ADZENYS XR-ODT

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

Route-Specific Administration

Oral Administration
-May administer with or without food.
Oral Solid Formulations
Immediate-release tablets
-Administer the first dose of the day upon awakening; additional doses may be given at 4 to 6 hour intervals.
-Late evening doses may result in insomnia; the last dose of the day should be administered at least 6 hours before bedtime to avoid sleep interference.
-When used as an anorectic, administer the dose 30 to 60 minutes before meals.

Immediate-release oral disintegrating tablets (ODT) (e.g., Evekeo ODT)

-Administer the first dose of the day in the morning. May give an additional dose, if prescribed, 4 to 6 hours later. May give with or without food or liquid.
-With dry hands, open the blister. Remove the tablet by pushing it through foil backing just prior to dosing. Do not store tablet for future use.
-Place tablet on the tongue and allow to dissolve without chewing or crushing. Once dissolved, the patient may swallow with saliva.

Extended-release tablets (e.g., Dyanavel XR)

-Administer once daily in the morning.
-May be chewed or swallowed whole.
-5 mg tablet is scored and may be divided into equal halves (2.5 mg) at the score line.

Extended-release oral disintegrating tablets (ODT) (e.g., Adzenys XR ODT)

-Administer once daily in the morning.
-DO NOT attempt to push ODT tablets through foil backing.
-With dry hands, bend the blister where indicated and peel back the foil to remove the tablet just prior to dosing.
-Place tablet on the tongue and allow to dissolve. Do not chew or crush. Once dissolved, the patient may swallow with saliva.

Oral Liquid Formulations
-Administer the extended-release suspension once daily in the morning.
-Shake well prior to administration.
-Measure dosage with an oral syringe or calibrated measuring device.
-Do not add to food or mix with other liquids before consuming.

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

Insomnia is one of the most common adverse reactions to amphetamine use. Insomnia was reported in 4% to 10% of pediatric patients 6 to 12 years of age receiving amphetamine sulfate (Evekeo), and the medication was discontinued in one pediatric patient during clinical trials due to initial insomnia. 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, particularly extended-release formulations. 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.

Central nervous system adverse reactions, such as dizziness and restlessness, often occur with stimulant use. Dizziness and headache are common in adults. Irritability (14%) and headache (13%) have been reported in pediatric patients 6 to 12 years of age receiving amphetamine sulfate (Evekeo) and the product was discontinued in 3 pediatric patients during clinical trials due to irritability. Overstimulation, irritability, tremor, and paresthesias (including formication) have also been reported. Mild euphoria and restlessness have been noted in the first weeks of stimulant treatment. 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 can exacerbate behavioral disturbances, psychosis, or thought disorders. New-onset psychotic symptoms (e.g., hallucinations, delusional thinking, mania) can 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, consider discontinuation of therapy. Emotional lability and nervousness are among the most commonly reported adverse reactions in children taking amphetamine. Anxiety and agitation are common among adult patients. Infrequently, speech disorder (stuttering, excessive speech) and twitching have also been reported in adult patients. Emotional lability was reported in 3% to 9% of pediatric patients 6 to 12 years of age receiving amphetamine sulfate (Evekeo), and the product was discontinued in one pediatric patient during clinical trials due to emotional lability. Aggression, hostility, and suicidal ideation or behaviors have been reported in both clinical trials and postmarketing experience with medications used to treat attention-deficit hyperactivity disorder (ADHD). Although causality has not been established and these behaviors may be related to the presence of ADHD itself, close monitoring is recommended. Advise patients and their caregivers to promptly report any changes in mood or behavior. If suicide-related events emerge during treatment, consider dose reduction or drug discontinuation, especially if symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Dermatillomania, teeth grinding (bruxism), teeth clenching, speech disorders (e.g., stuttering or dysphemia, excessive speech, logorrhea), dysphoria, and anger have also been reported with amphetamine use. Psychosis and hallucinations may also be associated with amphetamine toxicity or abuse. Due to its toxic effects in overdose, amphetamine 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 during postmarketing use of CNS stimulants, including amphetamines. 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 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. Discontinue stimulant medications if seizures develop. Seizures may be associated with amphetamine toxicity; evaluate patients presenting with convulsions for other signs and symptoms of overdose.

Data are inadequate to determine whether chronic use of stimulants, such as amphetamine, 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. Proposed mechanisms of growth inhibition include the suppression of appetite or an alteration in growth hormone secretion. Growth rebound has been observed after stimulant discontinuation and some experts recommend the use of drug holidays to allow growth to 'catch-up'. However, drug holidays are typically reserved for children with well-controlled attention-deficit hyperactivity disorder (ADHD) symptoms and are of unproved value in limiting growth suppression.

Anorexia (lack or loss of appetite) is one of the most common adverse reactions associated with stimulant use. In pediatric patients 6 to 12 years of age receiving amphetamine sulfate (Evekeo), anorexia (4% to 28%) was reported. Weight loss is a dose-related adverse reaction associated with stimulant use and is of particular concern in growing children and adolescents when amphetamine is not being used for its anorectic effect. Eating small, frequent meals or snacks may help limit appetite problems. Monitor weight and growth in children during treatment with stimulants; patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

Gastrointestinal (GI) adverse reactions are often associated with amphetamine use. Abdominal pain, nausea, and vomiting are common in children, while xerostomia and diarrhea are more often reported in adults. During clinical trials, upper abdominal pain was reported in 3.8% of pediatric patients receiving amphetamine extended-release (Dyanavel XR). In pediatric patients 6 to 12 years of age receiving amphetamine sulfate (Evekeo), abdominal pain (3% to 15%), nausea (6%), vomiting (6%), and xerostomia (6%) were reported. Other GI disturbances reported with stimulant use include dyspepsia, dysgeusia, and constipation. Persistent or excessive GI symptoms may lead to anorexia and weight loss. Eating small, frequent meals or snacks may help limit GI discomfort. Complaints of xerostomia or dysgeusia may be limited by sucking sugarless hard candy, crushed ice, and drinking plenty of water or other fluids. Clinicians should be aware that while GI adverse reactions are relatively common with the usual use of amphetamine, excessive abdominal cramping, nausea, vomiting, or diarrhea may represent excessive dosage and toxicity. Intestinal and bowel ischemia has been reported during postmarketing use. Cases of intestinal necrosis (bowel necrosis), including some deaths, have been reported with concomitant use of sodium polystyrene sulfonate and sorbitol, two of the inactive ingredients in the amphetamine extended-release oral suspension (Adzenys ER).

Amphetamine 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. Amphetamine tablets are contraindicated in patients with moderate to severe hypertension, and all formulations should be used with caution, even in patients with mild hypertension. Obtain blood pressure measurements 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). Fast heart beat is common in adult patients. In pediatric patients 6 to 12 years of age receiving amphetamine sulfate (Evekeo), tachycardia was reported in 9% of patients. In general, stimulant medications increase heart rate by an average of 3 to 6 bpm; however, some patients may experience higher increases. 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 treatment should undergo a prompt cardiac evaluation. Minor manifestations of these symptoms may indicate a need for dosage reduction or discontinuation. Severe cardiac adverse reactions (e.g., arrhythmia or arrhythmia exacerbation, severe hypertension or hypotension) may be associated with amphetamine toxicity; evaluate patients carefully who present with cardiac symptoms for possible overdose. Use amphetamine with caution in patients with conditions that would be expected to worsen by an increase in heart rate. Obtain pulse measurements at baseline, after dosage increases, and periodically throughout stimulant therapy.

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 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 derivatives. Urticaria, rash, hyperhidrosis, photosensitivity, and alopecia have also been reported during the administration of amphetamines. One pediatric patient aged 6 to 12 years discontinued amphetamine sulfate (Evekeo) during clinical trials due to rash.

Stimulants 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. Use caution 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.

Epistaxis (3.8%) and allergic rhinitis (3.8%) were among the most common adverse effects reported during pediatric clinical trials of amphetamine extended-release (Dyanavel XR).

Although a specific incidence was not reported from amphetamine clinical trials, during trials for amphetamine mixed salts, dysmenorrhea was reported in 2% to 4% of adult females.

In pediatric patients 6 to 12 years of age receiving amphetamine sulfate (Evekeo), infection (22%), fatigue (10%), and injury (3%) were reported as side effects. Although not reported specifically with amphetamine, additional adverse reactions were reported during clinical trials of amphetamine mixed salts that may be clinically relevant to patients taking amphetamine. Fever and infection (unspecified) were reported in 5% and 4% of pediatric patients, respectively, while drowsiness, asthenia/fatigue, and accidental injury were reported in 2% to 4% of pediatric patients. Adult patients reported asthenia (6%) and urinary tract infection (5%); infection (unspecified), tooth disorder (tooth infection/teeth clenching), drowsiness, and dyspnea were reported at an incidence of 2% to 4%.

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

Serotonin syndrome may occur when amphetamines are used in combination with other drugs that enhance serotonin activity. Symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and seizures. If such symptoms emerge, discontinue amphetamine 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 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.

Amphetamine 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 amphetamine.

Cases of intestinal necrosis, including some deaths, have been reported with concomitant use of sodium polystyrene sulfonate and sorbitol, 2 of the inactive ingredients in Adzenys ER oral suspension. In these cases, sodium polystyrene sulfonate was used to treat hyperkalemia at doses more than 200 times the amount present in Adzenys ER; however, no absolute safe levels for the interaction of sodium polystyrene and sorbitol have been established.

Central nervous system (CNS) stimulants, such as amphetamines, 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 therapy. Abrupt discontinuation or a significant dose reduction of CNS stimulants after prolonged use may produce withdrawal symptoms that include dysphoria, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation. Consider monitoring for withdrawal symptoms after significant dose reduction or discontinuation after prolonged use.

CNS stimulants should be used with caution in those with bipolar disorder or a pre-existing psychotic disorder (e.g., schizophrenia). CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychosis. These medications can also induce mania or a mixed episode in patients with bipolar disorder. Prior to initiating treatment with amphetamine, 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, 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 for hypertension and tachycardia.

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

Amphetamine may lower the seizure threshold; use 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, discontinue amphetamine. Because of a potential increased risk of seizures, do not use amphetamine during intrathecal radiographic contrast administration. Discontinue amphetamine 48 hours before the myelography and do not resume 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.

The elimination of amphetamine 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.

In rare instances, stimulant medications may cause prolonged and sometimes painful erections (priapism). Counsel all male patients and their caregivers 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. Use caution 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 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.

Amphetamine 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.

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.

Obesity treatment with amphetamine should be initiated only in short-term weight reduction programs for patients older than 12 years in whom alternative therapies, including repeated dietary reduction, exercise, or other medications, have been ineffective. Rule out eating disorders, such as anorexia nervosa or bulimia nervosa, prior to treatment with amphetamines. Patients with eating disorders may have physiologic complications, such as metabolic and electrolyte abnormalities, which increase their susceptibility to the adverse effects of stimulants. In addition, the abuse potential of stimulants should be considered in patients with an eating disorder.

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.

Ethanol ingestion may result in a more rapid release of amphetamine from certain extended-release (ER) products or their generic equivalents; advise patients taking these products to avoid alcohol. In vitro studies of Dyanavel XR oral suspension, Adzenys XR ODT, and Adzenys XR oral suspension products showed potential for alcohol-induced dose dumping in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations. Dose-dumping potential was not observed during in vitro studies of the Dynavel XR tablets.

Description: Amphetamine is an orally administered central nervous system (CNS) stimulant used primarily to treat attention-deficit hyperactivity disorder (ADHD) in pediatric patients; the immediate-release tablet also carries indications for narcolepsy and exogenous obesity in older pediatric patients. However, amphetamines and other anorectic agents are not generally recommended by guidelines for the pharmacotherapy of obesity in pediatric patients due to risks of these agents and the lack of longer-term health benefits. Stimulants, such as amphetamine, are highly effective in the treatment of ADHD and are considered first-line therapy. Amphetamine- and methylphenidate-containing products are considered equally effective in the treatment of ADHD; patients who do not respond to 1 may respond to the other. The most common adverse reactions associated with amphetamine use include anorexia, abdominal pain, irritability, restlessness, insomnia, emotional lability, and tachycardia. Rarely, priapism and peripheral vasculopathy can occur. Stimulants can induce or exacerbate psychiatric symptoms and should be used with caution in patients with a history of mania, psychosis, or substance abuse. Stimulants have also been associated with sudden death in pediatric patients with structural cardiac abnormalities; patients 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. Evekeo immediate release tablets are FDA-approved for use in pediatric patients 3 years and older; Evekeo ODT and extended-release oral formulations are FDA-approved for use in pediatric patients 6 years and older.

For the treatment of attention-deficit hyperactivity disorder (ADHD):
Oral dosage (immediate-release tablets; e.g., Evekeo):
Children 3 to 5 years: 2.5 mg PO once daily in the morning. May titrate in 2.5 mg/day increments at weekly intervals to minimum effective dose. An additional 1 to 2 doses per day may be given at 4 to 6 hour intervals if needed. Maximum dosage information is not available; however, do not exceed 40 mg/day, the maximum recommended dose for children 6 years and older. Although this dosing information is available in the FDA-approved package labeling, the American Academy of Pediatrics (AAP) does not recommend the use of amphetamine in this age group due to lack of safety and efficacy data.
Children and Adolescents 6 to 17 years: 5 mg PO once or twice daily, with the first dose given in the morning. May titrate by 5 mg/day at weekly intervals to minimum effective dose. An additional 1 to 2 doses per day may be given at 4 to 6 hour intervals if needed. Rarely is it necessary to exceed 40 mg/day.
Oral dosage (immediate-release orally disintegrating tablets; e.g., Evekeo ODT):
Children and Adolescents 6 to 17 years: 5 mg PO once or twice daily initially. May titrate in 5 mg/day increments at weekly intervals to minimum effective dose. An additional dose may be given after 4 to 6 hours if needed. Use the lowest effective dose after stabilization. Rarely is it necessary to exceed 40 mg/day. Switching from immediate-release tablets to immediate-release orally disintegrating tablets can be done on a mg-per-mg basis. Do not substitute for other amphetamine products on a mg-per-mg basis due to different amphetamine base compositions and differing pharmacokinetic profiles.
Oral dosage (extended-release oral suspension or extended-release tablets; e.g., Dyanavel XR):
Children and Adolescents 6 to 17 years: 2.5 to 5 mg PO once daily in the morning. May titrate in 2.5 to 10 mg/day increments every 4 to 7 days to minimum effective dose. Max: 20 mg/day. Use lowest effective dose after stabilization. SWITCHING PRODUCTS: The Dyanavel XR oral suspension can be substituted with Dyanavel XR tablets on a mg-per-mg basis. When switching from other amphetamine products, discontinue previous treatment, initiate with 2.5 or 5 mg PO once daily, then titrate. Do not substitute for other amphetamine products on a mg-per-mg basis due to different amphetamine base compositions and differing pharmacokinetic profiles.
Oral dosage (extended-release ODT or extended-release suspension; e.g., Adzenys XR-ODT and Adzenys ER oral suspension):
Children 6 to 12 years: CHILDREN NOT CURRENTLY TAKING AN AMPHETAMINE PRODUCT: Initially, 6.3 mg PO once daily in the morning. May titrate by 3.1 or 6.3 mg/day at weekly intervals. Max: 18.8 mg/day PO. SWITCHING FROM ANOTHER AMPHETAMINE PRODUCT (EXCEPT ADDERALL XR): After discontinuing the other amphetamine product, initiate Adzenys XR at 6.3 mg PO once daily in the morning. May titrate by 3.1 or 6.3 mg/day at weekly intervals. Individualize dosage to therapeutic effect. Max: 18.8 mg/day PO. Do not substitute for other amphetamine products on a mg-per-mg basis due to different compositions and pharmacokinetic profiles. CHILDREN CURRENTLY TAKING 5 MG/DAY OF ADDERALL XR: Initially, 3.1 mg PO once daily in the morning. May titrate in 3.1 or 6.3 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 10 MG/DAY OF ADDERALL XR: Initially, 6.3 mg PO once daily in the morning. May titrate in 3.1 or 6.3 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 15 MG/DAY OF ADDERALL XR: Initially, 9.4 mg PO once daily in the morning. May titrate in 3.1 or 6.3 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 20 MG/DAY OF ADDERALL XR: Initially, 12.5 mg PO once daily in the morning. May titrate in 3.1 or 6.3 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 25 MG/DAY OF ADDERALL XR: Initially, 15.7 mg PO once daily in the morning. May titrate in 3.1 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 30 MG/DAY OF ADDERALL XR: 18.8 mg PO once daily in the morning; do not exceed this dose.
Adolescents: ADOLESCENTS NOT CURRENTLY TAKING AN AMPHETAMINE PRODUCT: Initially, 6.3 mg PO once daily in the morning. May titrate by 3.1 or 6.3 mg/day at weekly intervals. Max: 12.5 mg/day PO. SWITCHING FROM ANOTHER AMPHETAMINE PRODUCT (EXCEPT ADDERALL XR): After discontinuing the other amphetamine product, initiate Adzenys XR at 6.3 mg PO once daily in the morning. May titrate by 3.1 or 6.3 mg/day at weekly intervals. Individualize dosage to therapeutic effect. Max: 12.5 mg/day PO. Do not substitute for other amphetamine products on a mg-per-mg basis due to different compositions and pharmacokinetic profiles. ADOLESCENTS CURRENTLY TAKING 5 MG/DAY OF ADDERALL XR: Initially, 3.1 mg PO once daily in the morning, then titrate if needed. ADOLESCENTS CURRENTLY TAKING 10 MG/DAY OF ADDERALL XR: Initially, 6.3 mg PO once daily in the morning, then titrate if needed. ADOLESCENTS CURRENTLY TAKING 15 MG/DAY OF ADDERALL XR: Initially, 9.4 mg PO once daily in the morning, then titrate if needed. ADOLESCENTS CURRENTLY TAKING 20 MG/DAY OF ADDERALL XR: 12.5 mg PO once daily in the morning.

For the treatment of narcolepsy:
Oral dosage (tablet):
Children 6 to 11 years: 5 mg PO once daily in the morning. May titrate in 5 mg/day increments at weekly intervals to minimum effective dose. Max: 60 mg/day. Give the first dose upon awakening; additional doses may be given at 4 to 6 hour intervals. If insomnia or anorexia appear, reduce dosage.
Children and Adolescents 12 to 17 years: 10 mg PO once daily in the morning. May titrate in 10 mg/day increments at weekly intervals to minimum effective dose. Max: 60 mg/day. Give the first dose upon awakening; additional doses may be given at 4 to 6 hour intervals. If insomnia or anorexia appear, reduce dosage.

For the short-term (i.e., 8 to 12 weeks) treatment of exogenous obesity:
Oral dosage (tablet):
Children and Adolescents 12 to 17 years: 5 to 10 mg PO up to 3 times per day, taken 30 to 60 minutes before meals. Max: 30 mg/day. Only continue if the patient has satisfactory weight loss within the first 4 weeks of treatment. When tolerance to the anorectic effect develops, do not exceed the dosage in an attempt to increase the effect; instead, discontinue. Use only for patients refractory to alternative therapy (e.g., repeated diets, group programs, increased activity, and other drugs). Use as monotherapy; for short-term (8 to 12 weeks) use only. The limited usefulness of amphetamines should be weighed against possible risks inherent in the use of this drug class. Guidelines state that short-term pharmacotherapy, such as with the amphetamine anorectics, has not been shown to produce longer-term health benefits in pediatric patients and cannot be generally recommended. In general, children with a BMI below the 95th percentile should not be treated with antiobesity drugs. Pharmacotherapy for overweight children (BMI of at least 85th but less than 95th percentile) should be reserved for those with significant, severe comorbidities who have not responded to lifestyle modification.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 2 years: Safety and efficacy have not been established.
3 to 5 years: 40 mg/day PO for Evekeo; safety and efficacy have not been established for Evekeo ODT or extended-release formulations.
6 to 12 years: 18.8 mg/day PO (Adzenys XR products); 20 mg/day PO (Dyanavel XR); 40 mg/day PO (immediate-release products).
-Adolescents
12.5 mg/day PO (Adzenys XR products); 20 mg/day PO (Dyanavel XR); 40 mg/day PO (immediate-release products).

Patients with Hepatic Impairment Dosing
Use with caution; hepatic dysfunction has the potential inhibit the elimination of amphetamine and result in prolonged exposures. However, specific guidelines for dosage adjustments in hepatic impairment are not available.

Patients with Renal Impairment Dosing
Use with caution; renal dysfunction has the potential inhibit the elimination of amphetamine and result in prolonged exposures. However, specific guidelines for dosage adjustments in renal impairment are not available.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Amphetamine is a central nervous system (CNS) stimulant. The exact mechanism of amphetamines for attention-deficit hyperactive disorder (ADHD) is not established. Amphetamines are non-catecholamine sympathomimetic agents that block the reuptake of dopamine (DA) and norepinephrine (NE) into the presynaptic neuron, increasing the release of both biologic amines into the extraneuronal space. Under normal circumstances, the DA transporter protein moves DA from the synapse into the cell. Amphetamine binds to the presynaptic DA transporter protein, inducing a reverse transport process and blocking DA reuptake back into the cell, therefore increasing concentrations of DA in the synapse. Amphetamines may also inhibit monoamine oxidase (MAO), but this is a minor action. Evidence suggests serotonergic transmission may regulate the effects of amphetamine; however this mechanism is not completely understood. Amphetamine-induced CNS stimulation produces a decreased sense of fatigue, an increase in motor activity and mental alertness, and mild euphoria. Improved attention spans, decreased distractibility, increased ability to follow directions or complete tasks, and decreased impulsivity and aggression have been noted when stimulants are prescribed for the treatment of ADHD.

In the periphery, the actions of amphetamines are believed to occur through release of NE from the adrenergic nerve terminals and by a direct stimulant action on alpha- and beta-receptors. Amphetamines increase systolic and diastolic blood pressure and cause respiratory stimulation and weak bronchodilation. Heart rate typically increases slightly with normal therapeutic doses of stimulants (about 3 to 6 bpm); however, a reflexive decrease in heart rate in response to increased blood pressure can also occur. At high doses, such as in overdoses, amphetamine and its derivatives can cause significant hypertension, tachycardia, arrhythmias, and other serious complications. Amphetamines may produce mydriasis and contraction of the bladder sphincter. It has been suggested that amphetamines decrease olfactory acuity, which may contribute to their anorexic properties.

Amphetamine is a racemic mixture of l-amphetamine and d-amphetamine. The l-isomer is more potent than the d-isomer in cardiovascular activity, but much less potent in causing CNS excitatory effects. The racemic mixture is also less effective as an anorectic when compared to dextroamphetamine.

Pharmacokinetics: Amphetamine is administered orally. It is a racemic compound (l-amphetamine and d-amphetamine). Amphetamines are weak bases with a pKa around 9.9, a low molecular weight, low protein binding (16%), and a moderately high volume of distribution (3 to 4 L/kg). These properties grant easy diffusion across cell membranes and lipid layers, leading to accumulation in biologic fluids and tissues with a more acidic pH than blood. Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain alpha- or beta- carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. The formation of 4-hydroxy-amphetamine is known to involve CYP2D6. Amphetamine and its metabolites are primarily excreted in the urine; with a normal urine pH, approximately 30% to 40% of the dose is recoverable in the urine as amphetamine and 50% as alpha-hydroxy-amphetamine (inactive metabolite).

Because amphetamine is a weak base, urinary recovery 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 remaining fraction of the dose is hepatically metabolized. Children exhibit a higher clearance than adolescents and adults when adjusted for body weight. Under normal conditions, the plasma half-life of amphetamine is roughly 9 to 11 hours in children 6 to 12 years, 11 to 14 hours in adolescents, and 10 to 13 hours in adults. Elimination half-life decreases in acidic urine, down to approximately 4 to 8 hours.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, 1A2, 3A4
Minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by 1 or more metabolites has been observed in vitro. CYP2D6 inhibitors may increase exposure to amphetamine. Since CYP2D6 is genetically polymorphic, variations in amphetamine metabolism are a possibility.


-Route-Specific Pharmacokinetics
Oral Route
Amphetamines have good oral bioavailability.
Immediate-release tablets: Amphetamine absorption is rapid, with a Tmax of approximately 4 hours. In a clinical trial of amphetamine tablets for the treatment of ADHD in children 6 to 12 years of age, onset of effect occurred 45 minutes after administration, with the greatest effect occurring 4 hours after ingestion. Amphetamine continued to demonstrate efficacy 10 hours after administration, which was the last time point measured.
Immediate-release orally disintegrating tablets (ODT): Amphetamine demonstrates linear pharmacokinetics over the dose range of 5 to 40 mg. In a crossover study of healthy patients, exposures (Cmax and AUC) to d- and l-amphetamine were comparable to that after administration of equal dose of immediate-release amphetamine tablets. Median Tmax of d- and l-amphetamine was reached at approximately 3.5 (2 to 8) hours and 3 (1 to 6 hours) hours after administration without water and with water, respectively. Administration of food (a high fat meal) does not affect the observed AUC and Cmax of d- and l-amphetamine after single-dose oral administration of amphetamine ODT tablets. Median Tmax (range) increased from 2.5 (1.5 to 6) hours to 4.5 (2.5 to 8) hours when administered without food compared to with food. The average half-life of d- and l-amphetamine was 10 and 11.7 hours, respectively, in healthy adult volunteers.
Extended-release suspension: Amphetamine extended-release (ER) suspension is well absorbed after oral administration; relative bioavailability of the ER suspension compared to an equal dose of mixed amphetamine salts tablets is 106% for d-amphetamine and 111% for l-amphetamine. In trials of healthy adults who received a single 18.8 mg dose, peak concentrations were achieved 4 hours (range: 2 to 7 hours) after dosing, and were similar to those achieved with mixed amphetamine salts tablets. Plasma terminal elimination half-life for the ER suspension was approximately 11 to 12 hours and 14 to 15 hours for d-amphetamine and l-amphetamine, respectively. A high-fat meal delayed the Tmax by approximately 1 hour, but did not significantly affect the extent of absorption. An in vitro dissolution study using the ER suspension showed alcohol-induced dose dumping potential in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations.
Extended-release tablets: Amphetamine extended-release (ER) tablets are well absorbed after oral administration. In trials of healthy adults who received a single 20 mg dose of the ER tablet, the Tmax was 5 (range: 2 to 9) hours and the plasma terminal elimination half-life was 13.5 hours and 17.3 hours for d-amphetamine and l-amphetamine, respectively. A high-fat meal did not delay the median Tmax or significantly affect the extent of absorption. An in vitro dissolution study using the ER tablet showed no alcohol-induced dose dumping potential in the presence of 40% alcohol or in the presence of lower alcohol concentrations. The relative bioavailability of ER tablets compared to an equal dose of ER oral suspension is 105% for d-amphetamine and 106% for l-amphetamine.
Extended-release orally disintegrating tablets (ODT): In a trial of 40 healthy adults who received a single 18.8 mg dose of amphetamine extended-release (ER) ODT (fasting conditions), mean peak plasma concentrations of d-amphetamine (44.9 ng/mL) and l-amphetamine (14.5 ng/mL) were achieved approximately 5 hours after dosing and were similar to those achieved with 30 mg ER mixed amphetamine salts capsules (i.e., Adderall XR). AUC was 876.9 ng/mL x hour and half-life was approximately 11 hours. Administration with food did not affect the extent of absorption, but resulted in a 19% reduction in Cmax (44.9 to 36.3 ng/mL) and prolonged the median Tmax by approximately 2 hours. These changes were not considered to be clinically significant. An in vitro study using the ER ODT showed alcohol-induced dose dumping potential in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations.


-Special Populations
Pediatrics
Children and Adolescents 6 to 17 years
Age and body weight are primary determinants of differences in the pharmacokinetics of amphetamine. Systemic exposure measured by AUC and Cmax decrease with increased body weight, while Vd, clearance, and elimination half-life increase with increased body weight. Upon dose normalization on a mg/kg basis, pediatric patients show 30% less systemic exposure compared to adults. In addition, when adjusted for body weight, children exhibit a higher clearance than adolescents and adults. Under normal conditions, the plasma half-life of amphetamine is roughly 9 to 11 hours in children 6 to 12 years, 11 to 14 hours in adolescents, and 10 to 13 hours in adults. The plasma terminal elimination half-life of the extended-release suspension was approximately 10 to 13 hours and 12 to 15 hours for d-amphetamine and l-amphetamine, respectively, in children 6 to 12 years of age. Comparatively, the plasma terminal half-life was 11 to 12 hours and 14 to 15 hours for d-amphetamine and l-amphetamine, respectively, in healthy adult patients. Tmax was similar in both groups.

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. Although no studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of extended-release amphetamine administration, urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining dose hepatically metabolized.

Gender Differences
Body weight is the primary determinant of apparent differences in the pharmacokinetics of amphetamine. Systemic exposure measured by AUC and Cmax decrease with increased body weight, while Vd, clearance, and elimination half-life increase with increased body weight. Due to the higher dose administered to women on a mg/kg body weight basis, systemic exposure to amphetamine was 20% to 30% higher in women (n = 20) compared to men (n = 20) during controlled trials; these differences diminished when Cmax and AUC were normalized by dose (mg/kg).