VYVANSE
  • VYVANSE

  • QTY 30 • 30 MG • Capsule • Near 77381

LISDEXAMFETAMINE (lis DEX am fet a meen) is used to treat attention-deficit hyperactivity disorder (ADHD) in adults and children. It is also used to treat binge-eating disorder in adults. Federal law prohibits giving this medicine to any person other than the person for whom it was prescribed. Do not share this medicine with anyone else.

VYVANSE Pediatric Monographs
  • 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.

    The sympathetic stimulation of amphetamines, including lisdexamfetamine, blocks aqueous outflow and may raise intraocular pressure, exacerbating ocular hypertension or glaucoma. Visual impairment such as blurred vision, diplopia, mydriasis, and accommodation disorder has been reported with stimulant use. Patients are encouraged to report any unusual changes in vision promptly for examination and evaluation.

    Dyskinesia and tics (2%) have been reported with lisdexamfetamine use; tics were responsible for drug discontinuation in 1% of children during pediatric clinical trials for attention-deficit hyperactivity disorder (ADHD). Patients with Tourette's syndrome or a family history of this syndrome may have motor or phonetic tics unmasked or exacerbated by the use of stimulants. Exacerbation of tics may respond to dosage reduction. In some cases, the stimulant may need to be discontinued.

    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, 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.

    Prolonged use of amphetamines, including lisdexamfetamine, may lead to habituation and psychological dependence or physiological dependence. Historical use of these agents as anorectics has been associated with both tolerance and dependence. Tolerance may manifest as frequent requests for prescription refills or requests for dosage increases. Signs and symptoms of chronic amphetamine abuse include severe dermatoses, choreoathetosis (chewing or grinding of the teeth, and unusual movements of the tongue or lips), oral ulceration, marked insomnia, social deterioration, personality changes, irritability, paranoia, auditory and visual hallucination, and psychosis with features indiscriminate from schizophrenia. Abuse and habituation is more likely to occur with inhalational and injectable street forms of the amphetamines versus careful oral administration via prescription. Compared to other amphetamines, lisdexamfetamine has a reduced potential for abuse. Because it is a prodrug, not only does it have a delayed pharmacologic effect, but mechanical manipulation of the capsule does not produce active drug, making it less desirable for recreational use. Abrupt withdrawal of amphetamines after chronic administration may unmask severe depression or symptoms of overactive behaviors, dysphoric mood, anxiety, suicidal ideation, psychomotor agitation, insomnia or hypersomnia, agoraphobia, and EEG changes. Carefully observe patients during drug discontinuation; gradual reductions in treatment have been recommended. Major physiologic withdrawal symptoms are not usually noted with usual prescription use and as such may not necessitate gradual dosage reductions in all patients.

    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.

    Stimulants, such as lisdexamfetamine, have a high potential for abuse and should be used with caution and only after a careful risk/benefit assessment in patients with a history of substance abuse or alcoholism. 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. Monitor patients for signs of abuse and overdose and periodically re-evaluate the need for stimulant use. Even though lisdexamfetamine is a DEA schedule II controlled substance, it is considered to have a lower potential for abuse when compared to some other stimulant medications. Because lisdexamfetamine is a prodrug of dextroamphetamine and requires enzymatic hydrolysis for conversion to its active form, there is a gradual release of dextroamphetamine. This results in less euphoria, reducing the potential for abuse. In addition, because free dextroamphetamine is not present in the capsules, mechanical manipulation (e.g., crushing or other forms of extraction) will not yield immediately-available active drug. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion. Misuse of amphetamines can cause sudden death and serious cardiovascular adverse events. Symptoms of chronic abuse include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from psychotic disorders.

    Administration of amphetamines for a prolonged period of time may lead to physical and psychological drug dependence. Abrupt discontinuation after chronic use (therapeutic and recreational) may result in severe depressive symptoms, extreme fatigue, sleep EEG changes, and symptoms of withdrawal. Close supervision during gradual withdrawal of therapy is recommended. Of note, drug 'holidays', the temporary discontinuation of drug during weekends, holidays, summer vacations, and etc. in patients with well-controlled attention-deficit hyperactivity disorder (ADHD) symptoms, are not usually associated with drug withdrawal symptoms.

    Lisdexamfetamine should be used with caution in patients in an agitated state. An assessment should be performed prior to initiation of therapy to determine the risk for developing a manic episode (e.g., comorbid history of depressive symptoms or a family history of suicide, bipolar disorder, and depression). In psychotic individuals (e.g., schizophrenia), amphetamine may exacerbate behavioral disturbances, psychosis, or thought disorders. New onset psychotic symptoms (e.g., hallucinations, delusional thinking, mania) may occur in individuals without a prior history of psychosis. If such symptoms occur, discontinuation of treatment should be considered. Aggressive behavior and hostility have been reported in both clinical trials and postmarketing experience of medications used to treat attention-deficit hyperactivity disorder (ADHD). Such behaviors are often observed in patients with ADHD. Monitor patients appropriately. Due to its toxic effects in overdose, lisdexamfetamine should only be used in those with major depression or suicidal ideation when absolutely necessary.

    Prior to initiating stimulant treatment with lisdexamfetamine, the child or adolescent should be assessed for the presence of cardiac disease (e.g., a careful history, family history of sudden death or ventricular arrhythmia, and a physical exam). Lisdexamfetamine generally should not be used in patients with known structural cardiac abnormalities, aortic stenosis, prosthetic heart valves, valvular heart disease, cardiomyopathy, serious cardiac arrhythmias, advanced arteriosclerosis, or other serious cardiac problems that may make them more vulnerable to the noradrenergic effects of amphetamines. According to the American Heart Association (AHA) all patients being considered for pharmacologic treatment of ADHD should have a careful history taken, including assessment for a family history of sudden death or ventricular arrhythmia, and a physical exam to assess for the presence of cardiac disease. If cardiac disease is suspected, further cardiac evaluation including an ECG and echocardiogram is warranted. For pediatric patients, the AHA states that it may be useful to obtain a baseline ECG as a part of the initial evaluation. If a child or adolescent has any significant findings on physical examination, ECG, or family history, consult a pediatric cardiologist before initiating the medication. The AHA states that it is reasonable to consider the use of medications for the treatment of ADHD in pediatric patients with congenital heart disease without current hemodynamic or arrhythmic concerns or congenital heart disease that is considered stable by the patient's pediatric cardiologist, unless the cardiologist has specific concerns. However, these patients should be closely monitored and treatment discontinuation should be considered if the patient develops any of the following conditions: heart condition associated with sudden cardiac death (SCD), arrhythmia requiring cardiopulmonary resuscitation, direct current cardioversion/defibrillation, or overdrive pacing, arrhythmia associated with SCD, any clinically significant arrhythmia that is not treated or controlled, QTc interval on electrocardiogram (ECG) more than 0.46 sec, or heart rate or blood pressure more than 2 standard deviations above the mean for age. The cardiovascular risk associated with CNS stimulant use has been studied. Despite earlier reports of an increased risk, it appears that the short-term risk of serious cardiac events is not significantly increased in otherwise healthy pediatric patients. Sudden death has been associated with stimulant use at usual doses in children and adolescents with structural congenital heart disease or other serious cardiac disease. Sudden death, myocardial infarction, and stroke have occurred in adults receiving standard dosages of stimulants. In contrast, a retrospective cohort study including over 1.2 million patients 2 to 24 years of age did not find an increased risk of serious cardiovascular events (sudden cardiac death, acute myocardial infarction, or stroke) in current users of drugs for the treatment of ADHD compared to nonusers (adjusted hazard ratio 0.75; 95% CI 0.31 to 1.85). This data is supported by results from another large population-based retrospective cohort study (patients aged 3 to 18 years) that found no increase in short-term risk of severe cardiac events in stimulant users vs. nonusers (adjusted odds ratio 0.62; 95% CI 0.27 to 1.44). Unlike other trials, this second study also included high risk patients (e.g., patients with malignancy, HIV, congenital heart disease, or cardiomyopathy); the odds ratio in the high risk group was 1.02 (95% CI 0.28 to 3.69). The portion of patients specifically using amphetamines was not specified in either study. The authors of both studies concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out. The effect of long-term use has not been evaluated.

    Stimulants cause an increase in blood pressure (mean increase about 2 to 4 mmHg) and heart rate (mean increase about 3 to 6 bpm); use lisdexamfetamine with caution in patients with cardiac conditions that would be expected to deteriorate from increases in blood pressure or heart rate. Such conditions may include pre-existing hypertension or tachycardia, cerebrovascular disease, serious structural cardiac abnormalities, cardiac rhythm disturbances (e.g., ventricular arrhythmias), symptomatic heart failure, severe coronary artery disease, ventricular dysfunction, or other serious cardiac conditions. In addition, sudden death has been associated with stimulant use at usual doses in children and adolescents with structural congenital heart disease or other serious cardiac disease. In general, lisdexamfetamine should not be used in patients with serious structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, or other serious cardiac problems that may make them more vulnerable to the noradrenergic effects of amphetamines. Pulse and blood pressure measurements should be obtained at baseline, after dosage increases, and periodically throughout lisdexamfetamine therapy. In patients with stable cardiac conditions, consider discontinuing therapy if the patient develops any of the following conditions: heart condition associated with sudden cardiac death (SCD), arrhythmia requiring cardiopulmonary resuscitation, direct current cardioversion/defibrillation or overdrive pacing, any clinically significant arrhythmia that is not treated or controlled, QTc more than 0.46 seconds, or heart rate or blood pressure more than 2 standard deviations above the mean for age.

    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.

    Stimulants, such as lisdexamfetamine, should be used with caution in patients with hyperthyroidism, including thyrotoxicosis, because sympathomimetic stimulation may induce cardiac arrhythmias or other side effects.

    Use lisdexamfetamine with caution in patients with glaucoma. The sympathetic stimulation of amphetamines blocks aqueous outflow and raises intraocular pressure. Occasionally, visual disturbance, such as change in visual accommodation or blurred vision, has been reported in individuals without ocular disease while they are taking amphetamines. Patients should report any new visual disturbance; ophthalmic evaluation may be needed. Of note, lisdexamfetamine gets converted to dextroamphetamine in vivo, and the FDA-approved product labeling for dextroamphetamine products contraindicates the use of dextroamphetamine in patients with glaucoma.

    Stimulants, such as lisdexamfetamine, may precipitate motor or phonetic tics in those with Tourette's syndrome. Some patients with Tourette's syndrome may benefit from stimulant therapy; administer under close supervision.

    The use of lisdexamfetamine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Patients should not use lisdexamfetamine for the prevention or treatment of normal fatigue states. Patients should avoid activities requiring coordination and concentration, such as gymnastics, riding a bicycle, or for older adolescents, operation of vehicles, until they are aware of how this medication affects them.

    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 concentrations; therefore, lisdexamfetamine may cause hypercortisolism. The elevation is greatest in the evening. Amphetamines may interfere with urinary steroid determinations; consider the possible effect of lisdexamfetamine if determination of plasma corticosteroid concentrations is desired.

    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.

    The safety and efficacy of lisdexamfetamine has not been established in infants and children younger than 6 years. In children 4 to 5 years, dextroamphetamine exposure was approximately 44% higher compared to patients 6 to 11 years; younger patients experienced elevated rates of adverse reactions including weight loss, decreased BMI, decrease appetite, insomnia, infections, irritability, and affect lability. 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. 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. 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 controlled clinical 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.

    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 years and older: Initially, 20 to 30 mg PO once daily in the morning. FDA-approved labeling specifies an initial dose of 30 mg PO once daily, titrated in 10 to 20 mg increments 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. Dosage should be individualized; use minimum effective dose. Maximum: 70 mg/day. Avoid afternoon doses due to the potential for sleep interference. Capsules and chewable tablets are interchangable.

    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.

DISCLAIMER: This drug information content is provided for informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always consult their physician with any questions regarding a medical condition and to obtain medical advice and treatment. Drug information is sourced from GSDD (Gold Standard Drug Database ) provided by Elsevier.

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