ADDERALL XR (Brand for DEXTROAMPHETAMINE-AMPHET ER)

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

Route-Specific Administration

Oral Administration
Oral Solid Formulations
Immediate-release tablets:
-Administer the first dose of the day upon awakening.
-Subsequent doses during the day, if given, should be administered at least 6 hours before bedtime to avoid sleep interference.

Extended-release capsules (Adderall XR):
-Administer dose once daily in the morning upon awakening. Swallow whole, do not crush, cut, or chew the capsule or capsule contents (beads).
-If swallowing is difficult, the capsule may be opened and the entire contents gently sprinkled on a spoonful of cool applesauce and swallowed immediately (do not store for future use). Follow with a drink of water or other liquid.
-Do not divide the dose of a single capsule.

Extended-release capsules (Mydayis):
-Administer dose once daily in the morning upon awakening consistently either with or without food. Swallow whole, do not crush, cut, or chew the capsule or capsule contents (beads).
-If swallowing is difficult, the capsule may be opened and the entire contents gently sprinkled on a spoonful of applesauce and swallowed immediately (do not store for future use).
-Do not divide the dose of a single capsule.

Adverse side effects of amphetamine; dextroamphetamine are frequent but usually mild to moderate in children with attention-deficit hyperactivity disorder (ADHD) at normally prescribed dosages. The side effects may be more frequent or severe with the initial days of therapy.

Adverse reactions affecting the central nervous system (CNS) are among the most common associated with stimulant use. Insomnia is reported in roughly 12% to 17% of pediatric patients receiving amphetamine; dextroamphetamine. Symptoms of insomnia may be more frequent or severe during initial therapy, but typically resolve within a few days provided the dosage is appropriate and doses are not administered within 6 hours of bedtime. Avoidance of exercising late in the day, limiting caffeinated beverages, and setting regular bedtime schedules may limit sleep disruption. Continued interrupted sleep patterns may indicate a need for dose reduction. Mild euphoria and restlessness have been noted in the first weeks of treatment. Other CNS adverse reactions reported include nervousness (6%), accidental injury (2% to 4%), dizziness (2% to 4%), fatigue (2% to 4%), drowsiness (2% to 4%), accidental injury (3%), and asthenia (2%). Dysphoria, overstimulation, paresthesias (including formication), and tremor have been reported with the use of amphetamine; dextroamphetamine; however, the frequencies of these reactions are unknown. Headache occurred in 26% of adult patients during clinical trials, and feeling jittery (2% of adults), speech disorder (e.g., stuttering or dysphemia, excessive speech, logorrhea) (2% to 4% of adults), and twitching (2% to 4% of adults) were also reported. Children who become overly preoccupied with a task (over-focused or inflexible) or are described as 'zombie-like' are considered to exhibit supranormalization; these behaviors typically require dosage reduction. Once-daily morning dosing of amphetamine; dextroamphetamine is effective in many children and may also help to limit intolerable adverse reactions.

Dyskinesia has been reported during postmarketing use of CNS stimulants, including amphetamine; dextroamphetamine products. The onset or exacerbation of motor and verbal tics has also been reported. 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.

Anorexia is one of the most common gastrointestinal (GI) adverse reactions associated with stimulant use. Loss of appetite was reported in 22% of children and 36% of adolescents receiving extended-release amphetamine; dextroamphetamine in clinical trials. Weight loss is a dose-related adverse reaction commonly associated with stimulant use and is of particular concern in growing children and adolescents. In clinical trials of extended-release amphetamine; dextroamphetamine, weight loss occurred in 4% of children and 9% of adolescents. In a controlled trial of extended-release amphetamine; dextroamphetamine in adolescents, the mean change in weight during the first 4 weeks of therapy was -1.1 pounds and -2.8 pounds, respectively for patients who received 10 mg and 20 mg daily. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment. Dyspepsia (2% to 4%), nausea (2% to 5%), and vomiting (2% to 7%) have also been reported. Eating small, frequent meals or snacks may help limit appetite problems. Other GI adverse reactions include abdominal pain (11% to 14%) and xerostomia (2% to 4% of adolescents; 35% of adults). Dysgeusia, constipation, diarrhea, and teeth grinding (bruxism) have also been reported with amphetamine use. Bowel ischemia has been reported during postmarketing use. 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 amphetamine; dextroamphetamine, excessive abdominal cramping, nausea, vomiting, or diarrhea may represent excessive dosage and toxicity. 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.

Data are inadequate to determine whether chronic use of stimulants, such as amphetamine; dextroamphetamine, causes long-term growth inhibition. Although data are limited, available studies do not indicate that stimulant use compromises the attainment of normal adult height and weight in most children. Practitioners should monitor height and weight parameters relative to age at treatment initiation and periodically thereafter (at minimum yearly). Patients who are not growing or gaining weight as expected may need to have their treatment interrupted. In a 24-month follow-up, the MultiModal Treatment Study showed a deceleration of growth of roughly 1 cm per year with stimulant use. In general, growth remained in the normal curve for most children, except those in the lowest percentiles of height for age. Data obtained on the effects of stimulants on growth suppression in children 7 to 10 years of age suggested that regularly medicated children (7 days/week throughout the year) had a temporary average slowing in growth of 2 cm in height and 2.7 kg in weight over 3 years. Reduction of annual growth rate was maximal in the first year, decreased in the second year, and absent in the third year of treatment; however, no compensatory growth rebound effects were found while on stimulant therapy. In clinical trials, some degree of weight loss occurred in 4% of children and 9% of adolescents receiving extended-release amphetamine; dextroamphetamine. In a controlled trial of amphetamine; dextroamphetamine in adolescents, mean weight loss within 4 weeks from the start of therapy was 1.1 pounds for patients receiving 10 mg and 2.8 pounds for patients receiving 20 mg. 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.

Amphetamine; dextroamphetamine may cause hypertension. In a single dose pharmacokinetic study of adolescents (n = 23), increases in systolic blood pressure (above the upper 95% CI for age, gender, and stature) occurred in 12% of patients given 10 mg of amphetamine; dextroamphetamine extended release and 35% of patients given 20 mg. Maximal increases occurred 2 to 4 hours after dosing, were transient, and were not associated with symptoms. In a second study of adolescents treated over a 4-week period, systolic blood pressure increases (15 mmHg or more) occurred in 7% of patients receiving amphetamine; dextroamphetamine extended-release (n = 100) and 11% of patients receiving placebo (n = 64). Diastolic blood pressure increases (8 mmHg or more) occurred in 22% of patients receiving active drug and 25% of patients receiving placebo. In general, stimulant medications cause an average increase in blood pressure of 2 to 4 mmHg. Amphetamine; dextroamphetamine is contraindicated in patients with moderate to severe hypertension; caution is recommended for mild hypertension. Blood pressure measurements should be obtained at baseline, after dosage increases, and periodically throughout amphetamine; dextroamphetamine 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 amphetamine; dextroamphetamine use range in severity from mild to life-threatening and include palpitations, sinus tachycardia, myocardial infarction (reported in adults), and stroke (reported in adults). 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. Patients who develop symptoms such as exertional chest pain (unspecified), unexplained syncope, or other symptoms suggestive of cardiac disease during amphetamine; dextroamphetamine treatment should undergo a prompt cardiac evaluation. Minor manifestations of any of these symptoms may indicate a need for dosage reduction or discontinuation. Severe cardiac adverse effects (e.g., arrhythmia or arrhythmia exacerbation, sinus tachycardia, hypertension, hypotension) may be associated with amphetamine toxicity; evaluate patients carefully who present with cardiac symptoms for possible overdose. Amphetamine; dextroamphetamine should be used with caution in patients with conditions that would be expected to worsen by an increase in heart rate. Pulse measurements should be obtained at baseline, after dosage increases, and periodically throughout stimulant therapy.

Dermatologic and allergic reactions to amphetamines are rare, however serious events such as angioedema, anaphylactoid reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis have all been reported with the use of amphetamine or amphetamine; dextroamphetamine. Urticaria, rash (unspecified), photosensitivity, and alopecia have also been reported.

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

Stimulant medications 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 are associated with amphetamine; dextroamphetamine toxicity; patients presenting with convulsions should be evaluated for other signs and symptoms of overdose.

Amphetamine; dextroamphetamine may exacerbate behavioral disturbances, psychosis, or thought disorders. New onset psychotic symptoms (e.g., hallucinations, delusional thinking, or mania) may occur in individuals without a prior history of psychosis. These symptoms occurred in approximately 0.1% of patients treated with stimulants (methylphenidate or amphetamine at usual doses) compared to 0% in placebo-treated patients in a pooled analysis of short-term, placebo-controlled studies. 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, discontinuation of therapy should be considered. 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. Patients and their caregivers should be advised to promptly report any changes in mood or behavior. If suicide-related events emerge during treatment, consideration should be given to dose reduction or drug discontinuation, especially if symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Agitation (8%), anxiety (8%), and emotional lability (9%) have been reported during clinical trials of amphetamine; dextroamphetamine. Depression, irritability, anger, logorrhea, and dermatillomania have also been reported with amphetamine use. Psychosis and hallucinations may be associated with amphetamine toxicity or abuse. Due to its toxic effects in overdose, amphetamine; dextroamphetamine 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.

Amphetamines have been reported to occasionally cause dysmenorrhea. This effect has been reported in adult patients in clinical trials with Adderall XR; while not reported in adolescents during clinical trials, it may be reasonable to expect this adverse effect to occur.

During clinical trials of extended-release formulations, children experienced fever (4%) and infection (3%) at a higher rate than placebo (2%). Viral infection was reported in 1% of adolescent patients. A tooth disorder, including dental caries, was reported in 2% to 4% of adult patients during clinical trials.

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 amphetamine; dextroamphetamine are more variable in children than in adults and appear to occur over a wide dosage range. Practitioners should be alert to the signs of excessive dosages or overdose which may include: anxiety, agitation, confusion, assaultiveness, abdominal cramping, nausea, vomiting, diarrhea, blurred vision, delirium, hyperhidrosis (sweating), flushing or pallor, hallucinations, hyperthermia, labile blood pressure and heart rate (hypotension or hypertension), mydriasis, palpitations, paranoia, purposeless movements, hyperreflexia, psychosis, restlessness, sinus tachycardia, tachypnea, or tremor. 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, rhabdomyolysis, renal failure (unspecified), seizures, coma, and death.

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 amphetamine; dextroamphetamine and any concomitant serotonergic agent immediately and initiate supportive symptomatic treatment. Amphetamines 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.

Psychological dependence, physiological dependence, and tolerance may occur with amphetamine; dextroamphetamine 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. Signs and symptoms of chronic amphetamine abuse include severe dermatoses, marked insomnia, irritability, hyperactivity, personality changes, and psychosis with features indiscriminate from schizophrenia.

Stimulants, such as amphetamine; dextroamphetamine, 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.

Amphetamine; dextroamphetamine mixed salts is contraindicated for use in patients with known hypersensitivity or idiosyncrasy to the sympathomimetic amines or any component of these products. Hypersensitivity reactions including angioedema and anaphylactic reactions have been reported in patients treated with amphetamines.

Central nervous system (CNS) stimulants, such as amphetamine; dextroamphetamine mixed salts, have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Assess each individual's risk for substance abuse (including alcoholism), 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 amphetamine; dextroamphetamine 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.

Amphetamine; dextroamphetamine is not FDA-approved for obesity treatment. Eating disorders, such as anorexia nervosa or bulimia nervosa, should be ruled out prior to treatment 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.

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 amphetamine/ dextroamphetamine, 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 amphetamine; dextroamphetamine, 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 amphetamine; dextroamphetamine for hypertension and tachycardia.

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.

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

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 amphetamine; dextroamphetamine products, 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 amphetamine;dextroamphetamine, carefully assess family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome. Regularly monitor amphetamine;dextroamphetamine-treated patients for the emergence or worsening of tics or Tourette's syndrome and discontinue treatment if clinically appropriate.

Amphetamine; dextroamphetamine may lower the seizure threshold and should be used cautiously in patients with a history of seizure disorder or EEG abnormalities. Rarely, seizures have occurred in patients with no prior history or EEG evidence of seizure. If seizures occur, amphetamine; dextroamphetamine 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 and other sympathomimetic drugs. There may be a risk of sudden blood pressure increases during administration of halogenated anesthetics.

Use amphetamine; dextroamphetamine with caution in patients with significant hepatic disease or renal impairment. The elimination of amphetamine; dextroamphetamine is dependent on hepatic metabolism, urinary pH and urinary flow rates, as well as active secretion. Both hepatic disease and renal impairment have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. Amphetamine; dextroamphetamine dosage should be reduced in patients with an eGFR less than 30 mL/minute/1.73 m2, and use of these dosage forms in patients with renal failure (end-stage renal disease) is not recommended.

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.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. The potential for growth inhibition in pediatric patients should be monitored during stimulant therapy. 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.

Amphetamine; dextroamphetamine is contraindicated in patients who have received monoamine oxidase inhibitor therapy (MAOI therapy), including linezolid or intravenous methylene blue, within the past 14 days. 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.

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: Amphetamine and dextroamphetamine mixed salts are used in combination as an oral preparation to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy. Amphetamine; dextroamphetamine is classified as a central nervous system (CNS) stimulant and stimulants are considered first-line agents in the treatment of ADHD. Lack of response to one stimulant does not predict a response to other stimulants, and a trial with a different agent (i.e., methylphenidate or derivatives) may be warranted if treatment fails with the initial stimulant. Stimulants can induce or exacerbate psychiatric symptoms and should be used with caution in patients with a history of mania, psychosis, or substance abuse. Stimulant use has also been associated with new or worsening tics or worsening Tourette's syndrome. Close monitoring for the emergence or worsening of psychiatric symptoms, tics, or Tourette's syndrome is recommended. Stimulants have also been associated with sudden death in patients (including children) with structural cardiac abnormalities or other serious cardiac disease when used at recommended ADHD doses; patients with structural heart defects, cardiomyopathy, coronary artery disease, serious cardiac arrhythmias, or other serious cardiac disease may be at risk for adverse cardiac events. The American Academy of Pediatrics and the American Heart Association recommend careful screening of all children and adolescents prior to initiating pharmacologic therapy for ADHD, including a detailed patient and family history and physical examination; any significant findings should be further assessed and referred for consultation with a pediatric cardiologist prior to initiating treatment Immediate-release amphetamine; dextroamphetamine products are FDA approved for use in pediatric patients as young as 3 years of age; the extended-release formulations are approved for use in pediatric patients as young as 6 years of age.

For the treatment of attention-deficit hyperactivity disorder (ADHD):
Oral dosage (immediate-release):
Children 3 to 5 years: 2.5 mg PO once daily in the morning, initially. May increase the dose by 2.5 mg/day at weekly intervals based on clinical response. Usual Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The American Academy of Pediatrics (AAP) does not recommend the use of dextroamphetamine in this age group due to lack of safety and efficacy data.
Children and Adolescents 6 to 17 years weighing 50 kg or less: 5 mg PO once or twice daily, initially. May increase the dose by 5 mg/day at weekly intervals based on clinical response. Usual Max: 40 mg/day. Doses more than 40 mg/day are rarely needed. Use the lowest effective dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 6 to 17 years weighing more than 50 kg: 5 mg PO once or twice daily, initially. May increase the dose by 5 mg/day at weekly intervals based on clinical response. However, a maximum dose of 60 mg/day may be considered. Use the lowest effective dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release, i.e., Adderall XR):
Children 6 to 12 years: 5 to 10 mg PO once daily in the morning, initially. May increase the dose by 5 to 10 mg/day at weekly intervals based on clinical response. Max: 30 mg/day. Persons taking divided doses of immediate-release amphetamine; dextroamphetamine (e.g., twice daily), may be switched to extended-release amphetamine; dextroamphetamine at the same total daily dose taken once daily. Use the lowest effective dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 10 mg PO once daily in the morning, initially. May increase the dose to 20 mg/day after 1 week based on clinical response. Max: 20 mg/day. Persons taking divided doses of immediate-release amphetamine; dextroamphetamine (e.g., twice daily), may be switched to extended-release amphetamine; dextroamphetamine at the same total daily dose taken once daily. Use the lowest effective dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release; i.e., Mydayis):
Adolescents 13 to 17 years: 12.5 mg PO once daily in the morning, initially. May increase the dose by 12.5 mg/day at weekly intervals based on clinical response. Max: 25 mg/day. Use the lowest effective dose. For patients switching from another medication or amphetamine product, discontinue that treatment, and titrate using the titration schedule. Do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of narcolepsy:
Oral dosage (immediate-release oral tablets; e.g., Adderall):
Children 6 to 11 years: Initially, 5 mg PO once daily in the morning. May titrate daily dose in 5 mg increments at weekly intervals to minimum effective dose. Daily dose may be given in 1 to 3 divided doses at 4 to 6 hour intervals. If insomnia or anorexia appear, reduce dosage. Max: 60 mg/day PO.
Children and Adolescents 12 years and older: Initially, 10 mg PO once daily in the morning. May titrate daily dose in 10 mg increments at weekly intervals to minimum effective dose. Daily dose may be given in 1 to 3 divided doses at 4 to 6 hour intervals. If insomnia or anorexia appear, reduce dosage. Max: 60 mg/day PO.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
Less than 3 years: Safety and efficacy have not been established.
3 to 5 years: Maximum dosage information is not provided by FDA-approved labeling; doses should not exceed 40 mg/day PO for immediate-release tablets. Do not use extended-release capsules.
6 years and older: For immediate-release tablets, 40 mg/day PO for ADHD (doses up to 60 mg/day PO have been used for weight more than 50 kg) or 60 mg/day PO for narcolepsy. For extended-release Adderall XR capsules, 30 mg/day PO for ADHD. For extended-release Mydayis capsules, safety and efficacy have not been established.
-Adolescents
For immediate-release tablets, 40 mg/day PO for ADHD (doses up to 60 mg/day PO have been used for weight more than 50 kg) or 60 mg/day PO for narcolepsy. In clinical trials of extended-release Adderall XR capsules, titration doses were allowed up to 40 mg/day PO for weight 75 kg or less and from 50 to 60 mg/day PO for weight more than 75 kg; however, there was no consistent evidence that doses above 20 mg/day PO conferred additional benefit. For extended-release Mydayis capsules, 25 mg/day PO for ADHD.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; the FDA-approved product labeling states that hepatic dysfunction has the potential to inhibit the elimination of amphetamine and result in prolonged exposures; use caution.

Patients with Renal Impairment Dosing
Immediate-release products:
Specific guidelines for dosage adjustments of immediate-release products for pediatric patients with renal impairment are not available; the FDA-approved product labeling states that renal dysfunction has the potential to inhibit the elimination of amphetamine and result in prolonged exposures; use caution.

Pediatric renal dose adjustments (6 to 17 years of age) for extended-release capsules (Adderall XR)
eGFR 15 to 29 mL/minute/1.73 m2: 5 mg PO once daily is the recommended dose. The maximum dose for children 6 to 12 years of age is 20 mg PO once daily.
eGFR less than 15 mL/minute/1.73 m2: Initiation of extended-release capsules (Adderall XR) is not recommended.

Pediatric renal dose adjustments (13 to 17 years of age) for extended-release capsules (Mydayis)
eGFR 15 to 29 mL/minute/1.73 m2: Starting and maximum dose is is 12.5 mg PO daily.
eGFR less than 15 mL/minute/1.73 m2: Initiation of extended-release capsules (Mydayis) is not recommended.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Amphetamine and dextroamphetamine are central nervous system (CNS) stimulants. 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. 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 (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.

Pharmacokinetics: Amphetamine and dextroamphetamine mixed salts are administered orally. Commercially available products contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Amphetamine; dextroamphetamine is widely distributed throughout the body, including the central nervous system (CNS). Volume of distribution (Vd) increases as body weight increases. Amphetamine; dextroamphetamine is metabolized in the liver via oxidation to form 4-hydroxy-amphetamine and norephedrine, both active metabolites. The specific enzymes involved in amphetamine 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. Children exhibit a higher clearance than adolescents and adults when adjusted for body weight. Under normal conditions, the plasma half-life of amphetamine; dextroamphetamine mixed salts (Adderall and Adderall XR) is roughly 9 to 11 hours in children 6 years and older, 11 to 14 hours in adolescents, and 10 to 13 hours in adults. In both pediatric and adult patients receiving amphetamine; dextroamphetamine mixed salts (Mydayis), the mean plasma elimination half-life for d-amphetamine ranges from about 10 to 11 hours and l-amphetamine from 10 to 13 hours.

With 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). Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. 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 been reported to range from 1% to 75% depending on urinary pH. The urinary elimination of amphetamines and their metabolites may be affected by agents that acidify or alkalinize the urinary fluids.

Possibly affected cytochrome P450 isoenzymes and drug transporters: CYP2D6
The specific enzymes involved in amphetamine 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. Amphetamines are not an in vitro inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A, nor an in vitro inducer of CYP1A2, CYP2B6, or CYP3A4/5. Amphetamines are not an in vitro substrate for P-gp.


-Route-Specific Pharmacokinetics
Oral Route
Immediate-release tablets
After oral administration, peak plasma concentrations occur approximately 3 hours post-dose. The effect of food on the bioavailability of immediate-release tablets has not been studied.

Extended-release capsules (Adderall XR)
After oral administration, the maximum systemic absorption of extended-release capsules is completed within 7 hours compared to 3 hours for immediate-release tablets. In a pharmacokinetic study assessing 51 children with attention-deficit hyperactivity disorder (ADHD), after initial exposure to extended-release 20 mg capsules, mean maximum plasma concentration (Cmax) was 40.1 ng/mL for the d-isomer and 11.89 ng/mL for the l-isomer, consistent with the 3:1 ratio found in the parent compound. At steady state, mean Cmax reported was 47.22 ng/nL and 14.92 ng/nL for the d- and l-isomers, respectively. Area under the curve (AUC) and Cmax decreases with increases in body weight; children have a higher systemic exposure when compared to adults. However, based upon dose normalization on a mg/kg basis, children show approximately 30% less systemic exposure compared to their adult counterparts. Sprinkling extended-release capsules on applesauce gives comparable plasma concentrations to administration of the intact capsule in the fasted state. Otherwise, food does not affect the extent of absorption of amphetamine, but prolongs Tmax by approximately 2.5 hours. Pharmacokinetic parameters are linear over the normal dosage range.

Extended-release capsules (Mydayis)
After oral administration, peak plasma concentrations occurred in about 7 to 10 hours in adolescents (13 to 17 years) and about 8 hours in adults (19 to 51 years) for both d-amphetamine and l-amphetamine. Pharmacokinetic parameters are linear over the normal dosage range. Steady-state is achieved between days 7 and 8 of dosing with mean accumulation ratio of 1.6. Body weight is the primary determinant of apparent differences in pharmacokinetics across the age range. Based on dose proportionality, a single dose administered to adolescents would produce about 21% to 31% higher Cmax and AUC for d- and l-amphetamine, compared to the same dose administered to adults. Administration with a high-fat meal does not affect the extent of absorption, but prolongs the Tmax by 5 hours (7 hours at fasted state to 12 hours after a high-fat meal) for d-amphetamine and 4.5 hours (7.5 hours at fasted state to 12 hours after a high-fat meal) for l-amphetamine. Sprinkling on applesauce results in comparable absorption and exposure to the intact capsule taken in the fasted state. The presence of alcohol potentially increases release of amphetamine. At an alcohol concentration of 20% or 40%, in vitro testing showed increases in amphetamine release rate. There is no in vivo study for the effect of alcohol on drug exposure.


-Special Populations
Pediatrics
Extended-release capsules (Adderall XR)
Children and Adolescents 6 years and older
Children exhibit a higher clearance than adolescents and adults when adjusted for body weight. Under normal conditions, the plasma half-life of amphetamine; dextroamphetamine is roughly 9 to 11 hours in children 6 years and older, 11 to 14 hours in adolescents, and 10 to 13 hours in adults. However, children exhibit higher systemic exposure to amphetamine (based on Cmax and AUC) than adults for a given dose of extended-release amphetamine; dextroamphetamine; this difference is attributed to the higher dose administered to children on a mg/kg basis. Upon dose-normalization on a mg/kg basis, children showed 30% less systemic exposure when compared to adults.

Extended-release capsules (Mydayis)
Adolescents 13 years and older
Body weight is the primary determinant of apparent pharmacokinetic differences in adolescents (13 to 17 years old) compared to adult patients (19 to 62 years). Based on dose proportionality, a single dose administered to adolescents would produce about 21% to 31% higher Cmax and AUC for d- and l-amphetamine, compared to the same dose administered to adults.

Hepatic Impairment
Hepatic dysfunction has the potential to inhibit the elimination of amphetamine and result in prolonged exposures.

Renal Impairment
Renal dysfunction has the potential to inhibit the elimination of amphetamine and result in prolonged exposures.