FOCALIN (Brand for DEXMETHYLPHENIDATE HCL)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
Immediate-release Tablets
-Administer twice daily, with doses at least 4 hours apart. Individualize the timing of administration based on the needs and responses of the patient. In general, avoid dosing late in the day (e.g., less than 6 hours before bedtime) to prevent sleep interference.
-May be administered with or without food.

Extended-release Capsules
-Administer once daily in the morning.
-Swallow whole; do not crush, chew, or divide the capsule. If swallowing is difficult, the capsule may be opened and the entire contents sprinkled on a teaspoon of cool applesauce. Swallow the mixture immediately; do not store for future use. The capsule contents (beads) should not be crushed or chewed. Drinking fluids should follow the intake of the beads with applesauce. In addition, the capsule contents may be administered via nasogastric tube as long as they are not crushed and an adequate amount of fluid is used to wash the full dose down the tube.
-May be administered with or without food; however, administration times relative to food and food composition may need to be individually titrated. A high-fat meal may delay absorption and time to peak effect.

In general, adverse reactions to dexmethylphenidate are relatively frequent but mild at normally prescribed dosages. In addition, adverse reactions may be more frequent and severe during the initial days of stimulant therapy; most will disappear within a few weeks of continued use. During pediatric clinical trials, 7.3% of patients (n = 684; aged 6 to 17 years) treated with immediate-release dexmethylphenidate experienced an adverse reaction that resulted in drug discontinuation; none of the patients receiving extended-release dexmethylphenidate (n = 53) discontinued treatment due to an adverse reaction. The most common reasons for treatment discontinuation were twitching/tics, loss of appetite, sleep disturbance, and tachycardia. These events, along with abdominal discomfort, may occur more frequently in children compared to adults.

During clinical trials of immediate-release or extended-release dexmethylphenidate for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents, gastrointestinal (GI) adverse reactions that occurred in at least 5% of patients receiving dexmethylphenidate and with an incidence of at least twice that of patients in the placebo group included: dyspepsia (8% vs. 4%), decreased appetite (30% vs. 9%), anorexia (6% vs. 1%), nausea (9% vs. 1%), and abdominal pain (15% vs. 6%). In a separate placebo-controlled fixed-dose study in pediatrics, the following dose-related GI reactions were reported versus placebo: vomiting (2% to 9% vs. 24%) and anorexia (5% to 7% vs. 0%). Xerostomia (7% to 20% vs. 4%) was also reported at a higher incidence than placebo in a study of adult patients receiving dexmethylphenidate. Approximately 1% of pediatric patients discontinued treatment due to anorexia. Diarrhea and constipation have also been reported with other methylphenidate-containing products. In pediatric patients, loss of appetite, abdominal pain, and weight loss during prolonged treatment may occur more frequently than other reactions associated with the drug. Anorexia and other appetite changes occur in many pediatric patients in the first days of therapy. Eating small, frequent meals or snacks may help limit appetite problems. Xerostomia may be limited by sucking sugarless hard candy, crushed ice, and drinking plenty of water or other fluids. Abdominal pain is generally mild and infrequent and may respond to dosage reduction if it becomes a continual problem for the patient. Monitor height and weight parameters relative to age at the initiation of treatment and periodically during therapy; interrupt treatment in patients who are not growing or gaining weight as expected.

Cardiovascular events, including sudden death, have been associated with stimulant use in pediatric patients with structural cardiac abnormalities or other serious heart problems. Cardiovascular or cerebrovascular effects associated with dexmethylphenidate or methylphenidate use range in severity from mild to life-threatening and include cardiac murmur, palpitations, angina, chest pain (unspecified), cardiac arrhythmia (arrhythmia exacerbation), sinus tachycardia, bradycardia, hypertension, hypotension, myocardial infarction (reported in adults), stroke (reported in adults), and cerebral arteritis or occlusion. In a nationwide self-controlled case series (n = 1,224), use of methylphenidate in children and adolescents was associated with an increased risk of arrhythmia during the first 8 weeks of therapy (incidence rate ratio [IRR] 1.61; 95% CI 1.48 to 1.74), with the highest risk observed within the first 3 days of treatment (IRR 2.01; 95% CI 1.74 to 2.31) and in those with congenital heart disease (IRR 3.49; 95% CI 2.33 to 5.22). Overall, no significant risk of myocardial infarction was observed, but risk was elevated after the first week of treatment through week 8. Sinus tachycardia may be more common in children than adults. During pediatric clinical trials of dexmethylphenidate, tachycardia was responsible for drug discontinuation in approximately 1% of study participants. In general, stimulant medications at usual doses increase heart rate and blood pressure by an average of 3 to 6 bpm and 2 to 4 mmHg, respectively. The effect of single doses of 40 mg extended-release dexmethylphenidate on the corrected QT interval (QTcF) was evaluated in healthy adult volunteers; dexmethylphenidate did not prolong the QTc interval to any clinically relevant extent. Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during dexmethylphenidate treatment should undergo a prompt cardiac evaluation. Minor manifestations of any of these symptoms may indicate a need for dosage reduction or discontinuation. Severe cardiac adverse effects (e.g., arrhythmia, tachycardia) may be associated with dexmethylphenidate toxicity; evaluate patients carefully who present with cardiac symptoms for possible overdose. Dexmethylphenidate should be used with caution in patients with conditions that would be expected to worsen by an increase in heart rate or blood pressure. Pulse and blood pressure measurements should be obtained at baseline, after dosage increases, and periodically throughout dexmethylphenidate therapy.

During a clinical trial of extended-release dexmethylphenidate for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents, centrally-mediated adverse reactions that occurred in at least 5% of patients receiving dexmethylphenidate and with an incidence of at least twice that of patients in the placebo group included: headache (25%) and insomnia (5% to 17%). Other events occurring more frequently with dexmethylphenidate than placebo in adult clinical trials included feeling jittery or restlessness (12%) and dizziness (6%). In pediatric clinical trials, approximately 1% of patients discontinued treatment due to insomnia. Mild euphoria may occur in the first weeks of treatment. Convulsions (seizures) and drowsiness have also been reported with dexmethylphenidate use. Fatigue and migraine have been reported with other methylphenidate-containing products. Nervousness and insomnia are common adverse reactions during the use of methylphenidate-class products and may occur more frequently in pediatric patients. These effects may be limited by dosage reduction or omitting the afternoon or evening doses. Insomnia and restlessness will typically resolve within a few days of use, provided the dosage is appropriate, and doses are not administered within 6 hours of bedtime. Avoidance of exercising late in the day, limiting caffeinated beverages, and setting regular bedtime schedules may limit sleep disruption. Interrupted sleep patterns may indicate a need for dosage reduction. Once-daily morning dosing may be effective in some patients and may also help to limit intolerable adverse reactions.

During a clinical trial of extended-release dexmethylphenidate for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, anxiety occurred in at least 5% of patients receiving dexmethylphenidate and with an incidence of at least twice that of patients in the placebo group (6% vs. 0%). In a separate placebo-controlled fixed-dose study in pediatric patients, the following psychiatric effects occurred more frequently with active treatment than placebo: depression (0% to 3% vs. 0%), emotional lability (0% to 3% vs. 2%), and irritability (0% to 5% vs. 0%). In adult clinical trials, 1.2% of patients discontinued treatment due to anxiety. Disorientation has been reported with other methylphenidate-containing products. Aggression, hostility, and suicidal ideation or behaviors have been reported in both clinical trials and postmarketing experience with medications used to treat ADHD. Although causality to the drugs has not been established and these behaviors are often observed in children and adolescents with ADHD, close monitoring is recommended. Patients and their caregivers should be advised to promptly report any changes in mood or behavior. If suicide-related events emerge during treatment, consideration should be given to dose reduction or drug discontinuation, especially if symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Treatment emergent psychotic or manic symptoms (e.g., psychosis, hallucinations, delusional thinking, or mania) in patients without a prior history of such events can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% of stimulant-treated patients compared to 0% placebo. In a cohort study assessing 221,846 adolescents and young adults who received a prescription for a stimulant for ADHD, new-onset psychosis occurred in approximately 1 in 660 patients. The percentage of patients who had a psychotic episode was 0.1% in patients receiving methylphenidate compared to 0.21% in patients receiving amphetamine (hazard ratio with amphetamine use, 1.65; 95% CI 1.31 to 2.09). The median time from when the stimulant was dispensed to the psychotic episode was 128 days. Clinicians should be aware that while such effects are relatively common with both ADHD and stimulant use, excessive symptoms (agitation, euphoria, delirium, confusion, hallucinations) may be a sign of excessive dosage or toxicity.

During clinical trials of dexmethylphenidate in pediatric patients for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), 1 of the most common reasons for treatment discontinuation was twitching (described as motor or vocal tics, 1% incidence). Arthralgia, dyskinesia, muscle cramps, rhabdomyolysis, and tremor have also been reported with dexmethylphenidate; stimulant-induced rhabdomyolysis is most often associated with sympathomimetic toxicity. Myalgia has been reported with other methylphenidate-containing products.

Data are inadequate to determine whether chronic use of stimulants, such as dexmethylphenidate, causes long-term growth inhibition. Although data are limited, available studies do not indicate that stimulant use compromises the attainment of normal adult height and weight in most children. Practitioners should monitor height and weight parameters relative to age at treatment initiation and periodically thereafter (at minimum yearly). Patients who are not growing or gaining weight as expected may need to have their treatment interrupted. In a 24-month follow-up, the MultiModal Treatment Study showed a deceleration of growth of roughly 1 cm per year with stimulant use. In general, growth remained in the normal curve for most children, except those in the lowest percentiles of height for age. Data obtained on the effects of stimulants on growth suppression in children 7 to 10 years of age suggested that regularly medicated children (7 days/week throughout the year) had a temporary average slowing in growth of 2 cm in height and 2.7 kg in weight over 3 years. Reduction of annual growth rate was maximal in the first year, decreased in the second year, and absent in the third year of treatment; however, no compensatory growth rebound effects were found while on stimulant therapy. In a 7-week double-blind placebo-controlled trial of extended-release dexmethylphenidate, mean weight gain was greater for patients receiving placebo (+0.4 kg) than for patients receiving active drug (-0.5 kg). Proposed mechanisms of growth inhibition include the suppression of appetite or an alteration in growth hormone secretion. Growth rebound has been observed after stimulant discontinuation and some experts recommend the use of drug holidays to allow growth to 'catch-up'. However, drug holidays are typically reserved for children with well-controlled attention-deficit hyperactivity disorder (ADHD) symptoms and are of unproved value in limiting growth suppression.

The onset or exacerbation of motor and verbal tics has been reported with use of methylphenidate-class products. In clinical trials of pediatric patients treated with dexmethylphenidate, 1% of patients discontinued treatment due to motor or verbal tics. Patients should be monitored for the emergence or worsening of tics or Tourette's syndrome; consider a dose reduction or discontinuation of treatment if clinically indicated.

Hypersensitivity reactions, including anaphylactoid reactions and angioedema, have been reported with dexmethylphenidate. In addition, immune reactions including rash, urticaria, fever, exfoliative dermatitis, erythema multiforme, thrombocytopenic purpura, vasculitis, and alopecia have also been reported. Pruritus was reported in 3% or less of pediatric patients during dexmethylphenidate clinical trials and was considered dose-related.

Liver abnormalities, including elevated hepatic enzymes and severe hepatic injury (hepatic failure), have been reported with dexmethylphenidate. Hyperbilirubinemia has also been reported with other methylphenidate-containing products.

Psychological dependence, physiological dependence, and tolerance may occur with dexmethylphenidate therapy. Abrupt discontinuation or a significant dose reduction of CNS stimulants after prolonged use may produce withdrawal symptoms that include dysphoria, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.

Stimulants, such as dexmethylphenidate, are associated with peripheral vasculopathy. Effects of peripheral vasoconstriction, including Raynaud's phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms are usually intermittent and mild and generally improve after reduction in dose or discontinuation of drug. However, very rare sequelae include digital skin ulcer and/or soft tissue breakdown. Carefully monitor for digital changes during treatment with stimulant medications. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

The sympathetic stimulation of stimulants, including dexmethylphenidate, may block aqueous outflow and raise intraocular pressure, exacerbating ocular hypertension or glaucoma. Visual impairment such as blurred vision, mydriasis, diplopia, ocular pain, and accommodation disorder has been reported with stimulant use. Patients should report any new or worsening visual disturbance; ophthalmic examination may be required.

Dexmethylphenidate overdosage primarily presents as central nervous system overstimulation and excessive sympathomimetic effects. Signs and symptoms of toxicity may include vomiting, agitation, tremor, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperhidrosis, flushing, headache, hyperthermia, tachycardia, hypertension, palpitations, hypotension, mydriasis, and dryness of mucous membranes. Severe manifestations of dexmethylphenidate overdose include rhabdomyolysis, cardiac arrhythmias, seizures, and coma. Treatment consists of appropriate supportive measures.

Frequent or prolonged erections and priapism, sometimes requiring surgical intervention, have been reported with methylphenidate products, such as dexmethylpheindate, in both adult and pediatric patients. Prolonged erections (more than 4 hours) in male patients should be promptly reported, as immediate diagnosis and treatment are essential to avoid tissue damage. Priapism can occur in males of any age; younger males, particularly those who have not reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs. In a review of methylphenidate products by the FDA, the median age of patients who experienced priapism was 12.5 years (range: 8 to 33 years). Reported cases of priapism did not occur with drug initiation, but have occurred after a period of time on stimulant therapy and often subsequent to a dose increase. Priapism has also been reported during periods of drug withdrawal (e.g., drug holidays or discontinuation). Caution should be used when considering changing male patients from stimulant to non-stimulant medications; atomoxetine is also associated with priapism in young males and appears to carry a higher risk of the condition compared to methylphenidate. Gynecomastia has also been reported with other methylphenidate-containing products.

Serotonin syndrome has been reported during postmarketing use when methylphenidate products are used in combination with serotonergic drugs. Symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and seizures. If such symptoms emerge, discontinue dexmethylphenidate and any concomitant serotonergic agent immediately and initiate supportive symptomatic treatment.

Hematologic disorders, including anemia, leukopenia, and thrombocytopenia, have been reported with dexmethylphenidate. Pancytopenia and hematuria have also been reported with other methylphenidate-containing products. Periodic monitoring of blood counts is advisable for those on chronic therapy.

During a fixed-dose study of extended-release dexmethylphenidate for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents, nasal congestion (0% to 5%) occurred more frequently with dexmethylphenidate than placebo and was dose-related. The following side effects occurred in treated adults at rates higher than with placebo: pharyngolaryngeal pain (4% to 7%), Fever, cough, dyspnea, and naso-pharyngitis have also been reported with dexmethylphenidate and/or with other methylphenidate-class products.

Dexmethylphenidate is contraindicated in patients with a known hypersensitivity to dexmethylphenidate, methylphenidate, or any component of these products.

CNS stimulants should be used with caution in those with bipolar disorder or a pre-existing psychotic disorder (e.g., schizophrenia). CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychosis. These medications can also induce mania or a mixed episode in patients with bipolar disorder. Prior to initiating treatment with dexmethylphenidate, screen patients for risk factors for bipolar disorder or developing an episode of mania (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). At recommended doses, CNS stimulants may also cause psychotic or manic symptoms (such as hallucinations, delusions, or mania) in patients without a prior history of psychosis or mania. Advise patients and their caregivers to promptly report suicidal ideation or any changes in mood or behavior and consider discontinuing treatment if these symptoms occur.

Central nervous system (CNS) stimulants, such as dexmethylphenidate, have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Caution is recommended in patients with a known history of substance abuse, including alcoholism; evaluate patients for a personal or family history of abuse or dependence on alcohol (alcoholism), prescription medications, or street drugs. Assess each individual's risk for abuse, misuse, or addiction before prescribing a CNS stimulant, and monitor for the development of these behaviors or conditions throughout treatment. Children and adolescents with attention-deficit hyperactivity disorder (ADHD) are more prone to substance abuse compared to those without ADHD, and those with co-occurring mental health conditions (e.g., depression, disruptive behavior disorders) are at even greater risk; however, appropriate treatment of ADHD with medication and behavior therapy may reduce the risk of developing a substance abuse disorder. The American Academy of Pediatrics recommends an active substance abuse disorder be treated appropriately before beginning stimulant medication. In patients with well-documented ADHD that predates the onset of substance abuse, a careful risk/benefit assessment must be conducted and appropriate consultation (e.g., a psychiatrist or addiction specialist) is suggested. To reduce the risk of substance abuse in patients who are prescribed stimulants, prescribers should take special care to 1.) confirm an accurate diagnosis of ADHD, 2.) screen older children and adolescents for use of alcohol, marijuana, and other drugs, 3.) provide age-appropriate anticipatory guidance (e.g., discuss proper medication use, risk of misuse, diversion, and abuse, safe storage of medication, appropriate transition to self-administration in older children), and 4.) carefully document and monitor prescription records closely. Prescribing and dispensing the smallest appropriate quantity may help to minimize abuse, misuse, and overdosage. CNS stimulants can be diverted for non-medical use into illicit channels or distribution. The most common source of non-medical use is sharing from family or friends with misuse of the patient's own prescription or obtaining from illicit channels occurring less frequently. Sharing of CNS stimulant medications can lead to substance abuse disorder and addiction in those they are shared with. Misuse and abuse of CNS stimulants can result in potential for overdose or poisoning and death; the risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Educate patients and their families about these risks, proper storage, and proper disposal of any unused medication. Misuse or abuse may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with stimulant abuse or misuse.

Psychological dependence, physiological dependence, and tolerance may occur with dexmethylphenidate therapy. Abrupt discontinuation or a significant dose reduction of CNS stimulants after prolonged use may produce withdrawal symptoms that include dysphoria, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation. Consider monitoring for withdrawal symptoms after significant dose reduction or discontinuation after prolonged use.

Dexmethylphenidate is not FDA-approved for obesity treatment. Eating disorders, such as anorexia nervosa or bulimia nervosa, should be ruled out prior to treatment with stimulants. Patients with eating disorders may have physiologic complications and metabolic abnormalities that increase their risk of drug-induced adverse effects. Because stimulants are known to cause appetite suppression and weight loss, the potential for abuse in patients with eating disorders should be considered.

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosages. Avoid use of CNS stimulants in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. Prior to initiating any CNS stimulant, carefully assess patient for the presence of cardiac disease (i.e., perform a careful patient history, assess for any family history of sudden death or ventricular arrhythmia, and complete a physical exam) and counsel patients to report symptoms of cardiac disease (i.e., exertional chest pain, unexplained syncope) immediately. Although it is reasonable for a health care provider to obtain an ECG as part of the cardiovascular evaluation, it is not mandatory. Treatment with stimulants should not be withheld because an ECG is not performed. However, any patient with significant findings on physical examination, ECG, or from patient or family history (such as known congenital heart disease, structural heart disease, arrhythmias, or a family history of sudden cardiac death in members younger than 35 years of age) should be referred for consultation with a pediatric cardiologist prior to starting the stimulant medication. Overall, studies have not shown an association between the use of ADHD medications and adverse cardiovascular events; however, long-term cardiovascular risks associated with ADHD medications are unknown. Careful monitoring should be performed after initiation of stimulant medications; if any abnormal findings or arrhythmias are diagnosed during treatment, consider discontinuation of the stimulant.

CNS stimulant medications, including dexmethylphenidate, can cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Some individuals may have larger increases. Monitor all patients receiving dexmethylphenidate for hypertension and tachycardia.

In rare instances, stimulant medications may cause prolonged and sometimes painful erections (priapism). All male patients and their caregivers should be counseled on the signs and symptoms of priapism and the importance of seeking immediate medical attention if an erection lasting longer than 4 hours occurs. Immediate diagnosis and treatment are essential to avoid tissue damage. Priapism can occur in males of any age; younger males, particularly those who have not reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs. In a review of methylphenidate products by the FDA, the median age of patients who experienced priapism was 12.5 years (range: 8 to 33 years). Reported cases have occurred after a period of time on stimulant therapy and often subsequent to a dose increase. Priapism has also been reported during periods of drug withdrawal (e.g., drug holidays or discontinuation). Caution should be used when considering changing male patients from stimulant to non-stimulant medications; atomoxetine is also associated with priapism in young males and appears to carry a higher risk of the condition compared to methylphenidate.

Stimulant medications are associated with peripheral vasculopathy, including Raynaud's phenomenon. Worsening of peripheral vascular disease is possible. Effects on circulation have been observed with therapeutic doses at different times throughout therapy in all age groups. Signs and symptoms are usually intermittent and mild and generally improve after reduction in dose or discontinuation of drug. However, very rare sequelae include digital skin ulcer and/or soft tissue breakdown. Carefully monitor all patients for digital changes during treatment with stimulant medications, especially those with pre-existing circulation problems. Instruct patients to seek immediate medical attention if any new digital numbness, pain, skin discoloration, or temperature sensitivity occur, or if unexplained wounds appear on their fingers or toes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Concomitant use of halogenated anesthetics and dexmethylphenidate may increase the risk of sudden blood pressure and heart rate increase during surgery. Monitor blood pressure and avoid use of dexmethylphenidate in patients being treated with anesthetics on the day of surgery.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Monitor for growth inhibition by monitoring height and weight parameters relative to age at treatment initiation and periodically thereafter (at minimum yearly). Patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

Dexmethylphenidate is contraindicated with concurrent use or use within 14 days of MAOI therapy. Concurrent use may precipitate hypertensive crisis.

Because stimulants cause vasoconstriction, they may decrease placental perfusion. Neonates born to stimulant-dependent mothers are at increased risk for premature delivery and low birth weight. In addition, neonates with in utero exposure to stimulants may experience withdrawal after delivery; monitor the newborn for symptoms of withdrawal such as feeding difficulty, irritability, agitation, and excessive drowsiness.

CNS stimulants, including dexmethylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported. Prior to initiating dexmethylphenidate, carefully assess family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome. Regularly monitor dexmethylphenidate-treated patients for the emergence or worsening of tics or Tourette's syndrome and discontinue treatment if clinically appropriate.

Dexmethylphenidate should be used cautiously in patients at risk of glaucoma. Increased intraocular pressure (IOP) and angle closure glaucoma have been reported in association with dexmethylphenidate treatment. While the mechanism is not clear, dexmethylphenidate-treated patients considered at risk for acute angle closure glaucoma (e.g. patients with significant hyperopia) should be evaluated by an ophthalmologist. Patients with a history of open-angle glaucoma or abnormally increased IOP should only receive dexmethylphenidate if the benefit of treatment outweighs the risk. These patients should be monitored closely for changes in vision. Visual disturbance has been reported with the use of dexmethylphenidate and may present as difficulties with accommodation and blurring of vision.

Description: Dexmethylphenidate is a central nervous system (CNS) stimulant used to treat attention-deficit hyperactivity disorder (ADHD). It consists of the d-threo-enantiomer of methylphenidate, which is primarily responsible for the beneficial effects of racemic methylphenidate (the l-enantiomer appears to have negligible activity). Dexmethylphenidate is considered twice as potent as racemic methylphenidate. Researchers originally postulated that this increase in CNS potency might improve the adverse reaction profile when compared to racemic methylphenidate; however, actual clinical differences are uncertain. Stimulant medications, such as dexmethylphenidate, are considered first-line agents for ADHD. When compared to amphetamines, methylphenidate stimulants have equal efficacy and a similar adverse reaction profile. Peripheral pharmacologic activities are milder than those of the amphetamines, slightly decreasing the likelihood of appetite suppression and tic exacerbation. As a class, stimulants have been associated with sudden death in patients with structural cardiac abnormalities or other serious cardiac disease when used at recommended ADHD doses, and they should be avoided in pediatric patients with structural heart defects, cardiomyopathy, coronary artery disease, serious cardiac arrhythmias, or other serious cardiac disease as these patients may be at risk for adverse cardiac events. The American Academy of Pediatrics and the American Heart Association recommend careful screening of all children and adolescents prior to initiating pharmacologic therapy for ADHD, including a detailed patient and family history and physical examination; any significant findings should be further assessed and referred for consultation with a pediatric cardiologist prior to initiating treatment. Dexmethylphenidate is FDA-approved for use in pediatric patients 6 years and older.

For the treatment of attention-deficit hyperactivity disorder (ADHD):
-for the treatment of ADHD in persons naive to methylphenidate or switching from a stimulant other than methylphenidate:
Oral dosage (immediate-release):
Children and Adolescents 6 to 17 years: 2.5 mg PO twice daily, initially. May increase the dose by 2.5 to 5 mg/day at weekly intervals based on clinical response. The FDA-approved maximum dose is 20 mg/day. However, a maximum dose of 50 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release):
Children and Adolescents 6 to 17 years: 5 mg PO once daily in the morning, initially. May increase the dose by 5 mg/day at weekly intervals based on clinical response. The FDA-approved maximum dose is 30 mg/day. However, a maximum dose of 50 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
-for the treatment of ADHD in persons currently receiving methylphenidate:
Oral dosage (immediate-release):
Children and Adolescents 6 to 17 years: 50% of total daily dose of racemic methylphenidate given as dexmethylphenidate PO in 2 divided doses, initially. May increase the dose by 2.5 to 5 mg/day at weekly intervals based on clinical response. The FDA-approved maximum dose is 20 mg/day. However, a maximum dose of 50 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.
Oral dosage (extended-release):
Children and Adolescents 6 to 17 years: 50% of total daily dose of racemic methylphenidate given as dexmethylphenidate PO once daily in the morning, initially. Persons taking immediate-release dexmethylphenidate may be switched to extended-release dexmethylphenidate at the same total daily dose taken once daily. May increase the dose by 5 mg/day at weekly intervals based on clinical response. The FDA-approved maximum dose is 30 mg/day. However, a maximum dose of 50 mg/day may be considered. Reduce dose or, if necessary, discontinue therapy if paradoxical aggravation of symptoms or other adverse reactions occur. If improvement is not observed after appropriate dosage adjustment over a 1-month period, discontinue therapy.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 5 years: Safety and efficacy have not been established.
6 to 12 years: 20 mg/day PO immediate-release formulation and 30 mg/day PO extended-release formulation (FDA-approved labeling); however, up to 50 mg/day PO has been used off-label (both formulations).
-Adolescents
20 mg/day PO immediate-release formulation and 30 mg/day PO extended-release formulation (FDA-approved labeling); however, up to 50 mg/day PO has been used off-label (both formulations).

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; use with caution, as dexmethylphenidate is metabolized by the liver.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Dexmethylphenidate, the more pharmacologically active d-enantiomer of racemic methylphenidate, is a central nervous system (CNS) stimulant. Its exact mechanism of action for the treatment of attention-deficit hyperactivity disorder (ADHD) is not established. Dexmethylphenidate is an indirect agonist; it inhibits the reuptake of dopamine and norepinephrine, facilitating their release into the synaptic cleft. As a result, sympathomimetic activity in the CNS is increased. There is some evidence that the alteration of dopamine transport systems by dexmethylphenidate may indirectly augment the action of serotonin, but further pharmacologic research is needed to understand these processes. The main sites of CNS activity appear to be the brain stem arousal system and the cerebral cortex, including the subcortical structures of the thalamus. Dexmethylphenidate-induced CNS stimulation produces a decreased sense of fatigue, an increase in motor activity and mental alertness, and mild euphoria. Improved attention spans, decreased distractibility, increased ability to follow directions or complete tasks, and decreased impulsivity and aggression have been noted when stimulants are prescribed for the treatment of ADHD.

In the periphery, the sympathomimetic actions of dexmethylphenidate are minimal at therapeutic doses and are less than those of the amphetamines or cocaine. Heart rate typically increases slightly with normal therapeutic doses of stimulants (about 3-6 bpm); however, a reflexive decrease in heart rate in response to increased blood pressure can also occur. At high doses, such as in overdoses, stimulants can cause significant hypertension, tachycardia, arrhythmias, and other serious complications.

Pharmacokinetics: Dexmethylphenidate is administered orally. Plasma protein binding of the d-enantiomer is not known; however, racemic methylphenidate is approximately 12% to 15% protein bound. Volume of distribution (Vd) is 2.65 +/- 1.11 L/kg. Dexmethylphenidate is metabolized in the liver via de-esterification to the primary metabolite d-alpha-phenyl-piperidine acetic acid (d-PPA, d-ritalinic acid), which has little or no pharmacological activity. There is no in vivo interconversion to the l-threo-enantiomer. Only small quantities (less than 0.5%) of unchanged drug are eliminated in the urine, most of the dose (80%) is renally excreted as the inactive metabolite. Mean elimination half-life in pediatric patients is approximately 2 to 3 hours; adults have a slightly longer half-life of 3 hours.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Dexmethylphenidate is well absorbed after oral administration; however, mean bioavailability is only 22% to 25% due to first pass metabolism. Plasma concentrations decline exponentially after oral administration. Both formulations, when given to pediatric patients and adults as a single dose (immediate-release: 2.5 mg, 5 mg, or 10 mg; extended-release: 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg), result in a Cmax and AUC proportional to the dose given. Plasma dexmethylphenidate concentrations are comparable to those achieved after a single racemic methylphenidate dose given in twice the total mg amount (equimolar with respect to dexmethylphenidate). Pharmacokinetic parameters are similar with single and repeat dosing indicating no significant drug accumulation.

Immediate-release formulations
Immediate-release dexmethylphenidate is readily absorbed, reaching maximum concentrations approximately 1 to 1.5 hours after administration (fasted state). When given with a high fat meal, Tmax increases from 1.5 hours to 2.9 hours; however, Cmax and AUC are comparable in fasted and non-fasted states.

Extended-release formulations
Extended-release dexmethylphenidate produces a biphasic pharmacokinetic profile to provide day-long medication availability with once daily administration. Using Spheroidal Oral Drug Absorption (SODAS) technology, the capsules contain the drug in both rapid-release and enteric-coated delayed-release beads that allow for 50% of the dose to be released rapidly and 50% to be released approximately 4 hours later. Extended-release dexmethylphenidate is readily absorbed, with an early Tmax of 1.5 hours (range: 1 to 4 hours) and a late Tmax of 6.5 hours (range: 4.5 to 7 hours) after administration. Mean time to interpeak minimum (Tmin) is slightly shorter and time to late Tmax is slightly longer for the extended-release product given once daily compared to the immediate-release product (2 doses given 4 hours apart); ranges observed are greater with the extended-release product. In addition, extended-release dexmethylphenidate given once daily exhibits a lower late Cmax and higher interpeak Cmin, resulting in fewer fluctuations in plasma concentrations compared to twice daily dosing with the immediate-release tablet.

The effects of food on dexmethylphenidate extended-release capsules have not been studied. However, the effects of food on extended-release methylphenidate (Ritalin LA) capsules, also formulated with SODAS technology, have been studied and, per FDA-approved labeling, are applicable to extended-release dexmethylphenidate. When the drug is given with a high-fat meal, absorption is delayed, resulting in variable delays in initial Tmax, interpeak Tmin, and late Tmax. The initial Cmax is unaffected, but late Cmax is decreased by approximately 25%. There is no evidence of dose dumping in the presence or absence of food. When administered with applesauce, the pharmacokinetic profile does not differ from that of the fasted state.


-Special Populations
Pediatrics
Children
Cmax was similar, and AUC was somewhat lower in children (aged 6 to 12 years) compared to adults after single dose administration of immediate-release dexmethylphenidate during clinical trials. The pharmacokinetic profile of extended-release dexmethylphenidate has not been studied in the pediatric population. However, a similar formulation of racemic methylphenidate (Ritalin LA), when studied in children 7 to 12 years of age (n = 18) demonstrated a similar initial Tmax compared to adults. Time to interpeak minimum (Tmin) and late Tmax was delayed and more variable in children compared to adults.

Hepatic Impairment
Dexmethylphenidate pharmacokinetic parameters have not been evaluated in the presence of hepatic dysfunction.

Renal Impairment
Dexmethylphenidate pharmacokinetic parameters have not been evaluated in the presence of renal dysfunction. Because very little unchanged drug is excreted in the urine, renal insufficiency is not expected to appreciably alter the pharmacokinetic profile.

Gender Differences
Pharmacokinetic parameters were similar for boys and girls (mean age 10 years) who were given immediate-release dexmethylphenidate tablets during clinical trials. However, in a single dose study conducted in adults, mean AUC (adjusted for body weight) was 25% to 35% higher in females (n = 6) compared to males (n = 9) after a single 20 mg dose of immediate-release dexmethylphenidate. Tmax and half-life were comparable for both sexes. Additionally, initial Cmax (adjusted for body weight) was 45% higher in women who received extended-release dexmethylphenidate. Interpeak Cmin and late Cmax also tended to be slightly higher in women, although the difference was not clinically significant.