VA Class:CN802

AHFS Class:

• Respiratory and CNS Stimulants 28:20.32

Generic Name(s):

• Dexmethylphenidate Hydrochloride

• Serdexmethylphenidate Chloride

Chemical Name:

• (α R ,2 R )-α-Phenyl-2-piperidineacetic acid methyl ester hydrochloride

• 3-(((1 S )-1-carboxy-2-hydroxyethyl)carbamoyl)-1-((((2 R )-2-(2-(1 R )-methoxy-2-oxo-1-phenylethyl)piperidine-1- carbonyl)oxy)methyl)pyridinium chloride

Molecular Formula:

• C₁₄H₁₉NO₂•HCl

• C₂₅H₃₀N₃O₈•Cl

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 and lacks pharmacologic activity until converted to dexmethylphenidate in the GI tract.17,18

Dexmethylphenidate hydrochloride or the fixed combination of serdexmethylphenidate chloride and dexmethylphenidate hydrochloride is used in the treatment of attention deficit hyperactivity disorder (ADHD).1,4,17

Attention Deficit Hyperactivity Disorder

Dexmethylphenidate hydrochloride or the fixed combination of serdexmethylphenidate chloride and dexmethylphenidate hydrochloride is used in the treatment of ADHD in children 6 years of age and older, adolescents, and adults.1,4,17 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

Patients with ADHD may exhibit pronounced difficulties and impairment resulting from the disorder across their lifespan.19,506,513,517 The choice of therapeutic intervention(s) depends on the patient's age, comorbid conditions, specific target symptoms, and strengths and weaknesses of the patient, family, school, and community.500,504 A wide variety of treatments have been employed, 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.500,505,506,511,516 Stimulants remain the most effective and most commonly used first-line drugs for management of ADHD in pediatric patients and adults.504,510,511,518 Methylphenidate and amphetamines are associated with moderate to large improvements in ADHD symptoms in children and adolescents and moderate improvements in adults.504,517 An individual's response to methylphenidate versus amphetamines is idiosyncratic.500,505,510

The American Academy of Pediatrics (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 Methylphenidate may be slightly less effective and less well tolerated in preschool-aged children than in school-aged children.512 AAP states that nonstimulants and stimulants other than methylphenidate have not been adequately studied in this age group.500

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

For adolescents (12 years of age to the 18th birthday), AAP recommends that drugs with FDA-approved labeling for treatment of ADHD be used with the adolescent's assent.500 Concurrent use of evidence-based training interventions and/or behavioral interventions is encouraged.500 Educational interventions and individualized instructional supports are necessary 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 provide symptom control while the adolescent is driving.500

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

Nonstimulant drugs may be used alone or in combination with stimulants in patients with ADHD and comorbid conditions (e.g., aggression, anxiety, depression, tic disorders).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 stimulants should be avoided and drugs with 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

For further information on the management of ADHD, see Uses: Attention Deficit Hyperactivity Disorder, in Methylphenidate Hydrochloride 28:20.32.

Clinical Experience with Dexmethylphenidate and Serdexmethylphenidate

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 In the first controlled clinical trial, improvement in symptom scores from baseline to study end (4 weeks) was greater in children receiving dexmethylphenidate hydrochloride conventional tablets than in those receiving placebo.1 In the second trial, children 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 for an additional 2 weeks or to receive placebo.1 Treatment failure occurred in 63% of patients receiving placebo compared with 17% of those receiving dexmethylphenidate.1

Efficacy of dexmethylphenidate hydrochloride extended-release tablets for this indication was established in clinical trials in children 6 years of age and older, adolescents, and adults who met DSM-IV criteria for ADHD (inattentive, hyperactive-impulsive, or combined inattentive/hyperactive-impulsive presentation).4 In a controlled clinical trial in pediatric patients 6-17 years of age, improvement in symptoms from baseline to study end (7 weeks) was greater in children receiving dexmethylphenidate hydrochloride extended-release capsules than in those receiving placebo.4 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 In a controlled clinical trial in adults 18-60 years of age, improvement in signs and symptoms of ADHD from baseline to study end (5 weeks) was greater in adults receiving dexmethylphenidate hydrochloride extended-release capsules than in those receiving placebo.4

Efficacy of serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride for this indication was established in a clinical trial in children 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 Following a 3-week, open-label period during which dosage of the fixed combination was optimized, children were randomized to receive the individually optimized dosage of the fixed combination for an additional week or to receive placebo.17 A smaller mean change in symptom scores, indicating better symptomatic control, was observed in patients receiving serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride compared with those receiving placebo.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

General

Pretreatment Screening

• Prior to initiation of CNS stimulant therapy, pediatric patients and adults should be evaluated for the presence of cardiac disease through a careful medical history, physical examination, and screening for family history of sudden death or ventricular arrhythmias.1,4
• Patients should be evaluated for risk of abuse prior to initiation of CNS stimulant therapy.1,4

Patient Monitoring

• Patients should be monitored for signs of abuse and dependence during CNS stimulant therapy.1,4 (See Potential for Abuse and Dependence under Cautions.)

Administration

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 affect the extent of absorption.1

Dexmethylphenidate hydrochloride extended-release capsules are administered orally once daily in the morning, with or without food.4 The capsules should be swallowed intact and should not be crushed, chewed, 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

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 intact.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 affect the extent of absorption.17

Dosage

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

The recommended initial dosage of dexmethylphenidate hydrochloride as conventional tablets in pediatric patients 6 years of age and older 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 and older 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.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 and older or 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 may be increased at weekly intervals in increments of 5 mg daily in pediatric patients or 10 mg daily in adults, up to a maximum dosage of 30 mg daily in pediatric patients or 40 mg daily in adults.4 In dose-response studies evaluating fixed dosages of 10-30 mg daily in pediatric patients or 20-40 mg daily in adults, all of the dosages within these ranges were more effective than placebo, but there was no clear evidence that the higher dosages within these ranges provided greater average benefits; however, adverse effects and drug discontinuance were dose related.4

The recommended initial dosage of serdexmethylphenidate chloride in fixed combination with dexmethylphenidate hydrochloride in adults and pediatric patients 6 years of age or older is 39.2 mg of serdexmethylphenidate and 7.8 mg dexmethylphenidate once daily.17 Dosage in adults and 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 adults and 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 must be carefully 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 long-term efficacy of dexmethylphenidate preparations has not been evaluated systematically in controlled studies; therefore, the long-term usefulness of the drug should be reevaluated periodically in patients receiving the drug for extended periods, and dosage should be adjusted as needed.1,4,17 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

Special Populations

No special population dosage recommendations at this time.1,4,17

Contraindications

• Concomitant or recent (within 14 days) administration of monoamine oxidase (MAO) inhibitors, since hypertensive crisis could result.1,4
• Known hypersensitivity to dexmethylphenidate, methylphenidate, serdexmethylphenidate, or any ingredient in the formulation.1,4,17

Warnings/Precautions

Warnings

Potential for Abuse and Dependence

CNS stimulants, including dexmethylphenidate, methylphenidate, and amphetamines, have a high potential for abuse and dependence.1,4 The potential for abuse should be assessed prior to initiation of CNS stimulant therapy, and patients should be monitored for signs of abuse and dependence during therapy.1,4 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.1,4

Some evidence indicates that stimulant use does not lead to an increased risk of substance abuse and that effective stimulant therapy for ADHD actually may reduce the risk for subsequent substance use disorders.504,513,525,526,527 However, diversion of stimulants for nonmedical uses has increased in recent decades and is a particular concern among adolescents and young adults seeking enhanced academic or work performance.500,506,528 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

CNS stimulants may be abused by chewing, snorting, injecting, or administering the drugs by other unapproved routes of administration, which may result in overdosage and death.1,4 Manifestations of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and abdominal pain.1,4 Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation also have been observed.1,4

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.1,4

Other Warnings and Precautions

Dexmethylphenidate hydrochloride shares the toxic potentials of racemic methylphenidate, and the usual precautions of racemic methylphenidate therapy should be observed.1,4

Sudden Death and Serious Cardiovascular Events

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.1,4 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.1,4 Results of one retrospective, case-control epidemiologic study showed a possible association between use of stimulant medications (e.g., methylphenidate) and sudden unexplained death in healthy children and adolescents.8,9,10 (See Pediatric Use under Cautions.) Because of postmarketing reports and the results of this and other epidemiologic studies, the US Food and Drug Administration (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.13,14,15,16 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.13,14,15,16 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.13,16 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.14,15

In a study of the effects of dexmethylphenidate hydrochloride (40 mg as extended-release capsules) on the QT interval in healthy individuals, clinically important changes in the QT interval corrected for heart rate (QT_c) were not observed.1,4 In addition, in a study evaluating the abuse potential of serdexmethylphenidate (administered intranasally), clinically important changes in QT_c were not observed in healthy individuals at a mean concentration of 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, and should receive further cardiac evaluation (e.g., ECG, echocardiogram) if initial findings suggest such disease.1,4,8 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.1,4,13,14 Patients who develop exertional chest pain, unexplained syncope, arrhythmias, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.1,4,8

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.

Effects on Blood Pressure and Heart Rate

Stimulants 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.1,4 Although modest increases would not be expected to have short-term sequelae, all patients should be monitored for hypertension and tachycardia.1,4,13,14 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)13,14

Psychiatric Effects

Stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.1,4

Stimulants have the potential to precipitate mixed or manic episodes in patients with comorbid bipolar disorder.1,4 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).1,4

Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, mania) also have been reported in patients without a history of psychotic illness or mania who received usual dosages of stimulants.1,4 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 If psychotic or manic symptoms occur during stimulant therapy, discontinuance of therapy should be considered.1,4

Priapism

Prolonged and painful erections, in some cases requiring surgical intervention, have been reported in adult and pediatric patients receiving methylphenidate.1,4,12 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.1,4,12 Priapism also has occurred during temporary interruptions in therapy (e.g., drug holidays) or following drug discontinuance.1,4,12 If not treated immediately, priapism can lead to permanent penile damage.12 (See Advice to Patients.) 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.12

Peripheral Vascular Effects

Stimulants used to treat ADHD, including dexmethylphenidate, are associated with peripheral vascular disorders, including Raynaud's phenomenon.1,4 Manifestations usually are intermittent and mild, but ulceration of the digits and/or breakdown of soft tissue may occur rarely.1,4 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.1,4 Manifestations generally improve following dosage reduction or drug discontinuance.1,4 Careful observation for digital changes is warranted during ADHD stimulant therapy, and further clinical evaluation (e.g., referral to a rheumatologist) may be appropriate for certain patients.1,4

Growth Suppression

Prolonged administration of stimulants in children with ADHD has been associated with at least a temporary suppression of normal weight and/or height patterns in some patients.1,4 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.1,4,507 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 In a 7-week controlled study in children and adolescents, 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 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.1,4 (See Cautions: GI and Growth Effects, in Methylphenidate Hydrochloride 28:20.32.)

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported in patients receiving dexmethylphenidate.1,4

Specific Populations

Pregnancy

The National Pregnancy Registry for ADHD Medications monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy.1,4 Clinicians are encouraged to register women who become pregnant while receiving dexmethylphenidate by calling 866-961-2388 or visiting [Web].1,4

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.1,4 CNS stimulants can cause vasoconstriction and thereby decrease placental perfusion.1,4 While no fetal or neonatal adverse reactions have been reported with use of therapeutic dosages of methylphenidate during pregnancy, premature delivery and low birthweight have been reported in women dependent on amphetamines.1,4

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

Lactation

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 There are no reports of adverse effects of methylphenidate on breast-fed infants and no reported effects on milk production.1,4 Long-term neurodevelopmental effects resulting from infant exposure to CNS stimulants are unknown.1,4

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 Infants exposed to dexmethylphenidate through breast milk should be monitored for adverse effects such as agitation, insomnia, anorexia, and reduced weight gain.1,4

Pediatric Use

Safety and efficacy of dexmethylphenidate have not been established in children younger than 6 years of age.1,4,17

Long-term efficacy of dexmethylphenidate in pediatric patients has not been established.1,4

Therapy with stimulants may be associated with at least a temporary suppression of growth in children.1,4 (See Growth Suppression 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.1,4 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.8,9,10 (See Sudden Death and Serious Cardiovascular Events under Cautions.)

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

Geriatric Use

Safety and efficacy of dexmethylphenidate have not been established in geriatric patients.1,4

Renal Impairment

Safety and efficacy of dexmethylphenidate have not been established in patients with renal impairment.1,4 Renal impairment is expected to have minimal effect on the pharmacokinetics of the drug.1,4

Hepatic Impairment

Safety and efficacy of dexmethylphenidate have not been established in patients with hepatic impairment.1,4

Common Adverse Effects

Abdominal pain, fever, anorexia, and nausea each occurred in 5% or more of patients 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

Decreased appetite/anorexia, headache, dyspepsia, dry mouth, anxiety, insomnia, vomiting, and pharyngolaryngeal pain each occurred in 5% or more of 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 adults, insomnia, jittery feeling, anorexia, and anxiety each resulted in discontinuance of therapy in about 1-2% of patients.4

The possibility that drug interactions reported with racemic methylphenidate also could occur with dexmethylphenidate should be considered.1,4

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction is unlikely.1,4 Methylphenidate is not metabolized by cytochrome P-450 (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 do not substantially inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, and concomitant administration of methylphenidate with the CYP2D6 substrate desipramine did not increase plasma concentrations of desipramine.1,4

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

Alcohol

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

Anesthetic Agents

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 Use of dexmethylphenidate should be avoided on the day of surgery in patients receiving anesthetic agents.1,4

Antihypertensive Agents

Dexmethylphenidate 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).1,4 Blood pressure should be monitored and dosage of the antihypertensive agent adjusted as necessary.1,4

Monoamine Oxidase Inhibitors

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 Use of dexmethylphenidate concomitantly with MAO inhibitors or within 14 days following discontinuance of MAO inhibitor therapy is contraindicated.1,4

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.1,4 Patients receiving concomitant therapy with dexmethylphenidate and risperidone should be monitored for extrapyramidal symptoms.1,4

Description

Dexmethylphenidate hydrochloride, the more pharmacologically active ( d-threo ) enantiomer of racemic methylphenidate hydrochloride, is a CNS stimulant.1,4 Serdexmethylphenidate is a prodrug and has no pharmacologic activity until converted to dexmethylphenidate in the GI tract.17,18 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 children or 3 hours in 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 adults are approximately 5.7 and 11.7 hours, respectively.17

Advice to Patients

• Importance of providing patient or caregiver with a copy of the manufacturer's patient information (medication guide).1,4
• Risk of abuse and dependence.1,4 Importance of not sharing dexmethylphenidate with others and of storing the drug in a safe (preferably locked) location to prevent abuse.1,4 Advise patient or caregiver on proper disposal of any remaining unused or expired drug.1,4
• Potential risk for serious cardiovascular events, including sudden death, myocardial infarction, stroke, and hypertension.1,4 Importance of informing clinicians immediately of any adverse cardiovascular effects (e.g., exertional chest pain, unexplained syncope, other symptoms suggestive of cardiac disease).1,4,8
• Advise patient or caregiver that dexmethylphenidate can elevate blood pressure and pulse rate.1,4
• Potential for recommended dosages of dexmethylphenidate to cause psychotic or manic symptoms, even in patients without a history of psychotic symptoms or mania.1,4
• Importance of informing male patients and their caregivers about the signs and symptoms of priapism, stressing the need for immediate treatment if it occurs.1,4,12 Younger males, especially prepubertal males, may not recognize the problem or may be embarrassed to tell anyone if it occurs.12
• Importance of informing patients or caregivers about the risk of peripheral vascular disorders, including Raynaud's phenomenon, and the associated signs and symptoms (e.g., feelings of numbness, coolness, or pain in fingers or toes; changes in color from pale to blue to red).1,4 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; further clinical evaluation may be appropriate.1,4
• Potential for dexmethylphenidate to slow growth and cause weight loss.1,4
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,4 Inform women about the existence of a pregnancy registry for ADHD medications.1,4 (See Pregnancy under Cautions.) Advise nursing women to monitor their infants for agitation, poor feeding, and reduced weight gain.17
• Importance of not chewing or crushing the beads contained in dexmethylphenidate hydrochloride extended-release capsules and of not storing the sprinkle/food mixture for later use.4 If the contents of the capsules containing serdexmethylphenidate chloride and dexmethylphenidate hydrochloride are sprinkled in water or over applesauce, importance of administering the mixture immediately or within 10 minutes of mixing and of not storing the mixture for later use.17
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses/conditions (e.g., cardiac/cardiovascular disease, mental/psychiatric disorder, suicidal ideation or behaviors, history of substance abuse).1,4
• Importance of informing patients or caregivers of other important precautionary information.1,4 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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