On June 30, 2025, FDA issued a drug safety communication about a risk of weight loss in patients younger than 6 years of age taking extended-release stimulants for ADHD and will be revising the labeling for all these products to reflect this new safety information. Although extended-release stimulants are not approved for children younger than 6 years, health care professionals can prescribe them “off label” to treat ADHD. For additional information, see [Web] |
Dexmethylphenidate hydrochloride, the d-threo enantiomer of racemic methylphenidate hydrochloride, is a CNS stimulant that has pharmacologic actions that are qualitatively similar to those of amphetamines.1, 4 Serdexmethylphenidate chloride is a prodrug of dexmethylphenidate hydrochloride and probably lacks pharmacologic activity until it's converted to dexmethylphenidate in the GI tract.17
Attention Deficit Hyperactivity Disorder
Dexmethylphenidate hydrochloride and the fixed combination of serdexmethylphenidate chloride and dexmethylphenidate hydrochloride are used in the treatment of attention deficit hyperactivity disorder (ADHD) in patients 6 years of age and older.1, 4, 17
Efficacy of dexmethylphenidate hydrochloride conventional tablets for the treatment of ADHD was established in 2 placebo-controlled clinical trials in patients 6-17 years of age who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for ADHD (inattentive, hyperactive-impulsive, or combined inattentive/hyperactive-impulsive presentation); most of the patients were 6-12 years of age.1, 530, 531 In the first controlled clinical trial, 132 pediatric patients were randomized to receive dexmethylphenidate hydrochloride conventional tablets, racemic methylphenidate hydrochloride, or placebo twice daily for 4 weeks, with dose titration based on weekly clinic visits depending on clinical response and tolerability.1, 530 The main efficacy measure assessed was the change from baseline to week 4 in the average score of the teacher's version of the Swanson, Nolan, and Pelham (SNAP)-ADHD rating scale.1, 530 The SNAP scale is a scale that contains 18 items related to ADHD symptoms of inattention, hyperactivity, and impulsivity, which are rated on a scale of 0 (not at all) to 3 (very much).1, 530 There was substantially greater improvement in symptom scores from baseline to study end (4 weeks) in pediatric patients receiving dexmethylphenidate hydrochloride conventional tablets compared with those receiving placebo.1, 530 In the second trial, 75 pediatric patients who had responded to dexmethylphenidate hydrochloride as conventional tablets in a 6-week open-label trial were randomized to receive this formulation of the drug or placebo for a 2-week, double-blind withdrawal phase.1, 531 The main efficacy measure of this study was the proportion of treatment failures at the end of the 2-week withdrawal period; treatment failure was defined as an Investigator Clinical Global Impression-Improvement (CGI-I) score of 6 (much worse) or 7 (very much worse).1, 531 By the end of the 2-week, double-blind, withdrawal phase, treatment failure occurred in substantially more patients receiving placebo (63%) compared with those receiving dexmethylphenidate (17%).1, 531
Efficacy of dexmethylphenidate hydrochloride extended-release capsules for the treatment of ADHD was established in clinical trials in pediatric patients 6 years of age and older who met DSM-IV criteria for ADHD (inattentive, hyperactive-impulsive, or combined inattentive/hyperactive-impulsive presentation).4, 532 In a controlled clinical trial, 103 pediatric patients 6-17 years of age were randomized to receive dexmethylphenidate extended-release capsules or placebo once daily for 7 weeks.4, 532 During the first 5 weeks, patients randomized to receive dexmethylphenidate started at an initial dose of 5 mg daily and were titrated up to their optimal dose of up to 30 mg daily.4, 532 Patients remained on their optimal dose for the last 2 weeks of the study.4 The main efficacy measure assessed was the change from baseline to the final visit in the DSM-IV total subscale score of the Conners ADHD/DSM-IV Scale for teachers (CADS-T).4, 532 The CADS-T questionnaire includes 12 ADHD index items and 18 items of the DSM-IV total subscale.4, 532 From baseline to the end of week 7, there was substantial improvement in symptoms in pediatric patients receiving dexmethylphenidate hydrochloride extended-release capsules compared with those receiving placebo.4, 532 Because a limited number of adolescents were enrolled in the trial, data from the trial were insufficient to adequately assess efficacy of the extended-release capsules in adolescents; however, efficacy of dexmethylphenidate hydrochloride extended-release capsules in adolescents is supported by pharmacokinetic data and by evidence of the efficacy of conventional tablets of the drug in this population.4
Efficacy of dexmethylphenidate hydrochloride extended-release capsules for the treatment of ADHD is also supported by 2 additional crossover studies, both conducted in a laboratory classroom setting, in pediatric patients 6-12 years of age.4, 533, 534 Patients with ADHD were randomized to receive either dexmethylphenidate hydrochloride extended-release capsules 20 mg daily for 7 days followed by placebo daily for 7 days or placebo daily for 7 days followed by dexmethylphenidate hydrochloride extended-release capsules 20 mg daily for 7 days.533, 534 The main efficacy measure assessed for both crossover studies was the Swanson, Kotkin, Agler, M-Flynn, & Pelham (SKAMP) score at multiple time points from 0.5-12 hours after dosing.4, 533, 534 The SKAMP scale is a validated subjective laboratory classroom scale that contains 13 items on which subjects are rated on a 7-point scale for each item.4 At all time points post-dose, patients had substantial improvements in the SKAMP-Combined score after receiving dexmethylphenidate extended-release 20 mg capsules versus placebo.4, 533, 534
Efficacy of serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride for the treatment of ADHD was established in a clinical trial in pediatric patients 6-12 years of age who met DSM, Fifth Edition (DSM-5) criteria for ADHD (inattentive, hyperactive-impulsive, or combined inattentive/hyperactive-impulsive presentation).17, 535 Following a 3-week, open-label dose-optimization period , 150 pediatric patients were randomized to receive the individually optimized dosage of the fixed combination for an additional week or placebo.17 The main efficacy endpoint measured was the mean change from baseline of SKAMP-Combined scores averaged across assessments conducted at multiple time points from 0.5-13 hours post-dose.17 Serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride, compared to placebo, was found to substantially improve average SKAMP-Combined scores.17 Efficacy of this formulation in adolescents and adults is supported by pharmacokinetic data for the fixed-combination preparation compared with extended-release dexmethylphenidate hydrochloride.17
Efficacy of dexmethylphenidate hydrochloride extended-release capsules for the treatment of ADHD in adults was established in a randomized controlled clinical trial in 221 adults 18-60 years of age.4, 536 Patients who met DSM-IV criteria for ADHD (inattentive, hyperactive-impulsive, or combined inattentive/hyperactive-impulsive presentation) were randomized to receive dexmethylphenidate hydrochloride extended-release capsules (20, 30, or 40 mg) or placebo once daily for 5 weeks.4, 536 All patients randomized to receive dexmethylphenidate were initiated on a 10 mg per day starting dose and titrated in increments of 10 mg per week to their randomly assigned fixed dose.4, 536 Dosages were then maintained for at least 2 weeks.4, 536 The main efficacy measure assessed was the DSM-IV Attention-Deficit/Hyperactivity Disorder Rating Scale (DSM-IV ADHD-RS).4, 536 The DSM-IV ADHD-RS is a questionnaire of 18 items with a total score range of 0-54 points that measures core symptoms of ADHD.4, 536 There was substantial improvement in the DSM-IV ADHD-RS score from baseline to study end (5 weeks) in adults receiving dexmethylphenidate hydrochloride extended-release capsules (20-, 30-, or 40-mg capsules) versus those receiving placebo.4, 536
The American Academy of Pediatrics (AAP) has developed guidelines for children and adolescents with ADHD.500 For pediatric patients 6-12 years of age with ADHD, FDA-labeled medications for ADHD should be prescribed, in addition to parent training in behavior management (PTBM) and/or behavioral classroom interventions.500 For choice of medication, evidence is particularly strong for stimulant drugs (e.g., methylphenidate).500 Evidence is sufficient but not as strong for atomoxetine, extended-release guanfacine, and extended-release clonidine.500 For adolescents 12-18 years of age with ADHD, FDA-labeled medications should be prescribed with the adolescent's assent.500 The provider is also encouraged to prescribe behavioral and other evidence-based training interventions if available.500 Dosages should be titrated to achieve maximum benefit with tolerable adverse effects.500
International experts have published recommendations for the treatment of ADHD in adults.506, 559 Treatment of ADHD in adults should follow a multimodal approach that includes psychoeducation, pharmacotherapy, cognitive behavior therapy, and coaching for ADHD.506 First-line pharmacotherapy agents include long-acting stimulants such as mixed amphetamine salts, methylphenidate, and lisdexamfetamine.559 Short-acting and intermediate-acting stimulants are considered second-line and can also be adjunctive agents.559 Atomoxetine may also be used as a second-line or adjunctive agent.559
Dexmethylphenidate has also been used for the symptomatic treatment of inattention, impulsivity, and hyperactivity in pediatric patients with autism spectrum disorder (ASD)†.563
The AAP has developed guidelines for children and adolescents with ASD.563 While there are not currently any medications that correct core social and communication symptoms in patients with ASD, there are medications that may be used to help manage behavioral and psychiatric symptoms.563 Medication should only be considered after treatable medical conditions and behavioral factors are assessed and other interventions do not address the symptoms of concern; the family and patient should be included in the shared decision making process.563 For symptoms of hyperactivity, impulsivity, inattention, and distractibility, the AAP suggests the use of psychostimulants (e.g., methylphenidate, dexmethylphenidate, mixed amphetamine salts, lisdexamfetamine, dextroamphetamine) after behavioral approaches are implemented if problems persist.563 Patients should start with a low dose of the stimulant, with dosage increases as needed and tolerated.563 Stimulants may be most effective in children who do not have comorbid intellectual disability.563
Dispensing and Administration Precautions
Dexmethylphenidate Immediate-release Tablets
Dexmethylphenidate hydrochloride conventional tablets are administered orally twice daily without regard to meals; the manufacturer recommends that doses be administered at least 4 hours apart.1 Administration with a high-fat meal delays the peak concentration (from 1.5 hours in the fasted state to 2.9 hours in the fed state), but does not substantially affect the extent of absorption.1
Store dexmethylphenidate hydrochloride conventional tablets in tight, light-resistant containers at 20-25°C (excursions permitted from 15-30°C).1
Dexmethylphenidate Extended-release Capsules
Dexmethylphenidate hydrochloride extended-release capsules are administered orally once daily in the morning, with or without food.4 The capsules should be swallowed whole with water or other liquids and the capsule and beads in the capsule should not be chewed, crushed, or divided.4 Alternatively, the entire contents of the extended-release capsule(s) may be sprinkled onto a small amount (e.g., a spoonful) of applesauce immediately prior to administration.4 The entire sprinkle/applesauce mixture should be taken immediately without chewing and should not be stored for use at a later time.4 Administration with food may delay the onset of action.4
Store extended-release dexmethylphenidate hydrochloride capsules in tight containers at 20-25°C (excursions permitted from 15-30°C).4
Serdexmethylphenidate/Dexmethylphenidate Fixed-combination Capsules
Capsules containing serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride are administered orally once daily in the morning, with or without food.17 The capsules should be swallowed whole with water or other liquids.17 Alternatively, the entire contents of a capsule may be sprinkled into 50 mL of water or over 2 tablespoons of applesauce immediately or within 10 minutes prior to administration; the mixture should not be stored for use at a later time.17 Administration of the capsules with food delays the peak concentration (from a median of 2 hours in the fasted state to 4-4.5 hours in the fed state) but does not substantially affect the extent of absorption.17
Store serdexmethylphenidate/dexmethylphenidate capsules in tight containers at 20-25°C (excursions permitted from 15-30°C).17 Protect from moisture.17
Dosage of dexmethylphenidate hydrochloride generally is expressed in terms of the salt;1, 4 however, dosage of the fixed combination containing serdexmethylphenidate chloride and dexmethylphenidate hydrochloride is expressed in terms of serdexmethylphenidate and dexmethylphenidate.17 Each 26.1, 39.2, or 52.3 mg of serdexmethylphenidate is equivalent to 28, 42, or 56 mg, respectively, of serdexmethylphenidate chloride, and each 5.2, 7.8, or 10.4 mg of dexmethylphenidate is equivalent to 6, 9, or 12 mg, respectively, of dexmethylphenidate hydrochloride.17 The combined molar dose of serdexmethylphenidate and dexmethylphenidate in each dosage strength of the fixed combination (i.e., 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, or 52.3 mg/10.4 mg of serdexmethylphenidate/dexmethylphenidate, respectively) is equivalent to 20, 30, or 40 mg, respectively, of dexmethylphenidate hydrochloride.17
Attention Deficit Hyperactivity Disorder (ADHD)
The recommended initial dosage of dexmethylphenidate hydrochloride as extended-release capsules in patients who currently are not receiving dexmethylphenidate or racemic methylphenidate or who are receiving stimulants other than methylphenidate is 10 mg once daily for adults.4 Patients currently receiving dexmethylphenidate hydrochloride conventional tablets may be switched to the extended-release capsules at the same total daily dosage.4 In patients being transferred from racemic methylphenidate to dexmethylphenidate therapy, the initial dexmethylphenidate hydrochloride dosage is one-half the current methylphenidate hydrochloride dosage.4 Dosage of dexmethylphenidate hydrochloride in adults may be increased at weekly intervals in increments of 10 mg daily, up to a maximum dosage of 40 mg daily.4 In dose-response studies evaluating fixed dosages of 20-40 mg daily in adults, all of the dosages within this range were more effective than placebo, but there was no clear evidence that the higher dosages within this range provided greater average benefits; however, adverse effects and drug discontinuance were dose related.4 Dosages above 40 mg daily in adults have not been studied and are not recommended.4
The recommended initial dosage of serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride in adults is 39.2 mg of serdexmethylphenidate and 7.8 mg of dexmethylphenidate once daily.17 Dosage in adults should be increased after one week to 52.3 mg of serdexmethylphenidate and 10.4 mg of dexmethylphenidate once daily.17 The maximum recommended dosage in adults is 52.3 mg of serdexmethylphenidate and 10.4 mg of dexmethylphenidate once daily.17 This dosage titration schedule also should be followed for patients being transferred from other methylphenidate-containing preparations to the serdexmethylphenidate chloride and dexmethylphenidate hydrochloride fixed combination.17 The fixed combination should not be substituted for other methylphenidate-containing preparations on a milligram-per-milligram basis because of differences in pharmacokinetic profiles and methylphenidate base composition.17
Dosage of dexmethylphenidate hydrochloride and serdexmethylphenidate chloride/dexmethylphenidate hydrochloride for the treatment of ADHD should be adjusted based on clinical response and tolerability.1, 4, 17 If a beneficial effect is not attained after appropriate dosage adjustment over a 1-month period, therapy with the drug should be discontinued.1, 4, 17 If paradoxical aggravation of symptoms or other adverse effects occur during therapy, dosage should be reduced or the drug discontinued if necessary.1, 4, 17
The recommended initial dosage of dexmethylphenidate hydrochloride as conventional tablets in pediatric patients ≥6 years of age who currently are not receiving racemic methylphenidate or are receiving stimulants other than methylphenidate is 2.5 mg twice daily.1 In pediatric patients ≥6 years of age who are being transferred from racemic methylphenidate to dexmethylphenidate therapy, the initial dexmethylphenidate hydrochloride dosage is one-half the current methylphenidate hydrochloride dosage.1 Dosage of dexmethylphenidate hydrochloride may be increased by 2.5-5 mg daily at weekly intervals, up to a maximum dosage of 20 mg daily (10 mg twice daily).1
The recommended initial dosage of dexmethylphenidate hydrochloride as extended-release capsules in patients who currently are not receiving dexmethylphenidate or racemic methylphenidate or who are receiving stimulants other than methylphenidate is 5 mg once daily for pediatric patients ≥6 years of age.4 Patients currently receiving dexmethylphenidate hydrochloride conventional tablets may be switched to the extended-release capsules at the same total daily dosage.4 In patients being transferred from racemic methylphenidate to dexmethylphenidate therapy, the initial dexmethylphenidate hydrochloride dosage is one-half the current methylphenidate hydrochloride dosage.4 Dosage of dexmethylphenidate hydrochloride in pediatric patients may be increased at weekly intervals in increments of 5 mg daily, up to a maximum dosage of 30 mg daily4 In dose-response studies evaluating fixed dosages of 10-30 mg daily in pediatric patients, all of the dosages within this range were more effective than placebo, but there was no clear evidence that the higher dosages within this range provided greater average benefits; however, adverse effects and drug discontinuance were dose related.4 Dosages above 30 mg daily in pediatric patients have not been studied and are not recommended.4
The recommended initial dosage of serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride in pediatric patients ≥6 years of age is 39.2 mg of serdexmethylphenidate and 7.8 mg of dexmethylphenidate once daily.17 Dosage in adolescents 13-17 years of age should be increased after one week to 52.3 mg of serdexmethylphenidate and 10.4 mg of dexmethylphenidate once daily.17 In children 6-12 years of age, dosage may be increased after one week to 52.3 mg of serdexmethylphenidate and 10.4 mg of dexmethylphenidate once daily or decreased after one week to 26.1 mg of serdexmethylphenidate and 5.2 mg of dexmethylphenidate once daily based on response and tolerability.17 The maximum recommended dosage in pediatric patients is 52.3 mg of serdexmethylphenidate and 10.4 mg of dexmethylphenidate once daily.17 This dosage titration schedule also should be followed for patients being transferred from other methylphenidate-containing preparations to the serdexmethylphenidate chloride and dexmethylphenidate hydrochloride fixed combination.17 The fixed combination should not be substituted for other methylphenidate-containing preparations on a milligram-per-milligram basis because of differences in pharmacokinetic profiles and methylphenidate base composition.17
Dosage of dexmethylphenidate hydrochloride and serdexmethylphenidate chloride/dexmethylphenidate hydrochloride for the treatment of ADHD should be adjusted according to individual requirements and response.1, 4 If a beneficial effect is not attained after appropriate dosage adjustment over a 1-month period, therapy with the drug should be discontinued.1, 4, 17 If paradoxical aggravation of symptoms or other adverse effects occur during therapy, dosage should be reduced or the drug discontinued if necessary.1, 4, 17
The manufacturers do not provide specific dosage recommendations in hepatic impairment.1, 4, 17
The manufacturers do not provide specific dosage recommendations in renal impairment.1, 4, 17
The manufacturers do not provide specific dosage recommendations in geriatric patients.1, 4, 17
A boxed warning is included in the prescribing information for dexmethylphenidate hydrochloride products concerning the high potential for abuse and misuse.1, 4, 17 The use of dexmethylphenidate products exposes patients to the risks of abuse and misuse, which can lead to the development of substance use disorder (including addiction).1, 4, 17 Misuse and abuse of CNS stimulants such as dexmethylphenidate can result in overdose or death.1, 4, 17 This risk is further increased with higher dosages or unapproved routes of administration (i.e., snorting, injection).1, 4, 17 Because CNS stimulants, including dexmethylphenidate, have a high potential for abuse and dependence, the risk of abuse, misuse, and addiction should be assessed prior to initiation and frequently for the duration of therapy.1, 4, 17 Patients receiving stimulants should also be frequently monitored for signs of abuse, misuse, and addiction.1, 4, 17
In addition, tolerance can develop during dexmethylphenidate therapy, which is characterized by a reduced response to the drug after repeated administration.1, 4, 17 In patients who are physically dependent on CNS stimulants, abrupt cessation of therapy or rapid dosage reduction may result in a withdrawal syndrome characterized by dysphoric mood, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.1, 4, 17
Patients and/or their caregivers should be advised that dexmethylphenidate products can be abused and can result in dependence; they should be advised that dexmethylphenidate products should not be shared with others and should be stored in a safe (preferably locked) location to prevent misuse and abuse.1, 4, 17 Dexmethylphenidate should be disposed of by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site when it is no longer needed.1, 4, 17 If there is no take-back program or authorized DEA collection site available, the drug can be mixed with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds and disposed of in a sealed plastic bag in the household trash.1, 4, 17
Risks to Patients with Serious Cardiac Disease
Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease receiving usual dosages of CNS stimulants for the treatment of attention deficit hyperactivity disorder (ADHD).1, 4, 17
In a study of the effects of dexmethylphenidate hydrochloride (40 mg as extended-release capsules) on the QT interval, clinically important changes in the QT interval corrected for heart rate (QTc) were not observed.1, 4 In addition, in a controlled study evaluating the abuse potential of serdexmethylphenidate (administered intranasally), clinically important prolongation of the QT interval was not observed at a mean concentration 40 times the peak concentration achieved with the highest recommended dosage of the fixed-combination preparation of serdexmethylphenidate chloride and dexmethylphenidate hydrochloride.17
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.1, 4, 17 In general, CNS stimulants should not be used in children, adolescents, or adults with known serious structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease.1, 4, 17
Patients or caregivers should inform clinicians immediately if adverse cardiovascular effects (e.g., exertional chest pain, unexplained syncope, other symptoms suggestive of cardiac disease) occur during stimulant therapy.1, 4, 17
Increased Blood Pressure and Heart Rate
Stimulants can cause 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.1, 4, 17 All patients should be monitored for hypertension and tachycardia.1, 4, 17
Stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.1, 4, 17
Stimulants have the potential to precipitate mixed or manic episodes in patients.1, 4, 17 Prior to initiating therapy, patients should be screened for risk factors for developing a manic episode (e.g., current or prior depressive symptoms; family history of suicide, bipolar disorder, or depression).1, 4, 17
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.1, 4, 17 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.1, 4, 17 If psychotic or manic symptoms occur during stimulant therapy, discontinuance of therapy should be considered.1, 4, 17
Prolonged and painful erections, in some cases requiring surgical intervention, have been reported in both adult and pediatric male patients receiving methylphenidate.1, 4, 17 Although not reported during drug initiation, priapism has developed after continued therapy with methylphenidate, typically after dosage increases.1, 4, 17 Priapism also has occurred during temporary interruptions in therapy (e.g., drug holidays) or following drug discontinuance.1, 4, 17
Patients who develop abnormally sustained or frequent and painful erections during dexmethylphenidate therapy should seek immediate medical attention.1, 4, 17
Peripheral Vasculopathy, including Raynaud's Phenomenon
Stimulants used to treat ADHD, including dexmethylphenidate, are associated with peripheral vascular disorders, including Raynaud's phenomenon.1, 4, 17 Manifestations usually are intermittent and mild, but ulceration of the digits and/or breakdown of soft tissue may occur rarely.1, 4, 17 Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed during postmarketing experience and at therapeutic dosages of CNS stimulants in patients in all age groups throughout the course of treatment.1, 4, 17 The manifestations generally improved following dosage reduction or drug discontinuance.1, 4, 17 Careful observation for digital changes is warranted during stimulant therapy, and further clinical evaluation (e.g., referral to a rheumatologist) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy.1, 4, 17
Long-term Suppression of Growth in Pediatric Patients
Therapy with CNS stimulants has been associated with weight loss and a slowing of growth in pediatric patients.1, 4, 17 Results of an analysis of weight and height patterns in pediatric patients 7-13 years of age suggested that treatment with methylphenidate for up to 3 years was associated with a slowing in growth rate (on average, height gain was suppressed by about 2 cm and weight gain was suppressed by 2.7 kg over 3 years), without evidence of growth rebound during this period of development.1, 4 In a 7-week controlled study in pediatric patients 6-17 years of age, patients receiving placebo gained a mean of 0.4 kg, while those receiving dexmethylphenidate hydrochloride extended-release capsules lost a mean of 0.5 kg.4 In a long-term, open-label study with serdexmethylphenidate/dexmethylphenidate capsules in pediatric patients 6-12 years of age, there was a less than expected average increase in height and weight compared to pediatric patients of the same age and sex.17
The manufacturers of stimulant preparations state that growth (weight and height) should be closely monitored during therapy with stimulants, and children who are not growing or gaining height or weight as expected may require temporary discontinuance of therapy.1, 4, 17
Angle closure glaucoma has been reported in patients receiving methylphenidate therapy.1, 4, 17 Although the mechanism has not been fully elucidated, patients receiving dexmethylphenidate therapy who are at increased risk for acute angle closure glaucoma (e.g., those with significant hyperopia) should undergo evaluation by an ophthalmologist.1, 4, 17
Increased Intraocular Pressure and Glaucoma
Elevations in intraocular pressure (IOP) have been reported in patients receiving methylphenidate therapy.1, 4, 17
The manufacturers recommend prescribing dexmethylphenidate therapy in patients with open-angle glaucoma or abnormally increased IOP only when the benefits outweigh the risks of treatment.1, 4, 17 If the drug is prescribed, patients with a history of abnormally increased IOP or open-angle glaucoma should be closely monitored during therapy.1, 4, 17
Motor and Verbal Tics and Worsening of Tourette's Syndrome
Onset or exacerbation of motor or verbal tics and worsening of Tourette's syndrome have been reported with CNS stimulants, including methylphenidate.1, 4, 17
Prior to initiation of therapy, patients should be screened for a family history and clinically evaluated for motor or verbal tics or Tourette's syndrome.1, 4, 17 Patients receiving dexmethylphenidate should be routinely monitored for the emergence or worsening of tics or Tourette's syndrome, and treatment discontinued if clinically needed.1, 4, 17
The National Pregnancy Registry for ADHD Medications monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy.1, 4, 17 Clinicians are encouraged to register women who become pregnant while receiving dexmethylphenidate products by calling 866-961-2388 or visiting [Web].1, 4, 17
Published studies and postmarketing reports 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.1, 4, 17 CNS stimulants can cause vasoconstriction and thereby decrease placental perfusion.1, 4, 17 While no fetal or neonatal adverse reactions have been reported with the use of therapeutic dosages of methylphenidate during pregnancy, premature delivery and low birthweight infants have been reported in women dependent on amphetamines.1, 4, 17
In animal embryofetal development studies, delayed fetal skeletal ossification was observed in rats at dexmethylphenidate dosages equivalent to up to 5 times an adult dosage of 20 mg daily.1, 4 In a pre- and post-natal development study, decreased pup weight was observed in male rats at a dexmethylphenidate dosage equivalent to 5 times a human dosage of 20 mg daily.1, 4
Limited data indicate that methylphenidate is distributed into milk, resulting in infant doses of 0.16-0.7% of the maternal weight-adjusted dosage and a milk-to-plasma ratio of 1.1-2.7.1, 4, 17 There are no reports of adverse effects of methylphenidate on breast-fed infants and no reported effects on milk production.1, 4, 17 Long-term neurodevelopmental effects resulting from infant exposure to CNS stimulants are unknown.1, 4, 17
The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for dexmethylphenidate and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1, 4, 17 Infants exposed to dexmethylphenidate through breast milk should be monitored for adverse effects such as agitation, insomnia, anorexia, and reduced weight gain.1, 4, 17
Safety and efficacy of dexmethylphenidate for the treatment of ADHD have been established in pediatric patients 6-17 years of age in controlled clinical studies.1, 4, 17 Safety and efficacy of dexmethylphenidate have not been established in pediatric patients <6 years of age.1, 4, 17
Long-term efficacy of dexmethylphenidate in pediatric patients has not been established.1, 4
Long-term administration of CNS stimulants has been associated with at least a temporary suppression of normal weight and height patterns in pediatric patients.1, 4, 17 Therefore, the manufacturers state that patients requiring long-term therapy with dexmethylphenidate should be carefully monitored, and children who are not growing or gaining height or weight as expected may require temporary discontinuance of therapy.1, 4, 17
In juvenile animal toxicity studies, rats receiving racemic methylphenidate beginning early in the postnatal period and continuing through sexual maturation at a dosage of 4 or more times the 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 maximum recommended pediatric dosage.1, 4 The no-effect level for juvenile neurobehavioral development in rats was approximately 0.5 times the maximum recommended pediatric dosage.1, 4 The clinical relevance of these long-term behavioral effects observed in rats is unknown.1, 4
Pharmacokinetics of dexmethylphenidate hydrochloride administered as conventional or extended-release preparations have not been established in pediatric patients younger than 6 or 18 years of age, respectively.1, 4 Following single-dose oral administration of conventional dexmethylphenidate hydrochloride in children 6-12 years of age, peak plasma concentrations were similar to those achieved in adults, although total systemic exposure (area under the concentration-time curve [AUC]) was somewhat less in children; pharmacokinetics of the drug were similar in boys and girls (mean age of 10 years).1 Following oral administration of equivalent doses of the fixed combination of serdexmethylphenidate chloride and dexmethylphenidate hydrochloride in adults and pediatric patients, dexmethylphenidate exposure in children 6-12 years of age was approximately twice that in adults and adolescents 13-17 years of age.17
Dexmethylphenidate hydrochloride and the fixed combination of serdexmethylphenidate chloride and dexmethylphenidate hydrochloride have not been studied in geriatric patients.1, 4, 17
Safety and efficacy of dexmethylphenidate have not been established in patients with renal impairment.1, 4, 17 Renal impairment is expected to have minimal effect on the pharmacokinetics of the drug.1, 4
Dexmethylphenidate hydrochloride and serdexmethylphenidate chloride have not been studied in patients with hepatic impairment.1, 4, 17
Dexmethylphenidate hydrochloride conventional tablets: Abdominal pain, fever, nausea, and anorexia each occurred in 5% or more of pediatric patients 6-17 years of age receiving dexmethylphenidate hydrochloride conventional tablets in clinical trials and were at least twice as frequent in patients receiving the drug as in those receiving placebo.1 Twitching (motor or vocal tics), anorexia, insomnia, and tachycardia each resulted in discontinuance of dexmethylphenidate hydrochloride conventional tablets in approximately 1% of patients.1
Dexmethylphenidate hydrochloride extended-release capsules: Dyspepsia, decreased appetite, headache, and anxiety each occurred in 5% or more of pediatric patients 6-17 years of age receiving dexmethylphenidate hydrochloride extended-release capsules in clinical trials and were at least twice as frequent in patients receiving the drug as in those receiving placebo.4 Dry mouth, dyspepsia, headache, pharyngolaryngeal pain, and anxiety each occurred in 5% or more of adult patients receiving dexmethylphenidate hydrochloride extended-release capsules in clinical trials.4 Twitching (motor or vocal tics), anorexia, insomnia, and tachycardia each resulted in discontinuance of dexmethylphenidate hydrochloride extended-release capsules in approximately 1% of pediatric patients.4 In adult patients, insomnia, jittery feeling, anorexia, and anxiety each resulted in discontinuance of therapy in about 1-2% of patients.4
Serdexmethylphenidate/dexmethylphenidate capsules: Based on accumulated data from other methylphenidate products, the most common adverse effects (reported in 5% or more of patients and at least twice the rate of placebo) are decreased appetite, insomnia, nausea, vomiting, dyspepsia, abdominal pain, decreased weight, anxiety, dizziness, irritability, affect lability, tachycardia, and increased blood pressure.17
Methylphenidate is not metabolized by cytochrome P-450 (CYP) isoenzymes to a clinically relevant extent.1, 4 Inducers or inhibitors of CYP isoenzymes are not expected to substantially impact the pharmacokinetics of methylphenidate.1, 4 The possibility that drug interactions reported with racemic methylphenidate could also occur with dexmethylphenidate should be considered.1, 4
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Pharmacokinetic interactions are unlikely.1, 4 Methylphenidate is not metabolized by CYP isoenzymes to a clinically important extent; therefore, CYP inducers or inhibitors are not expected to have a clinically important effect on the pharmacokinetics of methylphenidate.1, 4 The d- and l- enantiomers of methylphenidate and serdexmethylphenidate do not substantially inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, and concomitant administration of methylphenidate and the CYP2D6 substrate desipramine did not increase plasma concentrations of desipramine.1, 4, 17
Drugs Affecting or Affected by Transport Systems
Serdexmethylphenidate does not appear to be a substrate or inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1 or 1B3, organic anion transporter (OAT) 1 or 3, organic cation transporter (OCT) 2, or multidrug and toxin extrusion protein (MATE) 1 or 2K in vitro.17
In vitro studies indicate that the presence of alcohol at a concentration of 5 or 40% does have not a clinically important effect on the rate or extent of release of either drug component of the fixed-combination preparation containing serdexmethylphenidate chloride and dexmethylphenidate hydrochloride.17
Concomitant use of dexmethylphenidate 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.1, 4, 17 Use of dexmethylphenidate and serdexmethylphenidate should be avoided on the day of surgery in patients receiving halogenated anesthetic agents.1, 4, 17 The manufacturer of conventional dexmethylphenidate tablets also recommends that blood pressure be monitored during concurrent use.1
Dexmethylphenidate may decrease the efficacy of antihypertensive agents.1, 4, 17 Blood pressure should be monitored and dosage of the antihypertensive agent(s) adjusted as necessary.1, 4, 17
Concomitant use of monoamine oxidase (MAO) inhibitors (e.g., isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, tranylcypromine) and CNS stimulants, including dexmethylphenidate, can cause hypertensive crisis, possibly resulting in death, stroke, myocardial infarction, aortic dissection, ophthalmologic complications, eclampsia, pulmonary edema, and renal failure.1, 4, 17
Dexmethylphenidate is contraindicated in patients currently receiving, or having recently received (i.e., within 14 days), MAO inhibitor therapy.1, 4, 17
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.1, 4, 17 Patients receiving concomitant therapy with dexmethylphenidate and risperidone should be monitored for extrapyramidal symptoms.1, 4, 17
Dexmethylphenidate hydrochloride, the more pharmacologically active ( d-threo ) enantiomer of racemic methylphenidate hydrochloride, is a CNS stimulant.1, 4 Serdexmethylphenidate is a prodrug of dexmethylphenidate.17 The mechanism of action of dexmethylphenidate in the treatment of attention deficit hyperactivity disorder (ADHD) has not been determined.1, 4
Dexmethylphenidate hydrochloride is well absorbed following oral administration.1 Because of first-pass metabolism, mean absolute bioavailability is 22-25%.1, 4 When dexmethylphenidate hydrochloride is administered orally as conventional tablets in fasting patients, peak plasma concentrations are achieved within 60-90 minutes after a dose.1 When the drug is administered as extended-release capsules, peak plasma concentrations are attained at 1.5 hours and again at 6.5 hours after a dose.4 Extended-release capsules are absorbed more slowly but to the same extent as conventional tablets.4 Plasma concentrations of dexmethylphenidate achieved following single-dose oral administration of dexmethylphenidate hydrochloride capsules are comparable to the dexmethylphenidate concentrations achieved following single-dose oral administration of racemic methylphenidate hydrochloride capsules at equimolar doses (twice the total mg amount of dexmethylphenidate hydrochloride).1 Dexmethylphenidate is metabolized principally by de-esterification to form d -ritalinic acid, which has little or no pharmacologic activity.1, 4 In vitro studies indicate that the drug does not inhibit the cytochrome P-450 (CYP) enzyme system.1, 4 The mean plasma elimination half-life of dexmethylphenidate is 2-3 hours in pediatric patients and approximately 3 hours in healthy adults.4
Dexmethylphenidate hydrochloride is commercially available as conventional tablets and extended-release capsules.1, 4 Each bead-filled dexmethylphenidate hydrochloride extended-release capsule contains one-half of the dose as immediate-release beads and one-half as enteric-coated, delayed-release beads, thus providing an immediate release of dexmethylphenidate hydrochloride followed by a second delayed release of the drug.4
Capsules containing serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride contain a fixed molar ratio of 70% serdexmethylphenidate and 30% dexmethylphenidate.17 Conversion of serdexmethylphenidate to dexmethylphenidate is thought to occur mainly in the lower GI tract.17 Oral bioavailability of serdexmethylphenidate is less than 3%.17 Inclusion of the immediate-release dexmethylphenidate component in the fixed-combination preparation allows for rapid attainment of therapeutic concentrations of the active drug.18 Following single-dose oral administration of the fixed combination in the fasted state, peak plasma dexmethylphenidate concentrations are attained in approximately 2 hours, while following oral administration of serdexmethylphenidate alone, peak plasma dexmethylphenidate concentrations are attained in approximately 8 hours.17 The mean terminal elimination half-lives of serdexmethylphenidate and dexmethylphenidate in healthy adults are approximately 5.7 and 11.7 hours, respectively.17
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Dexmethylphenidate hydrochloride and serdexmethylphenidate chloride are subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules, extended-release (containing beads) | 5 mg (beads, delayed-release, enteric-coated extended-release 2.5 mg with immediate-release 2.5 mg)* | Dexmethylphenidate Hydrochloride Extended-release Capsules (C-II) | |
Focalin® XR (C-II) | Novartis | |||
10 mg (beads, delayed-release, enteric-coated extended-release 5 mg with immediate-release 5 mg)* | Dexmethylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
Focalin® XR (C-II) | Novartis | |||
15 mg (beads, delayed-release, enteric-coated extended-release 7.5 mg with immediate-release 7.5 mg)* | Dexmethylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
Focalin® XR (C-II) | Novartis | |||
20 mg (beads, delayed-release, enteric-coated extended-release 10 mg with immediate-release 10 mg)* | Dexmethylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
Focalin® XR (C-II) | Novartis | |||
25 mg (beads, delayed-release, enteric-coated extended-release 12.5 mg with immediate-release 12.5 mg) | Focalin® XR (C-II) | Novartis | ||
30 mg (beads, delayed-release, enteric-coated extended-release 15 mg with immediate-release 15 mg)* | Dexmethylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
Focalin® XR (C-II) | Novartis | |||
35 mg (beads, delayed-release, enteric-coated extended-release 17.5 mg with immediate-release 17.5 mg) | Focalin® XR (C-II) | Novartis | ||
40 mg (beads, delayed-release, enteric-coated extended-release 20 mg with immediate-release 20 mg)* | Dexmethylphenidate Hydrochloride Extended-release Capsules (C-II) | |||
Focalin® XR (C-II) | Novartis | |||
Tablets | 2.5 mg* | Dexmethylphenidate Hydrochloride Tablets (C-II) | ||
Focalin® (C-II) | Novartis | |||
5 mg* | Dexmethylphenidate Hydrochloride Tablets (C-II) | |||
Focalin® (C-II) | Novartis | |||
10 mg* | Dexmethylphenidate Hydrochloride Tablets (C-II) | |||
Focalin® (C-II) | Novartis |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | Serdexmethylphenidate Chloride 26.1 mg (of serdexmethylphenidate) and Dexmethylphenidate Hydrochloride 5.2 mg (of dexmethylphenidate) (equivalent to 28 mg serdexmethylphenidate chloride and 6 mg dexmethylphenidate hydrochloride) | Azstarys® (C-II) | Corium |
Serdexmethylphenidate Chloride 39.2 mg (of serdexmethylphenidate) and Dexmethylphenidate Hydrochloride 7.8 mg (of dexmethylphenidate) (equivalent to 42 mg serdexmethylphenidate chloride and 9 mg dexmethylphenidate hydrochloride) | Azstarys® (C-II) | Corium | ||
Serdexmethylphenidate Chloride 52.3 mg (of serdexmethylphenidate) and Dexmethylphenidate Hydrochloride 10.4 mg (of dexmethylphenidate) (equivalent to 56 mg serdexmethylphenidate chloride and 12 mg dexmethylphenidate hydrochloride) | Azstarys® (C-II) | Corium |
1. Novartis Pharmaceuticals Corporation. Focalin® (dexmethylphenidate hydrochloride) tablets prescribing information. East Hanover, NJ; 2023 Oct.
4. Novartis Pharmaceuticals Corporation. Focalin® XR (dexmethylphenidate hydrochloride) extended-release capsules prescribing information. East Hanover, NJ; 2023 Oct.
17. Corium, LLC. Azstarys® (serdexmethylphenidate chloride and dexmethylphenidate hydrochloride) capsules prescribing information. Boston, MA; 2023 Oct.
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