DEXTROAMPHETAMINE SULFATE ER (Generic for DEXEDRINE)

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

Route-Specific Administration

Oral Administration
-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.

Oral Solid Formulations
Immediate-release tablets:
-Immediate-release dextroamphetamine is typically administered in 1 to 3 daily doses; administer at 4 to 6 hour intervals.

Extended-release capsules:
-Extended-release dextroamphetamine is typically administered in 1 to 2 daily doses; administer at approximately 8 hour intervals. Do not crush or chew.
-Dexedrine Spansule is a bead-filled capsule containing both immediate-release and delayed-release beads. If swallowing is difficult, the capsule may be opened and the entire contents gently sprinkled on a teaspoon of applesauce, yogurt, or other soft food and swallowed immediately (do not store for future use). The capsule contents (beads) should not be crushed or chewed. Follow with a drink of water or other liquid.

Oral Liquid Formulations
Oral solution:
-Administer oral solution using an oral calibrated measuring device.
-Immediate-release dextroamphetamine is typically administered in 1 to 3 daily doses; administer at 4 to 6 hour intervals.



Topical Administration
Transdermal Patch Formulations
Xelstrym transdermal system:
-Patch should be applied 2 hours before the effect is needed and removed 9 hours after application.
-Do not cut or trim patch. Do not use if the patch is cut or damaged.
-Apply to intact, hairless or nearly hairless skin that was cleaned with soap and water (not alcohol-based product) and is dry and free of any powder, lotion, oil, or gel. Site of application can include chest, upper arm, upper back, flank, or hip. Do not apply a patch to any other site. Avoid areas of tight clothing. Choose a new site each time a new patch is applied.
-Apply the patch immediately after removing it from the pouch. Gently peel away half of the clear plastic liner and apply the sticky side of the patch to the application site selected. Hold the edge of the remaining protective liner and peel it away from the patch. Avoid touching the adhesive side of the patch to avoid absorption of the medication. If adhesive is touched, wash hands with soap and water immediately. Do not use hand sanitizer in place of soap and water. Smooth the patch down and press firmly to ensure a secure application. Do not use dressings, tape or other adhesives on the patch.
-Throughout the day during the wear-time, check to ensure the patch is still smoothly adhered to the application site. If patch edges lift, smooth down and press firmly with the palm of the hand. Patch adherence may be affected by showering, bathing, swimming, or sweating.
-Parents or caregivers should instruct children wearing the patch to tell an adult if the patch becomes loose or falls off.
-Avoid exposing the patch to direct external heat sources (such as heating pads, hair dryers, electric blankets, or heated water beds) while wearing the patch. Direct heat may increase the rate and extent of absorption of the medication.
-If the patch falls off, do not reapply it. Dispose of the patch and apply a new one to a different application site. The total wear time for both the first patch and the replacement patch should not exceed 9 hours in a 24-hour period.
-After 9 hours of wearing, the patch may be removed, folded in half with sticky sides together, and disposed of. Remaining adhesive on the skin may be removed with oil-based products or soap and water.
-Disposal: After 9 hours of wearing, the patient or caregiver should remove the patch and fold in half so that adhesive sides stick to one another. Place the folded patch in a lidded container. Do NOT flush the patch down the toilet.

Adverse side effects of 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.

Central nervous system adverse events are common with stimulant use. Insomnia, overstimulation, irritability, emotional lability, dizziness, tremor, paresthesias, and headache have been reported with dextroamphetamine use. Mild euphoria and restlessness have been noted in the first weeks of treatment. 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 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. 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.

Stimulant medications, such as dextroamphetamine, 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. 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 and 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 promptly report any changes in mood or behavior. If suicide-related events emerge during treatment, consider dose reduction or drug discontinuation, especially if symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Psychosis and hallucinations may also be associated with amphetamine toxicity or abuse. Practitioners should be alert to the signs of excessive dosages or overdose, which may include anxiety, agitation, confusion, delirium, hostility, hallucinations, paranoia, hyperreflexia, tachypnea, hyperthermia, hyperhidrosis, and panic; fatigue and depression usually follow central nervous system stimulation. Due to its toxic effects in overdose, 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.

Dyskinesia has been reported following the use of CNS stimulants, including dextroamphetamine. 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.

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

Anorexia is one of the most common gastrointestinal (GI) adverse reactions associated with stimulant use. Weight loss is a dose-related adverse effect commonly associated with stimulant use and is of particular concern in growing children and adolescents. Dyspepsia, nausea, and vomiting have also been reported. Eating small, frequent meals or snacks may help limit appetite problems. Other gastrointestinal adverse reactions include abdominal pain, xerostomia, dysgeusia, constipation, and diarrhea. 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 effects are relatively common with the usual use of 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 dextroamphetamine, causes long-term growth inhibition. Although data are limited, available clinical studies do not indicate that stimulant use compromises the attainment of normal adult height and weight in most children. Practitioners should monitor height and weight parameters relative to age at treatment initiation and periodically thereafter (at minimum yearly). Patients who are not growing or gaining weight as expected may need to have their treatment interrupted. In a 24-month follow-up, the MultiModal Treatment Study showed a deceleration of growth of roughly 1 cm per year with stimulant use. In general, growth remained in the normal curve for most children, except those in the lowest percentiles of height for age. Data obtained on the effects of stimulants on growth suppression in children 7 to 10 years of age suggested that regularly medicated children (7 days/week throughout the year) had a temporary average slowing in growth of 2 cm in height and 2.7 kg in weight over 3 years. Reduction of annual growth rate was maximal in the first year, decreased in the second year, and absent in the third year of treatment; however, no compensatory growth rebound effects were found while on stimulant therapy. In a dose-optimization and crossover trial of transdermal dextroamphetamine use in patients 6 to 17 years old, mean weight loss from baseline was -3.1 pounds after 5 weeks of use. 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.

Dextroamphetamine 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. 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 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). In general, stimulant medications increase heart rate by an average of 3 to 6 beats per minute (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 dextroamphetamine treatment should undergo a prompt cardiac evaluation. Minor manifestations of these symptoms may indicate a need for dosage reduction or discontinuation. Severe cardiac adverse effects (e.g., arrhythmia, severe hypertension or hypotension) may be associated with amphetamine toxicity; evaluate patients carefully who present with cardiac symptoms for possible overdose. Pulse measurements should be obtained at baseline, after dosage increases, and periodically throughout stimulant therapy. 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. 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 OR 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)[OR 1.02 (95% CI 0.28 to 3.69)]. The portion of patients specifically using dextroamphetamine 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. The American Heart Association (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 on electrocardiogram (ECG) more than 0.46 seconds, or heart rate or blood pressure more than 2 standard deviations above the mean for age. 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 sympathetic stimulation of amphetamines, including dextroamphetamine, blocks aqueous outflow and may raise intraocular pressure, exacerbating ocular hypertension or glaucoma. Visual impairment such as blurred vision, 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.

Dermatologic and allergic reactions to amphetamines, including dextroamphetamine, 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. Urticaria, rash (unspecified), photosensitivity, and alopecia have also been reported.

Stimulants, such as 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 after 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.

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 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.

Rhabdomyolysis may occur during therapeutic use of amphetamines or may occur with toxicity.

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

Dextroamphetamine is contraindicated for use in patients with known hypersensitivity or idiosyncrasy to dextroamphetamine, 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 dextroamphetamine, 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.

Dextroamphetamine is contraindicated for use in patients in an agitated state. Prior to initiating treatment, patients with comorbid depressive symptoms should be adequately screened to determine whether they are at risk for bipolar disorder and/or mania; such screening should include a detailed psychiatric history, including 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, dextroamphetamine should only be used in those with major depression or suicidal ideation when absolutely necessary.

CNS stimulant medications, including 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 dextroamphetamine for hypertension and tachycardia.

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.

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

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, 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. Patients should check with their surgeon prior to elective surgery regarding any adjustments needed in timing of medications for surgical procedures.

The elimination of amphetamine, including 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 amphetamines and result in prolonged exposures and increased risk of side effects.

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.

Use of the dextroamphetamine patch does not need to be interrupted during bathing or hot weather, but prolonged exposure to an external heat source (such as a heating pad, hair dryer, hot tub, sauna, or electric blanket) should be avoided in order to avoid potential adverse effects from increased dextroamphetamine exposure. In clinical bioavailability studies of the dextroamphetamine patch, application of a heating pad for 6 consecutive hours increased both the rate and extent of dextroamphetamine absorption. Time to maximum concentration decreased to 6.5 hours with heat application (compared to 8.5 hours without), maximum concentration increased to 116%, and total exposure increased to 150% of dextroamphetamine concentrations seen without the use of an external heat source.

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, such as metabolic and electrolyte abnormalities, which may increase their susceptibility to the adverse effects of stimulants. The use of sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The abuse potential of stimulants when used for weight loss should be considered. Dextroamphetamine products are not indicated or recommended for obesity treatment.

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

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

Dextroamphetamine is contraindicated in patients who are currently taking monoamine oxidase inhibitors (MAOIs) or have received MAOI therapy (including MAOIs such as linezolid or intravenous methylene blue) within the past 14 days because of an increased risk of hypertensive crisis. Clinicians should review drug-drug interactions. Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems, including the MAOIs. Discontinue treatment with any serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic 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.

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.

Description: Dextroamphetamine is an orally and transdermally administered amphetamine-class central nervous system (CNS) stimulant used to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy. Dextroamphetamine and other CNS stimulants are highly effective for the treatment of ADHD and are considered first-line therapy. When compared to methylphenidate, stimulants in the amphetamine class have equal efficacy and a similar side effect profile. Although the pharmacokinetic profile of amphetamines is more predictable compared to methylphenidate, amphetamines generally produce a slightly higher rate of tics and have a higher potential for abuse. As a class, stimulants have been associated with sudden death in children. A highlighted warning in the product labeling alerting that 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. Dextroamphetamine is FDA-approved for use in pediatric patients 3 years of age and older; the extended-release and transdermal formulations are FDA-approved for use in patients 6 years of age and older.

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. May administer total daily dose in 1 to 3 divided doses. Usual Max: 40 mg/day. 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. 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 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. May administer total daily dose in 1 to 3 divided doses. 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. May administer total daily dose in 1 to 3 divided doses. Usual Max: 40 mg/day. Doses more than 40 mg/day are rarely needed. 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):
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. May administer total daily dose as once-a-day dosage if appropriate. 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. May administer total daily dose as once-a-day dosage if appropriate. Usual Max: 40 mg/day. Doses more than 40 mg/day are rarely needed. However, a maximum dose of 60 mg/day may be considered. Use the lowest effective dose.
Transdermal dosage:
Children and Adolescents 6 to 17 years: 4.5 mg/9 hours transdermally every 24 hours, initially. May increase the dose by 4.5 mg/9 hours every 24 hours at weekly intervals based on clinical response and tolerability. Max: 18 mg/9 hours every 24 hours. For persons switching from another medication or amphetamine product, discontinue that treatment and titrate using the titration schedule. 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 formulations):
Children < 6 years: Safety and efficacy have not been established.
Children 6-11 years: Initially, 5 mg PO once daily in the morning. May titrate daily dose in 5 mg increments at weekly intervals to the 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. Although a specific maximum dose for children has not been identified, the usual maximum dose for narcolepsy is 60 mg/day.
Children 12 years and Adolescents: Initially, 10 mg PO once daily in the morning. May titrate daily dose in 10 mg increments at weekly intervals to the minimum effective dose. Max: 60 mg/day. Daily dose may be given in 1 to 3 divided doses at 4 to 6 hour intervals. If insomnia or anorexia appear, reduce dosage.
Oral dosage (extended-release formulations):
Children < 6 years: Safety and efficacy have not been established.
Children 6-11 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. Twice daily dosing should be given with an interval of approximately 8 hours. If insomnia or anorexia appear, reduce dosage. Although a specific maximum dose for children has not been identified, the usual maximum dose for narcolepsy is 60 mg/day.
Children 12 years and Adolescents: Initially, 10 mg PO once daily in the morning. May titrate daily dose in 10 mg increments at weekly intervals to minimum effective dose. Twice daily dosing should be given with an interval of approximately 8 hours. If insomnia or anorexia appear, reduce dosage. Max: 60 mg/day.

For the treatment of hypothalamic obesity* after craniopharyngioma surgical resection:
Oral dosage (immediate-release formulations):
Children and Adolescents 6 years and older: Very limited data are available; further studies needed. 5 mg PO once daily in the morning, titrated by 2.5 mg increments in weekly intervals until a decrease in appetite, significant improvement in behavior, or an adverse reaction occurred was used in a small open-label study of 5 children (age 6 to 9.8 years) who failed traditional weight loss therapy (i.e., diet modification and behavior therapy). The mean maximum daily dosage was 16 +/- 2 mg, which was divided into 3 doses given before meals; dosage did not exceed 20 mg/day PO. Weight stabilization was attained within 1 month of therapy initiation and remained stable throughout the 24-month protocol. Mean body mass index (BMI) was 21 +/- 3.5 prior to surgery, 32 +/- 2.8 at the start of therapy, and 31 +/- 3.3 at the end of the 24-month protocol. Mean time from surgery to therapy initiation was 10 months (range: 9 to 14 months). Weight stabilization was contributed to increased activity vs. decreased caloric intake or insulin concentrations. Dextroamphetamine at a dose of 5 mg PO twice daily has been described in a retrospective review of 12 patients (age 12 to 21 years) of similar circumstance.

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 in the FDA-approved labeling; doses should not exceed 40 mg/day PO for immediate-release formulations. Do not use extended-release or transdermal formulations.
6 years and older: 40 mg/day PO for ADHD (doses up to 60 mg/day PO have been used off-label for weight more than 50 kg) or 60 mg/day PO for narcolepsy; one 18 mg/9 hour transdermal patch applied per 24 hours for ADHD.
-Adolescents
40 mg/day PO for ADHD (doses up to 60 mg/day PO have been used off-label for weight more than 50 kg) or 60 mg/day PO for narcolepsy; one 18 mg/9 hour transdermal patch applied per 24 hours for ADHD.

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

Patients with Renal Impairment Dosing
Oral dosage forms:
Specific guidelines for dosage adjustments of oral dextroamphetamine in renal impairment are not available. Renal dysfunction has the potential to inhibit the elimination of amphetamines and result in prolonged exposure; use with caution and titrate dosages carefully.

Transdermal system (Xelstrym):
Severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2): Do not exceed one 13.5 mg/9 hour system applied once per 24 hours.
End stage renal disease (eGFR less than 15 mL/minute/1.73 m2): Do not exceed one 9 mg/9 hour system applied once per 24 hours.

Intermittent hemodialysis
Dextroamphetamine is not dialyzable.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Dextroamphetamine is a central nervous system (CNS) stimulant. It is the d isomer of d,l-amphetamine sulfate and is 3-5 times more potent than l-amphetamine. 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 distractability, 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 3-6 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: Dextroamphetamine is administered orally or transdermally. Distribution is to most body tissues with high concentrations found in the CNS. Metabolism occurs in the liver and excretion is via the kidney. Under normal physiologic conditions the plasma half-life is 10 to 12 hours in adults following oral administration. When the transdermal system is removed after 9 hours wear time, the mean apparent elimination half-life of dextroamphetamine ranged from 6.4 to 11.5 hours in the pediatric and adult population, respectively. The urinary elimination of amphetamines may be affected by agents that acidify or alkalinize the urinary fluids. In general, for every 1 unit increase in urinary pH, there is a reported 7-hour increase in amphetamine half-life. Conversely, acidification of the urine speeds amphetamine elimination.

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. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility. The concomitant use of dextroamphetamine and CYP2D6 inhibitors may increase the exposure of dextroamphetamine compared to the use of the drug alone. Amphetamines are not an in vitro inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, nor an in vitro inducer of CYP1A2, CYP2B6, or CYP3A4/5. Amphetamines are not an in vitro substrate for P-glycoprotein (P-gp).


-Route-Specific Pharmacokinetics
Oral Route
Dextroamphetamine is readily absorbed from the GI tract after oral administration. The extent of absorption is not significantly affected by food.

Immediate-release formulations
After administration of three 5 mg dextroamphetamine immediate-release tablets to 12 healthy subjects, a peak plasma concentration (Cmax) of 36.6 ng/ml was achieved in approximately 3 hours. In a pharmacokinetic study of healthy adult volunteers (n = 24), administration of dextroamphetamine 10 mg as a single dose resulted in a mean Cmax of 24.7 (+/- 5.9) ng/ml within a mean time of 2.6 (+/- 2) hours. Mean AUC was 431 (+/- 80) ng x hr/ml. Half-life is approximately 12 hours. Duration of action is approximately 4-6 hours.

Sustained-release formulations
After administration of one 15 mg dextroamphetamine sustained-release capsule to 12 healthy subjects, a peak plasma concentration of 23.5 ng/ml was achieved in approximately 8 hours. Half-life is approximately 12 hours. Duration of action is approximately 8 hours.

Topical Route
-Transdermal system (Xelstrym): After a single 9-hour transdermal system patch application in pediatric patients 6 to 12 years with ADHD, the max concentration and AUC of dextroamphetamine were dose-proportional over the dose range of 4.5 mg/9 hours to 18 mg/9 hours. Peak plasma levels of dextroamphetamine were typically reached at 6 to 9 hours after single application and 6 hours after repeat applications. In clinical bioavailability studies of the dextroamphetamine patch, application of a heating pad for 6 consecutive hours increased both the rate and extent of dextroamphetamine absorption. Time to maximum concentration decreased to 6.5 hours with heat application (compared to 8.5 hours without), maximum concentration increased to 116%, and total exposure increased to 150% of dextroamphetamine concentrations seen without the use of an external heat source.


-Special Populations
Pediatrics
Children
Elimination half-life is approximately 1 hour shorter for oral dextroamphetamine in children compared to adults. In clinical trials of transdermal dextroamphetamine, the elimination half-life decreased to 6.4 hours in the pediatric population (compared to 11.5 hours in 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. Dosage adjustments are recommended in patients with severe renal impairment (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). Dextroamphetamine is not dialyzable.