salt;114,118,125,129,145,157,158,168,169,170,171 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

Attention Deficit Hyperactivity Disorder

Methylphenidate hydrochloride dosage for the treatment of 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.114,169 If paradoxical aggravation of symptoms or other adverse reactions occur, dosage should be reduced or, if necessary, the drug should be discontinued.114,169

While extended-release formulations are more commonly used in the treatment of ADHD,510,518 therapy may be initiated in some patients with an immediate-release formulation to assess tolerability of the drug and determine approximate dosage requirements.510 In addition, some patients receiving intermediate- or long-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.137,500,510 Extended-release oral formulations may contain both immediate-release and extended-release methylphenidate in various proportions, generally ranging from 20% immediate-release and 80% extended-release drug to equal proportions of each in various delivery systems.125,129,157,168,169,171,172 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 (See Pharmacokinetics and also see Chemistry under Chemistry and Stability.)

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 For children or adolescents whose symptoms are not severe outside the school setting, planned breaks in drug treatment (i.e., drug holidays) may be attempted to assess continuing efficacy and need for such therapy, as well as to minimize adverse effects.501,502,503,504,505

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 and older is 5 mg before breakfast and lunch. Dosage may be increased by 5-10 mg daily at weekly intervals and can be administered in twice- or thrice-daily regimens. Although some clinicians have recommended weight-based dosing in children, variations in methylphenidate dosage have not been found to be related to weight.500 The duration of action of immediate-release formulations is approximately 3-4 hours.509,510

Oral dosage in children generally ranges from 5-20 mg 2 or 3 times daily and should not exceed 60 mg daily. Some clinicians have employed a regimen that included systematic intensive monitoring (referred to as “medical management”) in the treatment of ADHD, and such a regimen was shown to be more effective than less intensively titrated and monitored regimens (referred to as “community management”).115,116,117 In the medical management regimen, methylphenidate dosage was titrated over a 28-day period via daily-switch titration involving 5 randomly ordered repeats each of placebo and 5-, 10-, 15-, or 20-mg (higher for children weighing more than 25 kg) daily dosages; each dose was repeated at breakfast and lunch, with a half dose (rounded to nearest 5 mg) given in the afternoon.115 Based on clinical assessment of response, a best dose was chosen for initial maintenance.115 In addition to the systematic dosage titration, patients underwent 30-minute monthly drug therapy assessment visits during maintenance.115 Pharmacotherapists could increase or decrease therapy during such visits by 10 mg daily.115 In general, patients received higher than typical dosages of the drug when this titration and monitoring method was employed.115 Dosage at the end of a 14-month study period averaged 37.7 mg daily administered in 3 unequally divided doses daily as noted above.115,126

The usual adult dosage of methylphenidate hydrochloride as conventional preparations is 20-30 mg administered in 2 or 3 divided doses daily; 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.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 and pediatric patients 6 years of age and older 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 In some patients, supplemental doses of a short-acting (conventional) preparation may be needed.137 The usual dosage of methylphenidate hydrochloride administered as an intermediate-acting oral preparation is 20-40 mg once daily or 40 mg in the morning and 20 mg in the early afternoon.

Extended-release Chewable Tablets (QuilliChew ER®)

The recommended initial dosage of methylphenidate hydrochloride as QuilliChew ER^® extended-release chewable tablets in adults and pediatric patients 6 years of age and older 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 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 (See Chemistry under Chemistry and Stability and also see Absorption under Pharmacokinetics.) 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 Core Tablets (Concerta®; Generics)

The usual initial dosage of methylphenidate hydrochloride as extended-release trilayer core tablets (Concerta^®; generics) in children and adolescents 6-17 years of age is 18 mg once daily in the morning; adults 18-65 years of age may receive an initial dosage of 18 or 36 mg once daily in the morning.118 The duration of action of this preparation is approximately 10-12 hours.118,509 If adequate response does not occur, dosage may be increased at weekly intervals in increments of 18 mg daily.118 The maximum dosage recommended by the manufacturer is 54 mg daily for children 6-12 years of age, 72 mg daily (not to exceed 2 mg/kg daily) for adolescents 13-17 years of age, and 72 mg daily for adults.118

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 core tablets.118 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 core tablets.118 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 core tablets.118 The initial dosage of methylphenidate hydrochloride as extended-release trilayer core tablets in patients being switched from conventional tablets should not exceed 72 mg daily.118 A 27-mg extended-release trilayer core tablet also is available for patients who require a dosage in between 18 mg daily and 36 mg daily.118 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, 72 mg daily (not to exceed 2 mg/kg daily) in adolescents, and 72 mg daily in adults are not recommended.118

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 in children 6 years of age and older 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.157,509,510

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 (See Chemistry under Chemistry and Stability and also see Absorption under Pharmacokinetics.) 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 (See Chemistry under Chemistry and Stability and also see Absorption under Pharmacokinetics.) 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 and older 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.125 Some clinicians state that the duration of action of this formulation is approximately 6-8 hours.509

Some clinicians state that patients currently receiving methylphenidate hydrochloride conventional tablets may be switched to the CD extended-release capsules.126 Patients being transferred from methylphenidate hydrochloride therapy using conventional tablets at a dosage of 10 mg twice daily can be switched to a dosage of 20 mg every morning as the CD extended-release capsules.126 Patients receiving methylphenidate hydrochloride therapy using conventional tablets at a dosage of 20 mg twice daily can be switched to a dosage of 40 mg every morning as the CD extended-release capsules.

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 and older 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

Extended-release Capsules (Adhansia XR® )

The recommended initial dosage of methylphenidate hydrochloride as Adhansia XR^® extended-release capsules in adults and pediatric patients 6 years of age and older is 25 mg once daily in the morning.169 Dosage may be adjusted in increments of 10-15 mg daily at intervals of 5 days or longer.169 Dosages exceeding 100 mg daily in adults and 85 mg daily in pediatric patients have not been evaluated in clinical trials and are not recommended.169 Although efficacy was demonstrated in short-term controlled trials at dosages of 100 mg daily in adults and 70 mg daily in pediatric patients, dosages exceeding 85 mg daily in adults and dosages of 70 mg or more daily in pediatric patients were associated with a disproportionate increase in the incidence of certain adverse effects.169 Dosage adjustments should be individualized based on assessment of clinical benefit and tolerability with careful consideration of dose-related adverse effects.169 Clinical studies suggest that this formulation may have a duration of effect of approximately 13-16 hours.169,509,510

Adhansia XR^® 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.169 (See Chemistry under Chemistry and Stability and also see Absorption under Pharmacokinetics.) Patients being transferred from therapy with other methylphenidate formulations to therapy with this extended-release capsule formulation should receive the same initial dosage of Adhansia XR^® extended-release capsules and follow the same dosage titration schedule recommended for patients receiving this extended-release capsule formulation as their initial methylphenidate regimen.169

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 (see Delayed- and Extended-release Capsules under Dosage and Administration).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 (See Chemistry under Chemistry and Stability and also see Absorption under Pharmacokinetics.) 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

The recommended initial dosage of methylphenidate in patients who are receiving the transdermal formulation as their initial methylphenidate 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

Because differences in bioavailability exist between the methylphenidate transdermal system and other methylphenidate formulations, patients being transferred from therapy with other methylphenidate formulations to transdermal therapy with the drug should receive the same initial transdermal dosage and follow the same dosage titration schedule recommended for patients receiving transdermal methylphenidate as their initial methylphenidate regimen.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

Narcolepsy

In the treatment of narcolepsy, the usual oral adult dosage of methylphenidate hydrochloride is 10 mg 2 or 3 times daily, given 30-45 minutes before meals. Some patients may require 40-60 mg daily; in others, 10-15 mg daily may be adequate.

Methylphenidate generally is well tolerated.114,118,125,129 Common adverse effects of the drug include nervous system (insomnia, delayed sleep onset, headache, nervousness, anxiety, restlessness, affect lability, agitation, irritability, dizziness), cardiovascular (increased blood pressure, increased heart rate, tachycardia, palpitations), GI (decreased appetite/anorexia, nausea, abdominal pain, dyspepsia, vomiting), and other (weight loss, hyperhidrosis) effects.114,118,125,126,129,147,157,158,168

In controlled studies in children and adolescents, adverse effects requiring discontinuance of therapy occurred in 0.6% of patients receiving extended-release trilayer core tablets and 1.9% of patients receiving placebo; the reasons for discontinuance of methylphenidate included depressed mood in one patient and headache and insomnia in another patient.118 In controlled studies in adults, adverse effects requiring discontinuance of therapy occurred in 6% of patients receiving extended-release trilayer core tablets and 3% of patients receiving placebo; the principal reasons for discontinuance of methylphenidate were anxiety, irritability, increased blood pressure, and nervousness (each occurring in 0.7-1.7% of patients).118 In open-label studies in children, adolescents, and adults, adverse effects requiring discontinuance of therapy occurred in 7% of patients receiving extended-release trilayer core tablets; the principal reasons for drug discontinuance were insomnia, irritability, anxiety, decreased appetite, and tics (each occurring in 0.6-1.2% of patients).118

Discontinuance of methylphenidate therapy also occurred in 2 patients (1%) receiving methylphenidate hydrochloride CD extended-release capsules in controlled clinical trials, principally because of rash and pruritus in one patient and headache, abdominal pain, and dizziness in the other patient.125 In addition, discontinuance of methylphenidate therapy because of depression occurred in a child with ADHD (1.5%) receiving Ritalin^® LA extended-release capsules in a double-blind controlled clinical trial.129 Discontinuance also occurred in 6 patients (3.7%) receiving the drug in this trial during the initial single-blind titration period; the reasons for discontinuance were anger (2 patients), hypomania, anxiety, depressed mood, fatigue, migraine, and lethargy.129 Discontinuance of methylphenidate therapy also occurred in 2 patients (4.4%) receiving Aptensio XR^® extended-release capsules in controlled clinical trials; the reasons for discontinuance were insomnia in one patient and nausea and rapid heart rate in the other patient.168

In a 7-week controlled trial in children, adverse effects requiring discontinuance of therapy occurred in 7.1% of patients receiving transdermal methylphenidate and 1.2% of those receiving placebo; the most common reasons for discontinuance of transdermal methylphenidate therapy included application site reactions, headache, irritability, and tics.147 In a 7-week controlled trial in adolescents, adverse effects requiring discontinuance of therapy occurred in 5.5% of patients receiving transdermal methylphenidate and 2.8% of those receiving placebo; the most common reasons for discontinuance of transdermal methylphenidate therapy included application site reactions and decreased appetite/anorexia.147

Loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently in children than in adults receiving methylphenidate.114,118,125,129,145,152

Nervous System Effects

Nervousness and insomnia are among the most frequent adverse effects of methylphenidate and appear to be dose related.114,118,125,129,145,152,158 Insomnia has been reported in 3% of children and adolescents with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets, in 5% of children with ADHD receiving methylphenidate hydrochloride CD extended-release capsules, in 10% of children and adolescents with ADHD receiving Aptensio XR^® extended-release capsules, in about 3% of children with ADHD receiving Ritalin^® LA extended-release capsules, and in 13% of children and 6% of adolescents with ADHD receiving the drug as a transdermal system in clinical trials.118,125,129,147,168 Headache has been reported in 12% of children or adolescents with ADHD receiving methylphenidate hydrochloride extended-release capsules and 12-15% of children and adolescents receiving transdermal methylphenidate in clinical trials.125,147,168 Irritability has been reported in 7% of children and 11% of adolescents with ADHD receiving transdermal methylphenidate in clinical trials.147 Affect lability has been reported in 9% of children with ADHD receiving methylphenidate hydrochloride extended-release oral suspension in clinical trials.157 Affect lability (including emotionality and emotional sensitivity, instability, and lability) also has been reported in 6% of children with ADHD receiving methylphenidate as a transdermal system in clinical trials.147 Dizziness was reported in 2% of children and adolescents with ADHD receiving extended-release trilayer core tablets or Aptensio XR^® extended-release capsules and in 6% of adolescents receiving transdermal methylphenidate in clinical trials.118,147,168

In 2 uncontrolled studies, the cumulative incidence of new-onset tics in children receiving methylphenidate hydrochloride extended-release trilayer core tablets was reported to be 9% after 27 months of treatment (first study) and 1% after up to 9 months of treatment (second study).118 Tics were reported in 7% of children with ADHD receiving methylphenidate as a transdermal system in clinical trials.147 Tics and initial insomnia each were reported in 2% of children receiving methylphenidate hydrochloride extended-release oral suspension in clinical trials.157 There is a high frequency of comorbidity of chronic tic disorders and ADHD, and for many decades there was concern that use of stimulants to treat symptoms of ADHD in children with comorbid tic disorders would exacerbate tics.529 While most manufacturers previously warned against the use of methylphenidate in patients with motor tics or with a family history or personal diagnosis of Tourette's syndrome,118,529 newer evidence suggests that stimulant therapy generally is not associated with new onset or worsening of tics, although exacerbation of tics may occur in some individuals.529

Headache and insomnia were reported in 22 and 12%, respectively, and anxiety, dizziness, and irritability each were reported in 6-8% of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118 Other adverse nervous system effects reported in clinical trials in adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets included initial insomnia, depressed mood, nervousness, restlessness, and tremor (each occurring in approximately 3-4% of patients) and agitation, aggression, depression, affect lability, confusional state, tension, vertigo, paresthesia, sedation, and tension headache (each occurring in approximately 1-2% of patients).118

Toxic psychosis and Tourette's syndrome have been reported rarely in patients receiving methylphenidate.125,145,152 Neuroleptic malignant syndrome (NMS) also has been reported rarely in patients receiving methylphenidate; most of these patients also were receiving other drugs that have been associated with NMS.118,125,145,147,152

Other adverse nervous system effects reported in patients receiving methylphenidate include dyskinesia, drowsiness, psychomotor hyperactivity, lethargy, asthenia, fatigue, sleep disorder, somnolence, anger, hypervigilance, mood swings, panic attack, tearfulness, and aggressive behavior.118,158 Depression, anxiety, abnormal behavior, disorientation, hallucinations, mania, logorrhea, irritability, migraine, obsessive-compulsive disorder, suicidal behavior (including completed suicide), and seizures have been reported in patients receiving methylphenidate, but a causal relationship to the drug has not been definitely established.118,125,147,157,158,168

GI and Growth Effects

Abdominal pain and anorexia have been reported in 7 and 9%, respectively, of children with ADHD receiving methylphenidate hydrochloride CD extended-release capsules in clinical trials. 125 Anorexia also has been reported in about 3% of children with ADHD receiving Ritalin^® LA extended-release capsules and in 5% of children with ADHD receiving methylphenidate as a transdermal system in controlled clinical trials.129,147 Decreased appetite has been reported in 5% of children and adolescents receiving Aptensio XR^® extended-release capsules and in 2% of children receiving methylphenidate hydrochloride extended-release oral suspension in clinical trials.157,168 Upper abdominal pain has been reported in 8% of children and adolescents with ADHD receiving Aptensio XR^® extended-release capsules and in 6% of children and adolescents with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118,168 Abdominal pain, decreased appetite, and anorexia also have been reported in 5-7, 26, and 5%, respectively, of children and adolescents receiving transdermal methylphenidate in clinical trials.147

Methylphenidate therapy may cause suppression of normal weight gain in children. Results of an analysis of weight and height patterns in children 7-13 years of age who participated in the Multimodal Treatment Study of Children with ADHD (MTA) 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.114,118,147,507 Longer-term follow-up of these patients into early adulthood (average age of 25 years) suggested that consistent extended use of stimulants from childhood through adolescence may be associated with suppression of adult height.508 Therefore, the manufacturers of stimulant preparations state that growth should be 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 If weight loss is a concern, clinicians also suggest that alteration of drug administration and eating patterns (e.g., administration of the stimulant during or after meals rather than before meals, provision of additional meals or snacks when stimulant effects have worn off, provision of high-calorie foods with good nutritional value) or switching to alternative therapy may be considered.505

Vomiting has been reported in 3% of children and adolescents with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118 Nausea and vomiting each have been reported in 4% of children and adolescents with ADHD receiving Aptensio XR^® extended-release capsules.168 Nausea and vomiting also were reported in 12 and 10%, respectively, of children and 10 and 3%, respectively, of adolescents with ADHD receiving methylphenidate as a transdermal system in clinical trials.147 Vomiting also has been reported in 2% of children receiving methylphenidate hydrochloride extended-release oral suspension.157 Other adverse GI effects of methylphenidate include weight loss during prolonged therapy and dryness of the throat. Weight loss has been reported in 9% of children and 6% of adolescents receiving transdermal methylphenidate in clinical trials.147 Thirst, abdominal discomfort, and diarrhea also have been reported in patients receiving methylphenidate.118

Decreased appetite, dry mouth, nausea, and weight loss have been reported in 25, 14, 13, and 7%, respectively, of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets.118 Anorexia, bruxism, constipation, vomiting, and dyspepsia each were reported in 1-2% of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets.118

Hepatic Effects

Abnormal liver function, ranging from serum aminotransferase (transaminase) elevations to severe hepatic injury, has been reported in patients receiving methylphenidate, although a definite causal relationship has not been established.114,118,125,129,145,152

Dermatologic and Sensitivity Reactions

Hypersensitivity reactions including rash, macular rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathologic findings of necrotizing vasculitis, and thrombocytopenic purpura may occur in patients receiving methylphenidate.114,118,125,129,145,147,152,157,158,168 Stevens-Johnson syndrome has been reported rarely. Fixed drug eruption, angioedema, anaphylactic reaction, auricular swelling, bullous conditions, pruritus, eruptions, and exanthemas have been reported in patients receiving methylphenidate, although a definite causal relationship has not been established.118,147,157,158,168 Erythema occurs in a majority of patients receiving methylphenidate as the transdermal system but generally causes minimal or no discomfort.147 Excoriation has been reported in 4% of children receiving methylphenidate hydrochloride extended-release oral suspension.157

In an open-label study evaluating dermatologic reactions to methylphenidate transdermal system (9-hour wear time) in 305 children with ADHD, sensitization to methylphenidate (allergic contact dermatitis) was diagnosed and confirmed by patch testing in 1 child (0.3%).147 Sensitization was manifested by erythema and edema at application sites with concurrent urticarial lesions on the abdomen and legs; treatment with the transdermal system was discontinued and the child was not switched to oral methylphenidate therapy.147 No cases of systemic sensitization have been observed to date in clinical trials of the methylphenidate transdermal system.147 (See Precautions and Contraindications Associated with Specific Methylphenidate Formulations under Cautions.)

Chemical leukoderma (permanent loss of pigmentation due to repeated exposure to specific chemical compounds) has been reported in patients receiving methylphenidate as the transdermal system.147,163 In most cases, depigmentation or hypopigmentation has been limited to application sites.147,163 However, a small number of patients have reported skin color changes on areas of the body where the transdermal system was never applied.147,163 Time to onset of chemical leukoderma following initiation of transdermal methylphenidate therapy has ranged from 2 months to 4 years, and the affected areas have ranged up to 8 inches in diameter.163 Patients with a personal or family history of vitiligo may be at increased risk for chemical leukoderma with transdermal methylphenidate therapy.147 If loss of pigmentation occurs, transdermal methylphenidate should be discontinued and alternative therapy considered.147,163

Other application site reactions, including bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, excoriation, exfoliation, fissure, hyperpigmentation, induration, infection, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth, have been reported in patients receiving transdermal methylphenidate, but a causal relationship to the drug has not been established.147

Hyperhidrosis has been reported in 5% of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118

Alopecia also has been reported in patients receiving methylphenidate, but a causal relationship to the drug has not been established.118,147,157,168

Hematologic Effects

Thrombocytopenia and/or easy bruisability, epistaxis, and gingival bleeding; leukopenia; anemia; pancytopenia; and eosinophilia have been reported rarely in patients receiving methylphenidate, but a causal relationship to the drug has not been definitely established.

Cardiovascular Effects

Sudden death, stroke, myocardial infarction, angina, tachycardia, cardiac arrhythmias, palpitation, and increase or decrease in blood pressure and pulse rate may occur in patients receiving stimulants, including methylphenidate.114,118,125,129,145,147,152,153,154,155,157,158,168 (See Cardiovascular Precautions under Cautions.) Tachycardia and palpitations were reported in 5 and 3%, respectively, of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118 Cerebral arteritis and/or occlusion, cardiac murmur, and hot flush also have been reported in patients receiving methylphenidate.114,118,125,129,145,147,152 Tachycardia was reported in 1% of children and adolescents with ADHD receiving transdermal methylphenidate in clinical trials.147 Cardiac arrest,125 bradycardia,118,157,168 extrasystole,118,157,168 supraventricular tachycardia,118,157,168 ventricular extrasystole,118,157,168 peripheral coldness,125,158 and reversible ischemic neurologic deficit125 have been reported in patients receiving methylphenidate, although a definite causal relationship has not been established.118,125,157,168

Stimulants used to treat ADHD, including methylphenidate, are associated with peripheral vascular disorders, including Raynaud's phenomenon.114,118,125,145,147,152,157,158,168 Manifestations usually are intermittent and mild, but ulceration of the digits and/or breakdown of soft tissue may occur rarely.114,118,125,145,147,152,157,158,168 Peripheral vascular disorders, including Raynaud's phenomenon, have been reported during postmarketing experience in patients in all age groups receiving stimulants at therapeutic dosages and at various times throughout the treatment course.114,118,125,145,147,152,157,158,168 Manifestations generally improve following dosage reduction or drug discontinuance; however, further clinical evaluation (e.g., referral to a rheumatologist) may be appropriate for certain patients.114,118,125,145,147,152,157,158,168

Ocular Effects

Blurred vision has been reported in 2% of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118 Eye pain has been reported in 2% of children receiving methylphenidate hydrochloride extended-release oral suspension in clinical trials.157 Dry eye and difficulty with accommodation also have been reported in patients receiving methylphenidate.118,147 Diplopia,118,157,168 mydriasis,118,147,157,168 and visual disturbances or impairment118,147,157,168 have been reported in patients receiving methylphenidate, although a causal relationship to the drug has not been definitely established.118,147,157,168

Respiratory Effects

Cough, nasopharyngitis, and oropharyngeal pain were each reported in 1-3% of children and adolescents receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118 Upper respiratory infection and oropharyngeal pain were each reported in 2% of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118 Dyspnea and sinusitis also have been reported in patients receiving methylphenidate.118

Other Adverse Effects

Prolonged and painful erections, in some cases requiring surgical intervention, have been reported in adults and pediatric patients receiving methylphenidate.114,118,125,145,147,152,157,158,159,168 Priapism has not been reported with drug initiation but rather has developed after patients have received the drug for some time, often occurring following an increase in dosage.114,118,125,145,147,152,157,158,159,168 Priapism also has occurred during temporary interruptions in therapy (e.g., drug holidays) or following drug discontinuance.114,118,125,145,147,152,157,158,159,168 If not treated immediately, priapism can lead to permanent penile damage.159

Changes in libido114,118,125,145,147,152,157,158,168 and erectile dysfunction118 have been reported in patients receiving methylphenidate. Decreased libido has been reported in approximately 2% of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118

Motion sickness has been reported in 2% of children with ADHD receiving methylphenidate hydrochloride extended-release oral suspension in clinical trials.157 Pyrexia has been reported in 2% of children and adolescents with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118 Muscle tightness has been reported in 2% of adults with ADHD receiving methylphenidate hydrochloride extended-release trilayer core tablets in clinical trials.118

Rhabdomyolysis114,125,145,147,152,157,168 and muscle spasms118 have been reported in patients receiving methylphenidate. Arthralgia,118,157,168 myalgia,118,157,168 muscle twitching,118,157,168 hyperpyrexia,118,157,168 chest pain or discomfort,118,157,168 and scalp hair loss114,125,129,145,147,152 also have been reported, but a causal relationship to the drug has not been definitely established.114,118,125,145,147,152,157,168

Precautions and Contraindications

Abuse and Dependence Precautions

Because CNS stimulants, including methylphenidate, have a high potential for abuse and dependence, the risk of abuse should be assessed prior to initiation of therapy and patients receiving stimulants should be monitored for signs of abuse and dependence.114 In addition, tolerance can develop during long-term CNS stimulant therapy.114 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.114

Clinicians should maintain careful prescription records, educate patients and their families about CNS stimulant abuse and about proper storage and disposal of the drugs, monitor for signs of abuse and overdosage, and periodically reevaluate the need for continued therapy with the drug.114 In addition, clinicians can utilize prescription drug monitoring programs and consider implementing medication contracts and pill counts when appropriate.528 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.114,157,168 The drug should be disposed of properly when it is no longer needed.157,168 (See Chronic Toxicity.)

Psychiatric Precautions

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.114,118,147,168 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.114,118,147,168 If psychotic or manic symptoms occur during stimulant therapy, discontinuance of therapy should be considered.114,118,147

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

Each time methylphenidate is dispensed, a medication guide should be provided to the patient or caregiver, alerting them to the risks associated with stimulant therapy (e.g., adverse psychiatric effects) and advising them of necessary precautions.114,118,125,147 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

Cardiovascular Precautions

Stimulants, including methylphenidate, cause modest increases in average blood pressure (i.e., by about 2-4 mm Hg) and heart rate (i.e., by about 3-6 beats/minute); larger increases may occur in some patients.114,118,147,168 Although modest increases would not be expected to have short-term sequelae, all patients should be monitored for hypertension and tachycardia.114,118,147,164,165,168 Caution is advised in patients with underlying medical conditions that might be affected by increases in blood pressure or heart rate (e.g., hypertension, heart failure, recent myocardial infarction, ventricular arrhythmia).164,165

Although a causal relationship to stimulants has not been established, sudden unexplained death, stroke, and myocardial infarction have been reported in adults receiving usual dosages of stimulants for the treatment of ADHD.114,118,147,168 Sudden unexplained death also has been reported in pediatric patients with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of CNS stimulants.114,118,147,152,168 Results of one retrospective, case-control epidemiologic study showed that there may be an association between use of stimulant medications (e.g., methylphenidate) and sudden unexplained death in healthy children and adolescents.153,154,155 (See Pediatric Precautions under Cautions.) Because of postmarketing reports and the results of this and other epidemiologic studies, FDA collaborated with the Agency for Healthcare Research and Quality (AHRQ) to sponsor 3 large, related, retrospective cohort studies using data from several health care claims databases to evaluate possible associations between ADHD drug use (stimulants, atomoxetine, and pemoline [no longer commercially available in the US]) and the following serious cardiovascular events: myocardial infarction, stroke, and sudden cardiac death in children and young adults 2-24 years of a myocardial infarction and sudden cardiac death in adults 25-64 years of a and stroke and the composite end point of stroke, myocardial infarction, and sudden cardiac death in the same group of adults.164,165,166,167 None of the 3 studies showed an association between serious cardiovascular events and current use of ADHD drugs, as compared with nonuse or as compared with former or remote use, although small increases in cardiovascular risk could not be excluded.164,165,166,167 The study in children and young adults included data for approximately 1.2 million patients and approximately 2.6 million patient-years of follow-up, including approximately 370,000 patient-years of current ADHD drug use, and found only 7 serious cardiovascular events (4 strokes, 3 sudden deaths) in current users of the drugs.164,167 The analyses in adults included data for approximately 440,000 patients, including approximately 150,000 current users of ADHD drugs; for the composite outcome of stroke, myocardial infarction, and sudden cardiac death, there were approximately 107,000 patient-years of ADHD drug exposure and 234 such cardiovascular events in current users.165,166

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, and should receive further cardiac evaluation (e.g., ECG, echocardiogram) if initial findings suggest such disease.114,118,147,153,168 Although some serious cardiac conditions are independently associated with an increased risk of sudden death, CNS stimulants generally should not be used in children, adolescents, or adults with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac conditions.114,118,147,152,164,165,168 Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.114,118,147,153,168

Each time methylphenidate is dispensed, a medication guide should be provided to the patient or caregiver, alerting them to the risks associated with stimulant therapy (e.g., possible cardiovascular risks) and advising them of necessary precautions.114,118,125,147 Patients or caregivers should be instructed to inform clinicians of preexisting illnesses or conditions, including cardiac or cardiovascular disease.114,118,125,147 They also should be instructed to inform clinicians immediately if adverse cardiovascular effects (e.g., exertional chest pain, unexplained syncope, other symptoms suggestive of cardiac disease) occur during stimulant therapy.114,118,125,147,164,165,168

For further information on screening for cardiac conditions, selecting appropriate candidates for stimulant therapy, and monitoring for treatment-emergent cardiac conditions, see Cardiovascular Precautions under Cautions: Precautions and Contraindications, in the Amphetamines General Statement 28:20.04.

Precautions and Contraindications Associated with Specific Methylphenidate Formulations

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

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

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

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

Methylphenidate hydrochloride extended-release trilayer core tablets generally should not be used in patients with preexisting severe GI narrowing since obstruction may occur.118

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 (See Absorption under Pharmacokinetics.)

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

Patients receiving the methylphenidate transdermal system should be monitored for loss of skin pigmentation, especially at application sites, since chemical leukoderma has been reported in patients receiving this formulation.163 Patients should be advised to immediately report changes in skin color to their clinician.163

Other Precautions and Contraindications

The manufacturer's patient information (medication guide) should be provided to the patient or caregiver each time methylphenidate is dispensed.114,118,125,147

Patients or caregivers should be instructed to inform clinicians of preexisting illnesses or conditions (e.g., cardiac or cardiovascular disease, suicidal ideation or behaviors, mental or psychiatric disorder, history of substance abuse).114

If paradoxical aggravation of symptoms occurs during methylphenidate therapy, dosage should be reduced or the drug discontinued.

Methylphenidate may in rare instances cause prolonged and sometimes painful erections.114,118,125,145,147,152,157,158,159,168 If not treated immediately, priapism can lead to permanent penile damage.159 Clinicians should inform male patients and their caregivers about the signs and symptoms of priapism, stressing the need for immediate medical treatment if it occurs.114,118,125,145,147,152,157,158,159,168 Younger males, especially prepubertal males, may not recognize the problem or may be embarrassed to tell anyone if it occurs.159 FDA states that clinicians should be cautious if they consider switching patients from methylphenidate preparations because of this risk, since certain other alternative ADHD treatments (e.g., atomoxetine) also may cause priapism.159

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.114,118,125,145,147,152,157,158,168 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).114,118,125,145,147,152,157,158,168 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.114,118,125,145,147,152,157,158,168

Therapy with CNS stimulants may be associated with at least a temporary suppression of growth in children.114,118,147,152 (See GI and Growth Effects under Cautions.)

Methylphenidate is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation. Methylphenidate also is contraindicated during or within 14 days of administration of monoamine oxidase (MAO) inhibitors since hypertensive crisis could result.114,118,125,129,145,147,152,168 (See Monoamine Oxidase Inhibitors under Drug Interactions.)

Pediatric Precautions

Although safety and efficacy of methylphenidate in children younger than 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 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, 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 of the adverse behavioral effects reported 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.114,118,125,129,147,152 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.114,118,125,129,147 (See GI and Growth Effects under Cautions.)

Sudden death has been reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of CNS stimulants.114,118,147,152,153,154,155 Results of one retrospective, case-control epidemiologic study suggested a possible association between use of stimulant medications and sudden unexplained death in healthy children and adolescents.153,154,155 However, a subsequent large epidemiologic study found no evidence of increased risk of serious cardiovascular effects in children or young adults with ADHD receiving such therapy.164,167 (See Cardiovascular Precautions under Cautions.)

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

Pregnancy and Lactation

Pregnancy

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

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 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

The National Pregnancy Registry for ADHD Medications monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy.114 Clinicians are encouraged to register women who become pregnant while receiving methylphenidate by calling 866-961-2388 or visiting [Web].114

Lactation

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 1.1-2.7.168 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.168

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.168 If a woman receiving methylphenidate breast-feeds, the infant should be monitored for adverse effects (e.g., agitation, anorexia, reduced weight gain).168

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Because methylphenidate is not metabolized by cytochrome P-450 (CYP) isoenzymes to a clinically important extent, inducers or inhibitors of CYP isoenzymes are not expected to substantially affect the pharmacokinetics of methylphenidate.174 The d - and l -enantiomers of methylphenidate do not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A to a clinically important extent.174 Methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine.174

Anesthetic Agents

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

Antidepressants

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.118,125,145,147,152 Methylphenidate did not increase plasma concentrations of desipramine.174 (See also Monoamine Oxidase Inhibitors under Drug Interactions.)

Cardiovascular Agents

Methylphenidate should be used with caution in patients receiving pressor agents.118,125,145,147,152

Methylphenidate may decrease the efficacy of antihypertensive agents (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, β-adrenergic blocking agents, central α₂-adrenergic agonists, calcium-channel blocking agents, potassium-sparing and thiazide diuretics).114 Blood pressure should be monitored and dosage of the antihypertensive agent adjusted as necessary.114

Drugs Affecting Gastric pH

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., Adhansia XR^®, Cotempla XR-ODT^®) and thereby alter the pharmacokinetic and pharmacodynamic profiles of these formulations.169,172 The manufacturer states that patients receiving concomitant therapy with Adhansia XR^® and drugs that affect gastric pH should be monitored for changes in clinical effect; depending on clinical response, alternative therapy may be required.169 The manufacturer states that concomitant use of Cotempla XR-ODT^® with a histamine H₂-receptor antagonist or proton-pump inhibitor is not recommended.172

Monoamine Oxidase Inhibitors

Concomitant use of monoamine oxidase (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

Risperidone

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

Other Drugs

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.118,125,145,147,152 Although additional studies did not confirm the reported inhibition of metabolism of anticonvulsants and coumarin anticoagulants, the possibility that methylphenidate may raise the serum concentrations of these drugs to toxic concentrations necessitating a decrease in dosage should be considered. Some manufacturers state that dosage reduction of coumarin anticoagulants or anticonvulsants may be required in patients receiving concomitant methylphenidate therapy118,125,145,147,152 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.118,125,147

Some manufacturers state that clearance of methylphenidate may be affected by urinary pH, either being increased with acidifying agents or decreased with alkalinizing agents; clinicians should consider these potential effects when methylphenidate is administered concomitantly with agents that alter urinary pH.125

Acute Toxicity

Manifestations

Acute toxicity due to methylphenidate overdosage results in symptoms similar to those of acute amphetamine intoxication and may be manifested by cardiovascular symptoms including flushing, palpitation, hypertension, cardiac arrhythmias, and tachycardia. Mental disturbances such as confusion, delirium, euphoria, hallucinations, and toxic psychosis may also occur. Other symptoms of overdosage include agitation, headache, vomiting, dryness of mucous membranes, mydriasis, hyperpyrexia, sweating, tremors, hyperreflexia, muscle twitching, and seizures which may be followed by coma. Rhabdomyolysis also has been reported.114,118,125,145,147,152,157,168

Treatment

In the treatment of methylphenidate overdosage, general physiologic supportive measures, including maintenance of adequate circulation and respiratory exchange should be immediately instituted. The patient should be protected against self-injury and should be isolated to avoid possible external stimuli. In cases of overdosage involving transdermal methylphenidate, all transdermal systems of the drug should be removed immediately and the skin cleansed of any remaining adhesive; the potential for continued absorption of residual drug in the skin following system removal should be considered.147 If signs and symptoms of acute toxicity are not too severe and the patient is conscious, gastric contents may be evacuated following ingestion of oral dosage forms by induction of emesis or gastric lavage. In patients with severe intoxication, administration of a carefully titrated dose of a short-acting barbiturate may be required before beginning gastric lavage. External cooling procedures may be required for the treatment of hyperpyrexia. Effectiveness of peritoneal dialysis or extracorporeal hemodialysis for the treatment of methylphenidate overdosage has not been established.

Chronic Toxicity

CNS stimulants, including methylphenidate, have a high potential for abuse and dependence.157,168,158 Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating; dilated pupils; hyperactivity, restlessness, insomnia, loss of coordination, and tremors; flushed skin; decreased appetite; and vomiting and/or abdominal pain.114,157,168 Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation also have been observed.114,157,168 Abuse of CNS stimulants by unintended routes of administration (e.g., chewing, snorting, or injecting the formulation) can result in overdosage and death.157,168 (See Abuse and Dependence Precautions under Cautions.)

Tolerance can occur during chronic therapy with methylphenidate, and physical dependence can occur.157,168 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.114

The abuse potential of extended-release methylphenidate hydrochloride (Concerta^®, formulated to provide 22% of the total dose for immediate release) compared with an immediate-release formulation of the drug was evaluated in 2 placebo-controlled studies in individuals with a history of recreational stimulant use.118 In both studies, responses on subjective measures suggestive of abuse potential were evaluated over an 8-hour period following single-dose oral administration.118 The first study evaluated abuse potential at 1 dose level for each formulation: 108 mg of extended-release methylphenidate hydrochloride and 60 mg of the immediate-release drug.118 In this study, both formulations of methylphenidate produced greater responses compared with placebo on 5 subjective measures of abuse potential; the 108-mg dose of extended-release methylphenidate hydrochloride produced variable responses on positive subjective measures that were either statistically indistinguishable from (on measures of abuse potential, drug liking, amphetamine, and morphine benzedrine group [euphoria]) or less than (on measure of stimulation-euphoria) responses produced by 60 mg of immediate-release methylphenidate hydrochloride.118 The second study evaluated abuse potential following single oral doses at 2 dose levels for each formulation: 54 or 108 mg of extended-release methylphenidate hydrochloride and 50 or 90 mg of the immediate-release drug.118 Both doses of both formulations produced greater responses compared with placebo on 2 primary scales of abuse potential (drug liking, euphoria).118 The 54-mg dose of extended-release methylphenidate hydrochloride produced lower subjective responses compared with the 50-mg immediate-release dose; the same pattern was observed for the 108-mg extended-release dose and the 90-mg immediate-release dose.118 Responses following the 108-mg extended-release dose and the 50-mg immediate-release dose were indistinguishable.118 Although these findings indicated a relatively lower response to the extended-release formulation compared with the immediate-release formulation following oral administration at roughly equivalent total doses, the relevance of these findings to abuse potential in the community is unknown.118

Pharmacology

The pharmacologic actions of methylphenidate are qualitatively similar to those of the amphetamines and include CNS and respiratory stimulation and weak sympathomimetic activity. The mechanism of action involved in the central effect of methylphenidate has not been determined. The main sites of CNS action appear to be the cerebral cortex and subcortical structures including the thalamus; stimulation by methylphenidate causes an increase in motor activity, mental alertness, diminished sense of fatigue, brighter spirits, and mild euphoria. Methylphenidate apparently produces an anorexigenic effect. In usual therapeutic oral dosage, methylphenidate exhibits only moderate effects on the peripheral circulatory system. In a study of the effects of dexmethylphenidate (the pharmacologically active enantiomer of racemic methylphenidate) on the QT interval in healthy individuals, clinically important changes in the QT interval corrected for heart rate (QT_c) were not observed following administration of a single 40-mg dose of dexmethylphenidate hydrochloride as extended-release capsules.114,158

Pharmacokinetics

Absorption

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.129,157,168,169,170,171,172

Immediate-release Oral Formulations (Ritalin®, Methylin®; Generics)

Following oral administration of methylphenidate hydrochloride as conventional tablets, oral solution, or chewable tablets, 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 area under the concentration-time curve (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 Tablets (Generics)

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

Extended-release Chewable Tablets (QuilliChew ER®)

Following oral administration of a single 40-mg dose of methylphenidate hydrochloride as extended-release chewable tablets 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 extend-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

Extended-release Trilayer Core Tablets (Concerta®; Generics)

In adults, the relative bioavailability of the extended-release trilayer core tablets of methylphenidate hydrochloride administered once daily is comparable to that of the conventional tablets administered 3 times daily.118 Following oral administration of a single 18-mg dose of the extended-release trilayer core tablets 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 No substantial accumulation is observed with repeated once-daily administration over a dose range of 18-144 mg.118

Effects persist for about 10-12 hours after oral administration of the extended-release trilayer core tablets.118,509

Administration of the extended-release trilayer core tablets with a high-fat meal does not alter pharmacokinetics or pharmacodynamics of this preparation of methylphenidate hydrochloride.118

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 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

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

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 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

Extended-release Oral Suspension (Quillivant XR®)

Following oral administration of a single 60-mg dose of methylphenidate hydrochloride as extended-release oral suspension 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

Extended-release Capsules (Ritalin® LA; Generics)

Following oral administration of a single 20-mg dose of Ritalin^® LA extended-release capsules 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%;129 the manufacturer states that these results are representative for the available strengths of this preparation.129

Extended-release Capsules (Generic Equivalents of Metadate® CD)

After oral administration of methylphenidate hydrochloride 20 or 40 mg as methylphenidate hydrochloride CD extended-release capsules in children, peak plasma concentrations were attained at 1.5 hours and again at 4.5 hours after a dose.125,126 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.125,126

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%;125 the manufacturer states that these results are representative for the available strengths of this preparation.125

Extended-release Capsules (Aptensio XR®; Generics)

Following oral administration of Aptensio XR^® extended-release capsules 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

Extended-release Capsules (Adhansia XR®)

Following oral administration of Adhansia XR^® extended-release capsules in adults, peak plasma methylphenidate concentrations occur at approximately 1.5 hours and again at approximately 12 hours after a dose.169 In healthy adults receiving the extended-release capsules at a dosage of 100 mg once daily under fasted conditions, the second peak concentrations was comparable to steady-state concentrations achieved with immediate-release methylphenidate hydrochloride at a dosage of 60 mg daily (administered in 3 divided doses given 4 hours apart), but the first peak concentration, AUC, and trough concentrations were approximately 22, 50, and 288% higher, respectively, with the extended-release capsules.169

Effects persist for about 13-16 hours after oral administration of Adhansia XR^® extended-release capsules.169,509,510

Administration of Adhansia XR^® extended-release capsules with a high-fat meal delays the first and second peak concentrations by approximately 1 hour, but does not affect peak concentrations or extent of absorption.169 When administered following an overnight fast, the pharmacokinetic parameters were not affected by opening the capsules and sprinkling the contents onto applesauce or yogurt.169

In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated no increase in the rate of drug release from Adhansia XR^® extended-release capsules within 1 hour at an alcohol concentration of 5, 20, or 40% or within 2 hours at an alcohol concentration of 5 or 20%; however, 71 or 61% of the drug was released from the 70- or 100-mg capsules, respectively, within 2 hours at an alcohol concentration of 40%.169 In healthy adults, administration of the 70-mg extended-release capsules with 40% alcohol in the fasted state resulted in a 1.4-fold increase in peak plasma methylphenidate concentration and a 1.3-fold increase in the extent of absorption.169

Delayed- and Extended-release Capsules (Jornay PM®)

Following nighttime (9 p.m.) oral administration of Jornay PM^® delayed- and extended-release capsules 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

Transdermal System (Daytrana®)

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

Distribution

The extent of methylphenidate distribution in humans is unknown. Methylphenidate is about 10-33% bound to plasma proteins.129

Elimination

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 Adhansia XR^® extended-release capsules in healthy individuals, the mean elimination half-life was about 7 hours.169

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

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 20 mg of radiolabeled methylphenidate hydrochloride as conventional tablets, approximately 50, 80, and 95% of the dose was recovered as metabolites in urine within 6, 24, and 90 hours, respectively.

Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 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

Chemistry and Stability

Chemistry

Methylphenidate hydrochloride is a piperidine-derivative stimulant. The drug occurs as a fine, white, odorless, crystalline powder and is freely soluble in water and soluble in alcohol. 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 (Adhansia XR^®, Aptensio XR^®; generics), extended-release trilayer core tablets (e.g., Concerta^®; generics), 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^®); and delayed- and extended-release capsules (Jornay PM^®) with a longer duration of action following an initial delay of approximately 8-10 hours.114,118,125,126,129,130,145,152,157,158,168,169,170,171,172,173 Methylphenidate is commercially available as a transdermal system.147

Various formulations of methylphenidate hydrochloride extended-release capsules are commercially available.125,129,168,169 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,125,126 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 Adhansia XR^® extended-release capsules contain multilayered beads that are composed of an immediate-release layer containing approximately 20% of the dose and an extended-release layer containing approximately 80% of the dose.169

Extended-release trilayer core tablets of methylphenidate hydrochloride (Concerta^®; generics) contain the drug in an oral osmotic delivery system formulation.118 The 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 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.118,119 The rate of methylphenidate delivery in the GI tract is independent of GI pH or the presence of food in the GI tract.119 The inert tablet ingredients remain intact and are eliminated in feces.118

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 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

Stability

Oral formulations of methylphenidate hydrochloride and methylphenidate transdermal systems should be stored at controlled room temperature; the manufacturer's labeling should be consulted for specific storage recommendations.114,118,125,129,145,147,152,157,158,168,169,170,171,172 The transdermal systems should not be stored in a refrigerator or freezer.147 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 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

Only references cited for selected revisions after 1984 are available electronically.

100. Attention-deficit/hyperactivity disorder. In: diagnostic and statistical manual of mental disorders. 5th ed. DSM-5 Washington, DC: American Psychiatric Association. 2013:59-66.

101. National Institutes of Health Office of Medical Applications of Research. NIH Consensus statement: diagnosis and treatment of attention deficit hyperactivity disorder. 1998; 16(Nov 16-18): in press. From NIH web site (1998 Nov 19). [Web]

102. Swanson JM, Sergeant JA, Taylor E et al. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet . 1998; 351:429-33. [PubMed 9482319]

103. Goldman LS, Genel M, Bexman RJ et al for the Council on Scientific Affairs et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA . 1998; 279:1100-7. [PubMed 9546570]

105. Shaffer D. Attention deficit hyperactivity disorder in adults. Am J Psychiatry . 1994; 151:633-8. [PubMed 7909410]

106. Spencer T, Biederman J, Wilens TE et al. Adults with attention-deficit/hyperactivity disorder: a controversial diagnosis. J Clin Psychiatry . 1998; 59(Suppl 7):59-68. [PubMed 9680054]

107. Popper CW. Antidepressants in the treatment of attention-deficit/hyperactivity disorder. J Clin Psychiatry . 1997; 58(Suppl 14):14-29. [PubMed 9418743]

108. Ialongo NS, Horn WF, Pascoe JM et al. The effects of multimodal intervention with ADHD children: a 9-month follow-up. J Am Acad Child Adolesc Psychiatry . 1993; 32:182-9. [PubMed 8428870]

109. Pelham WE Jr, Carlson C, Sams SE et al. Separate and combined effects of methylphenidate and behavior modification of boys with attention deficit hyperactivity disorder in the classroom. J Consult Clin Psychol . 1993; 61:56-15.

110. Smith BH, Pelham WE, Gnagy E et al. Equivalent effects of stimulant treatment for attention-deficit hyperactivity disorder during childhood and adolescence. J Am Acad Child Adolesc Psychiatry . 1998; 37:314-21. [PubMed 9519637]

111. Dulcan M. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry . 1997; 36(Supp 10):85-121S. [PubMed 9000785]

112. Carrey NJ, Wiggins DM, Milin RP. Pharmacological treatment of psychiatric disorders in children and adolescents. Focus on guidelines for the primary care practitioner. Drugs . 1996; 51:750-9. [PubMed 8861545]

113. Hoechst Marion Roussel. Norpramin^® (desipramine hydrochloride) tablets prescribing information (dated 1996 Jan). In: Physicians' desk reference, 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998:1227-9.

114. Novartis. Ritalin^® (methylphenidate hydrochloride) tablets and Ritalin-SR^® (methylphenidate hydrochloride) extended-release tablets prescribing information. East Hanover, NJ; 2021 Jun.

115. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry . 1999; 56:1073-86. [PubMed 10591283]

116. Taylor E. Development of clinical services for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry . 1999; 56:10979.

117. The MTA Cooperative Group. Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the Multimodal Treatment Study of children with Attention-deficit/hyperactivity disorder. Arch Intern Med . 1999; 56:1088-96.

118. Janssen Pharmaceuticals. Concerta^® (methylphenidate hydrochloride) extended-release tablets prescribing information. Titusville, NJ; 2021 Jun.

119. Wilens TE, Spencer TJ. Combining methylphenidate and clonidine: a clinically sound medication opinion. J Am Acad Child Adolesc Psychiatry . 1999; 38:614-6. [PubMed 10230195]

120. Swanson JM Connor DF, Cantwell D. Combining methylphenidate and clonidine: ill-advised. J Am Acad Child Adolesc Psychiatry . 1999; 38:617-9.

121. Pliszka SR, Greenhill LL, Crismon ML et al. The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part II: Tactics. J Am Acad Child Adolesc Psychiatry . 2000; 39:920-7. [PubMed 10892235]

122. Pliszka SR, Greenhill LL, Crismon ML et al. The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I. J Am Acad Child Adolesc Psychiatry . 2000; 39:908-19. [PubMed 10892234]

123. Barrett J, Meehan O, Fahy T. SSRI and sympathomimetic interaction. Br J Psychiatry . 1996; 168:253. [PubMed 8837926]

124. Blue P. SSRI and sympathomimetic interaction. Br J Psychiatry . 1996; 168:653. [PubMed 8733810]

125. Lannett Company. Methylphenidate hydrochloride extended-release capsules CD prescribing information. Philadelphia, PA; 2021 May.

126. Anon. Another long-acting methylphenidate (Metadate CD). Med Lett Drugs Ther . 2001;43:83-4.

129. Novartis. Ritalin^® LA (methylphenidate hydrochloride) extended-release capsules prescribing information. East Hanover, NJ; 2021 Jun.

130. Anon. Dexmethylphenidate (Focalin) for ADHD. Med Lett Drugs Ther. 2002 ;44:45-6.

132. Pary R, Lewis S, Matuschka PR. Attention Deficit Disorder in Adults. Annals of Clinical Psychiatry . 2002; 14:105-111. [PubMed 12238735]

133. Wilens TE, Faraone SV, Biederman J et al. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics . 2003; 111:179-85. [PubMed 12509574]

134. Barkley RA, Fischer M, Smallish L et al. Does the treatment of attention-deficit/hyperactivity disorder with stimulants contribute to drug use/abuse? A 13-year prospective study. Pediatrics . 2003; 111:97-109. [PubMed 12509561]

135. Michelson D, Faries D, Wernicke J et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics . 2001; 108: E83. [PubMedCentral][PubMed 11694667]

136. Kratochvil CJ, Heiligenstein JH, Dittman R et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry . 2002; 41:776-84. [PubMed 12108801]

137. Adler LA, Chua HC. Management of ADHD in adults. J Clin Psychiatry . 2002;63(Suppl) 12:29-35 [PubMed 12562059]

138. Eli Lilly and Company. Strattera^® (atomoxetine hydrochloride) capsules prescribing information. Indianapolis, IN; 2008 May 7.

140. Connor DF. Preschool attention deficit hyperactivity disorder: a review of prevalence, diagnosis, neurobiology, and stimulant treatment. J Dev Behav Pediatr . 2002; 23: (Suppl 1):1-9. [PubMed 11875284]

141. Searight HR, Burke JM, Rottnek F. Adult ADHD: Evaluation and treatment in family medicine. Am Fam Physician . 2000; 62:2077-86. [PubMed 11087189]

142. Troller JN. Attention deficit hyperactivity disorder in adults: conceptual and clinical issues. MJA . 1999; 171:421-5. [PubMed 10590746]

143. Food and Drug Administration. Cylert and generic pemoline products [October 24, 2005]. Medwatch alert. Rockville, MD; October 2005. From FDA website. [Web]

144. Food and Drug Administration. Pemoline tablets and chewable tablets (marketed as Cylert). Alert for healthcare professionals. Rockville, MD; October 2005. From FDA website. [Web]

145. Shionogi Inc. Methylin^® (methylphenidate hydrochloride) oral solution prescribing information. Florham Park, NJ; 2021 Jun.

147. Noven Pharmaceuticals. Daytrana^® (methylphenidate) transdermal system prescribing information. Miami, FL; 2021 Jun.

152. Rising Pharmaceuticals. Methylphenidate hydrochloride chewable tablets prescribing information. Saddle Brook, NJ; 2021 Mar.

153. Food and Drug Administration. FDA Alert: Information for healthcare professionals: Communication about an ongoing safety review of stimulant medications [dexmethylphenidate (marketed as Focalin, Focalin XR), dextroamphetamine (marketed as Dexedrine, Dexedrine Spansules, Dextrostat, and generics), lisdexamfetamine (marketed as Vyvanse), methamphetamine (marketed as Desoxyn), methylphenidate (marketed as Concerta, Daytrana, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin-LA, and Ritalin-SR), mixed salts amphetamine (marketed as Adderall and Adderall XR), and pemoline (marketed as Cylert and generics)] used in children with attention-deficit/hyperactivity disorder (ADHD). Rockville, MD; 2009 Jun 23. From the FDA website. [Web]

154. Gould MS, Walsh BT, Munfakh JL et al. Sudden death and use of stimulant medications in youths. Am J Psychiatry . 2009; 166:992-1001. [PubMed 19528194]

155. Vitiello B, Towbin K. Stimulant treatment of ADHD and risk of sudden death in children. Am J Psychiatry . 2009; 166:955-7. [PubMed 19528196]

156. US Food and Drug Administration. AHRQ and FDA to collaborate in largest study ever of possible heart risks with ADHD medications. FDA News September 17, 2007. From FDA web site. [Web]

157. Tris Pharma. Quillivant XR^® (methylphenidate hydrochloride) for extended-release suspension prescribing information. Monmouth Junction, NJ; 2021 Jun.

158. KVK-Tech. Methylphenidate hydrochloride extended-release tablets prescribing information. Newtown, PA; 2021 Apr.

159. Food and Drug Administration. FDA Drug Safety Communication: FDA warns of rare risk of long-lasting erections in males taking methylphenidate ADHD medications and has approved label changes. 2013 Dec 17. From FDA website. Accessed 2015 May 21. [Web]

163. Food and Drug Administration. FDA Drug Safety Communication: FDA reporting permanent skin color changes associated with use of Daytrana patch (methylphenidate transdermal system) for treating ADHD. 2015 Jun 24. From FDA website. Accessed 2015 July 6. [Web]

164. Food and Drug Administration. FDA Drug Safety Communication: Safety review update of medications used to treat attention-deficit/hyperactivity disorder (ADHD) in children and young adults. 2011 Nov 1. From FDA website. Accessed 2015 Jul 24. [Web]

165. Food and Drug Administration. FDA Drug Safety Communication: Safety review update of medications used to treat attention-deficit/hyperactivity disorder (ADHD) in adults. 2011 Dec 12. From FDA website. Accessed 2015 Jul 24. [Web]

166. Habel LA, Cooper WO, Sox CM et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA . 2011; 306:2673-83. [PubMedCentral][PubMed 22161946]

167. Cooper WO, Habel LA, Sox CM et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med . 2011; 365:1896-904. [PubMedCentral][PubMed 22043968]

168. Rhodes Pharmaceuticals. Aptensio XR^® (methylphenidate hydrochloride) extended-release capsules prescribing information. Coventry, RI; 2021 Jun.

169. Adlon Therapeutics. Adhansia XR^® (methylphenidate hydrochloride) extended-release capsules prescribing information. Stamford, CT; 2021 Jun.

170. Ironshore Pharmaceuticals. Jornay PM^® (methylphenidate hydrochloride) extended-release capsules prescribing information. Cherry Hill, NJ; 2021 Jun.

171. Pfizer. QuilliChew ER^® (methylphenidate hydrochloride) extended-release chewable tablets prescribing information. New York, NY; 2018 Mar.

172. Neos Therapeutics Brands. Cotempla XR-ODT^® (methylphenidate hydrochloride) extended-release orally disintegrating tablets prescribing information. Grand Prairie, TX; 2021 Jun.

173. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209311Orig1s000: Product quality review. From FDA website. [Web]

174. Novartis. Focalin^® (dexmethylphenidate hydrochloride) tablets prescribing information. East Hanover, NJ; 2021 Jun.

500. Wolraich ML, Hagan JF Jr, Allan C et al. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics . 2019; 144 [PubMedCentral][PubMed 31570648]

501. Martins S, Tramontina S, Polanczyk G et al. Weekend holidays during methylphenidate use in ADHD children: a randomized clinical trial. J Child Adolesc Psychopharmacol . 2004; 14:195-206. [PubMed 15319017]

502. Ibrahim K, Donyai P. Drug Holidays From ADHD Medication: International Experience Over the Past Four Decades. J Atten Disord . 2015; 19:551-68. [PubMed 25253684]

503. Ibrahim K, Donyai P. What stops practitioners discussing medication breaks in children and adolescents with ADHD? Identifying barriers through theory-driven qualitative research. Atten Defic Hyperact Disord . 2018; 10:273-283. [PubMedCentral][PubMed 29982921]

504. Posner J, Polanczyk GV, Sonuga-Barke E. Attention-deficit hyperactivity disorder. Lancet . 2020; 395:450-462. [PubMedCentral][PubMed 31982036]

505. Cortese S. Pharmacologic Treatment of Attention Deficit-Hyperactivity Disorder. N Engl J Med . 2020; 383:1050-1056. [PubMed 32905677]

506. Kooij JJS, Bijlenga D, Salerno L et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatry . 2019; 56:14-34. [PubMed 30453134]

507. Swanson JM, Elliott GR, Greenhill LL et al. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry . 2007; 46:1015-1027. [PubMed 17667480]

508. Swanson JM, Arnold LE, Molina BSG et al. Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression. J Child Psychol Psychiatry . 2017; 58:663-678. [PubMedCentral][PubMed 28295312]

509. Pheils J, Ehret MJ. Update on methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder. Am J Health Syst Pharm . 2021; 78:840-849. [PubMed 33954419]

510. Steingard R, Taskiran S, Connor DF et al. New Formulations of Stimulants: An Update for Clinicians. J Child Adolesc Psychopharmacol . 2019; 29:324-339. [PubMedCentral][PubMed 31038360]

511. Austerman J. ADHD and behavioral disorders: Assessment, management, and an update from DSM-5. Cleve Clin J Med . 2015; 82:S2-7. [PubMed 26555810]

512. Wigal S, Chappell P, Palumbo D et al. Diagnosis and Treatment Options for Preschoolers with Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol . 2020; 30:104-118. [PubMedCentral][PubMed 31967914]

513. Katzman MA, Bilkey TS, Chokka PR et al. Adult ADHD and comorbid disorders: clinical implications of a dimensional approach. BMC Psychiatry . 2017; 17:302. [PubMedCentral][PubMed 28830387]

514. Gnanavel S, Sharma P, Kaushal P et al. Attention deficit hyperactivity disorder and comorbidity: A review of literature. World J Clin Cases . 2019; 7:2420-2426. [PubMedCentral][PubMed 31559278]

515. Hinshaw SP, Arnold LE, For the MTA Cooperative Group.. ADHD, Multimodal Treatment, and Longitudinal Outcome: Evidence, Paradox, and Challenge. Wiley Interdiscip Rev Cogn Sci . 2015; 6:39-52. [PubMedCentral][PubMed 25558298]

516. Supernus Pharmaceuticals. Quelbree^® (viloxazine hydrochloride) extended-release capsules prescribing information. Rockville, MD; 2021 Apr.

517. Faraone SV, Banaschewski T, Coghill D et al. The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder. Neurosci Biobehav Rev . 2021; 128:789-818. [PubMedCentral][PubMed 33549739]

518. Volkow ND, Swanson JM. Clinical practice: Adult attention deficit-hyperactivity disorder. N Engl J Med . 2013; 369:1935-44. [PubMedCentral][PubMed 24224626]

519. Verbeeck W, Bekkering GE, Van den Noortgate W et al. Bupropion for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev . 2017; 10:CD009504. [PubMedCentral][PubMed 28965364]

520. Otasowie J, Castells X, Ehimare UP et al. Tricyclic antidepressants for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev . 2014; :CD006997. [PubMed 25238582]

521. Ghanizadeh A, Freeman RD, Berk M. Efficacy and adverse effects of venlafaxine in children and adolescents with ADHD: a systematic review of non-controlled and controlled trials. Rev Recent Clin Trials . 2013; 8:2-8. [PubMed 23157376]

522. Coghill DR, Banaschewski T, Soutullo C et al. Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry . 2017; 26:1283-1307. [PubMedCentral][PubMed 28429134]

523. Cortese S, Adamo N, Del Giovane C et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry . 2018; 5:727-738. [PubMedCentral][PubMed 30097390]

524. Joseph A, Ayyagari R, Xie M et al. Comparative efficacy and safety of attention-deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison. Eur Child Adolesc Psychiatry . 2017; 26:875-897. [PubMedCentral][PubMed 28258319]

525. Molina BS, Hinshaw SP, Eugene Arnold L et al. Adolescent substance use in the multimodal treatment study of attention-deficit/hyperactivity disorder (ADHD) (MTA) as a function of childhood ADHD, random assignment to childhood treatments, and subsequent medication. J Am Acad Child Adolesc Psychiatry . 2013; 52:250-63. [PubMedCentral][PubMed 23452682]

526. Chang Z, Lichtenstein P, Halldner L et al. Stimulant ADHD medication and risk for substance abuse. J Child Psychol Psychiatry . 2014; 55:878-85. [PubMedCentral][PubMed 25158998]

527. Wilens TE, Morrison NR. The intersection of attention-deficit/hyperactivity disorder and substance abuse. Curr Opin Psychiatry . 2011; 24:280-5. [PubMedCentral][PubMed 21483267]

528. Faraone SV, Rostain AL, Montano CB et al. Systematic Review: Nonmedical Use of Prescription Stimulants: Risk Factors, Outcomes, and Risk Reduction Strategies. J Am Acad Child Adolesc Psychiatry . 2020; 59:100-112. [PubMed 31326580]

529. Osland ST, Steeves TD, Pringsheim T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev . 2018; 6:CD007990. [PubMedCentral][PubMed 29944175]

550. Abad VC, Guilleminault C. New developments in the management of narcolepsy. Nat Sci Sleep . 2017; 9:39-57. [PubMedCentral][PubMed 28424564]

551. Franceschini C, Pizza F, Cavalli F et al. A practical guide to the pharmacological and behavioral therapy of Narcolepsy. Neurotherapeutics . 2021; 18:6-19. [PubMedCentral][PubMed 33886090]

552. Bassetti CLA, Kallweit U, Vignatelli L et al. European guideline and expert statements on the management of narcolepsy in adults and children. J Sleep Res . 2021; :e13387. [PubMed 34173288]