VYVANSE (Brand for LISDEXAMFETAMINE DIMESYLATE)

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

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Administer once daily in the morning. Avoid afternoon doses due to the potential for sleep interference.
-May be given without regard to meals.
-Do not administer less than 1 chewable tablet or capsule per day; a single chewable tablet or capsule should not be divided.
-Chewable tablets: Must be chewed completely before swallowing.
-Capsules: Swallow whole. Alternatively, the capsule may be opened and the contents mixed with yogurt, water, or orange juice.-If the capsule contents include any compacted powder, use a spoon to break apart the powder.
-Mix the entire capsule contents in the medium until completely dispersed. The active ingredient will dissolve completely, but a film containing the inactive ingredients may remain in the glass or container after the mixture is consumed.
-Instruct the patient to consume the entire mixture immediately; do not store.

Adverse reactions to lisdexamfetamine are frequent but usually mild to moderate in pediatric patients with attention-deficit hyperactivity disorder (ADHD) at normally prescribed dosages. The adverse reactions may be more frequent or severe during the initial days of therapy. Such adverse reactions are often tolerable; however, lisdexamfetamine has also been reported as a frequently suspected drug in serious adverse drug reactions in children, according to the Institute for Safe Medication Practices (ISMP). Of the serious reactions reported to the FDA during a 5-year time span (2008 to 2012), psychiatric effects (e.g., suicidal behaviors, aggression, psychotic episodes) and movement disorders were predominant for lisdexamfetamine. Because reports submitted to the FDA likely represent only a portion of actual events and may be skewed, further investigation to determine frequency of occurrence and causality to the drug is warranted.

Insomnia (13% to 22%) is one of the most common adverse reactions to stimulant use. During lisdexamfetamine clinical trials for attention-deficit hyperactivity disorder (ADHD), insomnia was responsible for drug discontinuation in 1% of the pediatric study population. Insomnia may be more frequent or severe during initial therapy, but typically resolves within a few days provided the dosage is appropriate and doses are not administered late in the day. Avoidance of exercising late in the day, limiting caffeinated beverages, and setting regular bedtime schedules may limit sleep disruption. Continued interrupted sleep patterns may indicate a need for dose reduction. Nightmares were reported in 2% of adult patients receiving lisdexamfetamine for binge eating disorders during clinical trials.

Central nervous system adverse reactions are common with stimulant use. Dizziness (5%), drowsiness (2% vs. 1% placebo), restlessness (3% adults), and tremor (2% adults) have been reported during clinical trials of lisdexamfetamine for attention-deficit hyperactivity disorder. In children, psychomotor hyperactivity was responsible for drug discontinuation in 1% of the study population. In adult trials for binge eating disorder, feeling jittery (6%), increased energy (2%), restlessness (2%), and paresthesias (2%) have been reported. Mild euphoria and restlessness have been noted in the first weeks of stimulant treatment. In addition, headache, paresthesias, and overstimulation have been reported with dextroamphetamine use. Children who become overly preoccupied with a task (overfocused or inflexible) or are described as 'zombie-like' are considered to exhibit supranormalization; these behaviors typically require dosage reduction. Toxic effects of amphetamines are variable in children and can occur over a wide dosage range. Practitioners should be alert to the signs of excessive dosages or overdose which may include restlessness, tremor, and overactive reflexes. Of the serious events reported to the FDA during a 5-year time span (2008 to 2012), psychiatric effects (e.g., suicidal behaviors, aggression, psychotic episodes) and movement disorders were predominant for lisdexamfetamine.

Stimulant medications, such as lisdexamfetamine, can exacerbate behavioral disturbances, psychosis, or thought disorders. New onset psychotic symptoms (e.g., hallucinations, delusional thinking, euphoria, dysphoria, or mania) can occur in individuals without a prior history of psychosis. 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. If such symptoms occur, consider discontinuation of therapy. 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 has not been established and these behaviors may be related to the presence of ADHD itself, close monitoring is recommended. Advise patients and their caregivers 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. Irritability (10%), affect or emotional lability (3%), anxiety (5% to 6% adults), and agitation (3% adults) have been reported during clinical trials of lisdexamfetamine; irritability was responsible for drug discontinuation in 1% of the adolescent study population during ADHD trials. Dermatillomania, logorrhea, and anger have also been reported with amphetamine use. Psychosis and hallucinations may also be associated with amphetamine toxicity or abuse. Due to its toxic effects in overdose, lisdexamfetamine should only be used in those with major depression or suicidal ideation when absolutely necessary. Abrupt discontinuation of amphetamines after chronic administration may unmask severe depression, suicidal ideation, anxiety, agoraphobia, dysphoria, psychomotor agitation, or symptoms of overactive behaviors. Of the serious events reported to the FDA during a 5-year time span (2008 to 2012), psychiatric effects (e.g., suicidal behaviors, aggression, psychotic episodes) and movement disorders were predominant for lisdexamfetamine.

Visual impairment, including blurred vision, diplopia, mydriasis, or difficulties with visual accommodation, has been reported with postmarketing use of lisdexamfetamine. Patients are encouraged to report any unusual changes in vision promptly for examination and evaluation.

The onset or exacerbation of motor and/or verbal tics has been reported in clinical trials and postmarketing use of lisdexamfetamine. In clinical trials of pediatric patients, tics occurred in 2% of children receiving lisdexamfetamine compared to no reports in the placebo group. Tics were also the cause of drug discontinuation in 1% of children in pediatric clinical trials for attention-deficit hyperactivity disorder (ADHD). Dyskinesia has also been reported during postmarketing use of lisdexamfetamine. Patients should be monitored for the emergence or worsening of dyskinesias, tics, or Tourette's syndrome; consider dose reduction or discontinuation of treatment if clinically indicated.

Stimulant medications, including lisdexamfetamine, have the potential to lower the seizure threshold in patients with a prior history of seizures, in patients with a history of EEG abnormalities without a history of seizures, and rarely in patients without a seizure history or EEG abnormalities. Stimulant medications should be discontinued if seizures develop. Seizures may be associated with amphetamine toxicity; patients presenting with convulsions should be evaluated for other signs and symptoms of overdose.

Data are inadequate to determine whether chronic use of stimulants, such as lisdexamfetamine, 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. 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. Patients younger than 6 years (a population in which lisdexamfetamine is not approved for use) experience more long term weight loss than those 6 years and older. 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 clinical trials for attention-deficit hyperactivity disorder, some degree of weight loss occurred in 9% of pediatric patients. In a controlled trial of lisdexamfetamine in children (age 6 to 12 years), mean weight loss from baseline during the first 4 weeks of therapy was -0.9, -1.9, -2.5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of lisdexamfetamine; in comparison, subjects receiving placebo had a mean weight gain of 1 pound. In a similar trial of adolescents, mean weight loss from baseline was -2.7, -4.3, and -4.8 pounds, respectively; subjects receiving placebo had a mean weight gain of 2 pounds. Follow-up of children (age 6 to 12 years) receiving lisdexamfetamine for more than 12 months suggests that regularly medicated children had a slowing in growth rate, as demonstrated by a mean decrease of 13.4% from baseline to 12 months in age- and sex-normalized weights. 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.

Anorexia is 1 of the most common adverse reactions associated with stimulant use. Loss of appetite was reported in 39% of children and 34% of adolescents receiving lisdexamfetamine during attention-deficit hyperactivity disorder (ADHD) clinical trials and was responsible for drug discontinuation in 1% of the adolescent study population. Eating small, frequent meals or snacks may help limit appetite problems. Weight loss is a dose-related adverse reaction commonly associated with stimulant use and is of particular concern in growing children and adolescents. Weight loss occurred in 9% of children and adolescents during lisdexamfetamine clinical trials for ADHD. In a controlled trial of lisdexamfetamine in children (age 6 to 12 years), mean weight loss from baseline during the first 4 weeks of therapy was -0.9, -1.9, -2.5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of lisdexamfetamine; in comparison, subjects receiving placebo had a mean weight gain of 1 pound. In a similar trial of adolescents, mean weight loss from baseline was -2.7, -4.3, and -4.8 pounds, respectively; subjects receiving placebo had a mean weight gain of 2 pounds. Anorexia and weight loss have also been reported in adult patients; anorexia was reported in 27% and 8% of adult patients during trials for ADHD and binge-eating, respectively, while weight loss occurred in 3% to 4% of adult patients overall. Monitor growth in children during treatment with stimulants; patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

Gastrointestinal reactions are common with stimulant use. Upper abdominal pain (12%), nausea (6%), vomiting (9%), diarrhea (7% adults), and xerostomia (4% to 5%) have been reported during clinical trials of lisdexamfetamine for attention-deficit hyperactivity disorder (ADHD); vomiting was responsible for drug discontinuation in 1% of children during these trials. Xerostomia (36%), constipation (6%), diarrhea (4%), vomiting (2%), gastroenteritis (2%), upper abdominal pain (2%), and oropharyngeal pain (2%) were reported during adult trials for binge-eating disorder. Constipation, bowel ischemia, dysgeusia, and teeth grinding (bruxism) have been reported with postmarketing experience. In addition, dyspepsia has been associated with amphetamine use in general. Persistent or excessive gastrointestinal symptoms may lead to anorexia and weight loss. Eating small, frequent meals or snacks may help limit gastrointestinal discomfort. Complaints of xerostomia or dysgeusia may be limited by sucking sugarless hard candy, crushed ice, and drinking plenty of water or other fluids. Clinicians should be aware that while GI adverse reactions are relatively common with the usual use of lisdexamfetamine, excessive abdominal cramping, nausea, vomiting, or diarrhea may represent excessive dosage and toxicity.

Lisdexamfetamine may cause or exacerbate hypertension at typical therapeutic doses. In general, stimulant medications increase blood pressure by approximately 2 to 4 mmHg; however, some patients may experience larger increases. Blood pressure measurements should be obtained at baseline, after dosage increases, and periodically throughout stimulant therapy.

Cardiovascular events, including sudden death, have been associated with stimulant use in pediatric patients with structural cardiac abnormalities or other serious heart problems. Cardiovascular effects reported during stimulant use range in severity from mild to life-threatening and include palpitations, sinus tachycardia, myocardial infarction (reported in adults), and stroke (reported in adults). Ventricular hypertrophy was associated with drug discontinuation in 1% of pediatric patients during lisdexamfetamine clinical trials for attention-deficit hyperactivity disorder (ADHD). Increased heart rate occurred in 2% to 7% of adult patients receiving lisdexamfetamine during clinical trials. In general, stimulant medications increase heart rate by an average of 3 to 6 bpm; however, some patients may experience higher increases. A reflex bradycardia, which is not usually clinically significant, may occur. Cardiomyopathy has been associated with chronic amphetamine use. Cardiac effects occurring in at least 2% of adolescents receiving lisdexamfetamine and at least twice as often as placebo included palpitations (2%). Chest pain (unspecified) and cardiomyopathy have been reported during postmarketing use of lisdexamfetamine. Patients who develop symptoms such as exertional chest pain (unspecified), unexplained syncope, or other symptoms suggestive of cardiac disease during lisdexamfetamine 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 reactions (e.g., arrhythmia or arrhythmia exacerbation, severe hypertension or hypotension) may be associated with amphetamine toxicity; evaluate patients carefully who present with cardiac symptoms for possible overdose. Use lisdexamfetamine with caution in patients with conditions that would be expected to worsen by an increase in heart rate. Obtain pulse measurements at baseline, after dosage increases, and periodically throughout stimulant therapy.

Allergic reactions to amphetamines are rare; however, serious reactions such as angioedema, anaphylactoid reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. Rash (unspecified) was reported in 3% of children receiving lisdexamfetamine for attention-deficit hyperactivity disorder (ADHD) and was responsible for drug discontinuation in 1% of this population during pediatric clinical trials. Pruritus was reported in 2% of adult patients during clinical trials for binge eating disorder. Urticaria, photosensitivity, and alopecia have also been reported with amphetamine use.

Psychological dependence, physiological dependence, and tolerance may occur with lisdexamfetamine 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.

Fever (2% vs. 1% placebo) and hyperhidrosis (3% to 4% adults) have been reported during clinical trials of lisdexamfetamine. Hyperpyrexia and hyperhidrosis may also be a manifestation of amphetamine overdose; patients presenting with such symptoms should be carefully assessed for toxicity.

Stimulants, such as lisdexamfetamine, 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.

Frequent or prolonged erections and priapism have been reported with postmarketing use of stimulant medications. 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 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). Although priapism has been associated with both methylphenidate and amphetamine products during postmarketing use, causality in relation to the amphetamine products is uncertain because patients had been taking other medications thought to cause priapism. 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 stimulant medications.

Dyspnea and urinary tract infection have been reported in 2% of adult patients during lisdexamfetamine clinical trials compared to none of those receiving placebo.

Eosinophilic hepatitis has been reported during postmarketing use of lisdexamfetamine. The frequency is unknown and causality to the drug has not been established.

Rhabdomyolysis has been associated with the use of stimulants used to treat attention-deficit hyperactivity disorder. Stimulant-induced rhabdomyolysis is most often associated with sympathomimetic toxicity. Toxic effects of amphetamines, including lisdexamfetamine, are more variable in children than in adults and appear to occur over a wide dosage range; toxic symptoms may occur at idiosyncratically at low doses. Practitioners should be alert to the signs of excessive dosages or overdose which may include: anxiety, agitation, confusion, delirium, assaultiveness, psychosis, hallucinations, paranoia, panic, abdominal cramping, nausea, vomiting, diarrhea, hyperhidrosis, flushing or pallor, hyperthermia, labile blood pressure and heart rate (hypotension or hypertension), hyperreflexia, restlessness, sinus tachycardia, tachypnea, or tremor. Fatigue and depression usually follow central nervous system stimulation. Minor manifestation of any of these symptoms during prescription use indicates a need for dosage reduction or discontinuation. Severe manifestations of amphetamine overdose include cardiac arrhythmias, circulatory collapse, and rhabdomyolysis. Fatal poisoning is usually preceded by seizures and coma.

Serotonin syndrome may occur when amphetamines are used in combination with other drugs that enhance serotonin activity. 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 lisdexamfetamine and any concomitant serotonergic agent immediately and initiate supportive symptomatic treatment. Amphetamines, including lisdexamfetamine, stimulate the release of serotonin (5-HT) and may act as direct agonists on central serotonin receptors. Thus, amphetamines are both direct and indirect stimulants of serotonin activity.

Lisdexamfetamine is contraindicated in patients with a known hypersensitivity to amphetamines or any component of the lisdexamfetamine product.

Central nervous system (CNS) stimulants, such as lisdexamfetamine, 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. 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 lisdexamfetamine 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.

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 lisdexamfetamine, 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.

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 stimulant products 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 lisdexamfetamine, 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 lisdexamfetamine for hypertension and tachycardia.

Lisdexamfetamine is not indicated or recommended for obesity treatment or weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. Eating disorders, such as anorexia nervosa or bulimia nervosa, should be ruled out prior to treatment of attention-deficit hyperactivity disorder (ADHD) with amphetamines. 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.

Amphetamines should not be given to patients with thyrotoxicosis. The elevated levels of thyroid hormones in these patients make them extremely sensitive to sympathomimetic drugs.

CNS stimulants, including lisdexamfetamine, 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 lisdexamfetamine, carefully assess family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome. Regularly monitor lisdexamfetamine-treated patients for the emergence or worsening of tics or Tourette's syndrome and discontinue treatment if clinically appropriate.

Stimulants, such as lisdexamfetamine, may lower the seizure threshold and should be used cautiously in patients with a history of seizure disorder or EEG abnormalities. Seizures have been reported during postmarketing use of lisdexamfetamine; however, the frequency is unknown. If seizures occur, lisdexamfetamine should be discontinued. Because of a potential increased risk of seizures, amphetamines should not be used during intrathecal radiographic contrast administration. Amphetamines should be discontinued 48 hours before the myelography and should not be resumed until at least 24 hours after the procedure.

The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of amphetamines, such as lisdexamfetamine, and other sympathomimetic drugs. There may be a risk of sudden blood pressure increases during administration of halogenated anesthetics.

Amphetamines can cause a significant elevation in plasma corticosteroid levels; this increase is greatest in the evening. Amphetamines may cause laboratory test interference with urinary steroid determinations. These effects may need to be considered during testing.

Use lisdexamfetamine with caution in patients with significant hepatic disease or renal impairment. The elimination of amphetamine is dependent on hepatic metabolism, urinary pH and urinary flow rates, as well as active secretion; dysfunction of either system may inhibit elimination and result in prolonged exposure. The mean clearance of lisdexamfetamine's active moiety, d-amphetamine, is reduced in patients with severe renal impairment or renal failure; therefore, reduced maximum daily dosages are recommended. Dialysis does not significantly affect the clearance of d-amphetamine.

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 more 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). Practitioners should be aware that both methylphenidate and amphetamine products have been associated with postmarketing reports of priapism; however, causality in relation to the amphetamine products is uncertain because patients had been taking other medications thought to cause priapism. 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 stimulant medications.

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.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Monitor for growth inhibition during stimulant therapy including height and weight parameters relative to age at treatment initiation and periodically thereafter (at minimum yearly). Interrupt treatment in patients who are not growing or gaining weight as expected. Lisdexamfetamine is not approved for use in children less than 6 years of age. In a 4-week, placebo-controlled trial of lisdexamfetamine in pediatric patients ages 6 to 12 years old with ADHD, there was a dose-related decrease in weight in the treated groups relative to weight gain in the placebo group. Additionally, in studies of another stimulant, there was slowing of the increase in height.

Lisdexamfetamine is contraindicated in patients who have received MAOI therapy, including linezolid or intravenous methylene blue, within the past 14 days because of the possibility of precipitating a hypertensive crisis. MAOI antidepressants slow amphetamine metabolism, potentiating their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings. This may precipitate hypertensive crisis, malignant hyperthermia, and a variety of toxic neurologic effects; these events can be fatal. Increased risk for serotonin syndrome also may occur when amphetamines are co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans, and others), and may also occur during overdosage situations. If serotonin syndrome occurs, discontinue lisdexamfetamine and all other serotonergic agents, and initiate supportive treatment.

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

Description: Lisdexamfetamine is an orally administered central nervous system (CNS) stimulant used to treat attention-deficit hyperactivity disorder (ADHD). It is a prodrug of dextroamphetamine. Stimulants, such as lisdexamfetamine, are highly effective in the treatment of ADHD and are considered first-line therapy. Lisdexamfetamine is the first prodrug stimulant. Because it has a delayed pharmacologic effect, it has a lower potential for abuse when compared to other amphetamines. In addition, it offers an alternative treatment option with a long duration of action (10 to 12 hours) and a side effect profile consistent with other stimulant medications. As a class, stimulants have been associated with sudden death in children. Children with structural heart defects, cardiomyopathy, or heart-rhythm disturbances may be at risk for adverse cardiac events. The American Heart Association (AHA) recommends careful screening of all children and adolescents prior to initiating pharmacologic therapy for ADHD. Lisdexamfetamine is FDA-approved for use in pediatric patients 6 years and older.

For the treatment of attention-deficit hyperactivity disorder (ADHD):
Oral dosage:
Children and Adolescents 6 to 17 years: 30 mg PO once daily in the morning, initially. May increase the dose by 10 to 20 mg/day at weekly intervals. However, the American Academy of Pediatrics (AAP) recommends a lower initial dose of 20 mg PO once daily, titrated every 3 to 7 days. Individual dosage; use the lowest effective dose. Max: 70 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

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: 70 mg/day PO.
-Adolescents
70 mg/day PO.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available. Hepatic dysfunction has the potential to slow the elimination of amphetamine; use with caution and titrate dosages carefully.

Patients with Renal Impairment Dosing
GFR >= 30 ml/min/1.73 m2: Specific dosage adjustments not specified; titrate dosage carefully in patients with renal impairment.
GFR 15-29 ml/min/1.73 m2: Do not exceed 50 mg/day.
GFR < 15 ml/min/1.73 m2: Do not exceed 30 mg/day.

Intermittent hemodialysis
Lisdexamfetamine and d-amphetamine are not dialyzable.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Lisdexamfetamine is a central nervous system (CNS) stimulant. The exact mechanism of amphetamines for attention-deficit hyperactive disorder (ADHD) is not established. Amphetamines are non-catecholamine sympathomimetic agents that block the reuptake of dopamine (DA) and norepinephrine (NE) into the presynaptic neuron, increasing the release of both biologic amines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to sites responsible for NE and DA uptake, and requires enzymatic conversion to dextroamphetamine before it becomes pharmacologically active. Under normal circumstances, the DA transporter protein moves DA from the synapse into the cell. Amphetamine binds to the presynaptic DA transporter protein, inducing a reverse transport process and blocking DA reuptake back into the cell, therefore increasing concentrations of DA in the synapse. Amphetamines may also inhibit monoamine oxidase (MAO), but this is a minor action. Evidence suggests serotonergic transmission may regulate the effects of amphetamine; however, this mechanism is not completely understood. Amphetamine-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 actions of amphetamines are believed to occur through release of NE from the adrenergic nerve terminals and by a direct stimulant action on alpha- and beta-receptors. Amphetamines increase systolic and diastolic blood pressure and cause respiratory stimulation and weak bronchodilation. Heart rate typically increases slightly with normal therapeutic doses of stimulants (about 3 to 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, amphetamine and its derivatives can cause significant hypertension, tachycardia, arrhythmias, and other serious complications. Amphetamines may produce mydriasis and contraction of the bladder sphincter. It has been suggested that amphetamines decrease olfactory acuity, which may contribute to their anorexic properties.

Pharmacokinetics: Lisdexamfetamine is administered orally. Amphetamines are highly lipid soluble with a large volume of distribution (average adult Vd = 5 L/kg). Protein binding is highly variable. Amphetamine readily crosses the blood brain barrier. In amphetamine-dependent adults, cerebrospinal fluid (CSF) concentrations were found to be 80% that of plasma. Lisdexamfetamine is a prodrug of dextroamphetamine; it is pharmacologically inactive until it is converted to dextroamphetamine and l-lysine, which occurs primarily via enzymatic hydrolysis. Red blood cells have a high capacity for lisdexamfetamine metabolism; in vitro data has demonstrated substantial hydrolysis occurs at even low hematocrit concentrations (33% of normal). Though the prodrug lisdexamfetamine is not metabolized by cytochrome P450 enzymes, it is known that the formation of 4-hydroxy-amphetamine, an active metabolite of amphetamine, involves CYP2D6. Because CYP2D6 is genetically polymorphic, variations in amphetamine metabolism are a possibility. In addition, concomitant use of CYP2D6 inhibitors may increase amphetamine plasma concentrations.

The plasma elimination half-life of the prodrug lisdexamfetamine is less than 1 hour. The plasma elimination half-life of pharmacologically active dextroamphetamine is approximately 12 hours; however, elimination changes significantly with urinary pH. At normal urine pH, approximately 30% to 40% of the administered dose is recoverable in urine as amphetamine and 50% as alpha-hydroxy-amphetamine (inactive metabolite). Alkaline urine pHs result in less ionization and reduced renal elimination of amphetamine. Conversely, acidification of the urine and high urinary flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has be reported to range from 1% to 75% depending on urinary pH. After administration of lisdexamfetamine 70 mg to healthy adult subjects, 96% of the dose was recovered in the urine; 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine. The remainder of the dose is hepatically metabolized, which implies that there may be an increased risk for drug-drug interactions when the urine is alkalinized because a larger proportion of the drug is eliminated hepatically.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6 (theoretical)
Lisdexamfetamine is a prodrug of dextroamphetamine; it is pharmacologically inactive until it is converted to dextroamphetamine and l-lysine, which occurs primarily via enzymatic hydrolysis. The specific enzymes involved in dextroamphetamine metabolism have not been described; however, the formation of 4-hydroxy-amphetamine is known to involve CYP2D6. Because CYP2D6 is genetically polymorphic, variations in amphetamine metabolism are a possibility. However, pharmacokinetic data suggest dosage adjustment of CYP1A2, CYP2D6, CYP2C19, or CYP3A4 substrates is not necessary when lisdexamfetamine is co-administered.


-Route-Specific Pharmacokinetics
Oral Route
Oral capsules
Lisdexamfetamine capsules are readily absorbed from the GI tract after administration. Administration of a single dose of lisdexamfetamine results in a time to maximum concentration (Tmax) of 3.5 hours for dextroamphetamine and 1 hour for lisdexamfetamine. Administration with food does not affect the maximum concentration (Cmax) or AUC; however, the Tmax of dextroamphetamine is prolonged by about 1 hour (from 3.8 hours in a fasted state to 4.7 hours after a high fat meal or to 4.8 hours with yogurt).

Chewable tablets
After a single 60 mg dose of the chewable tablet in healthy subjects under fasting conditions, the Tmax of lisdexamfetamine and dextroamphetamine was reached in about 1 hour and 4.4 hours post dose, respectively. Compared to 60 mg of the lisdexamfetamine capsule, exposure (Cmax and AUC) to lisdexamfetamine chewable tablet was about 15% lower. The exposure (Cmax and AUC) of dextroamphetamine is similar between the chewable tablet and capsule.


-Special Populations
Pediatrics
Children
Weight/dose normalized exposure (AUC) and maximum concentration (Cmax) values were the same in pediatric patients ages 6 to 12 years as in adults after single doses of 30 mg to 70 mg of lisdexamfetamine. However, in children 4 to 5 years, dextroamphetamine exposure was approximately 44% higher compared to children 6 years and older. Lisdexamfetamine is a pro-drug for dextroamphetamine. The elimination half-life for dextroamphetamine is shorter in children 6 years and older (8.6 to 9.5 hours) compared to adults (10 to 11.3 hours).

Hepatic Impairment
The precise impact of hepatic dysfunction on lisdexamfetamine pharmacokinetics is not known. Theoretically, hepatic dysfunction has the potential to slow clearance because lisdexamfetamine gets converted to dextroamphetamine and dextroamphetamine is partially hepatically metabolized (degree varies depending on urinary pH).

Renal Impairment
Exposure to lisdexamfetamine, as measured by AUC, increases as renal function declines. Dosage adjustments are recommended in patients with severe renal disease (GFR 15 to less than 30 mL/minute/1.73 m2) and end stage renal disease (GFR less than 15 mL/minute/1.73 m2). Lisdexamfetamine and dextroamphetamine are not dialyzable.