Anorexia (reported as loss or decrease of appetite) and other appetite changes 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. In a controlled trial of extended-release amphetamine; dextroamphetamine in adolescents, the mean change in weight during the first 4 weeks of therapy was -1.1 lbs and -2.8 lbs, respectively for patients who received 10 mg and 20 mg daily. During clinical trial evaluations of extended-release amphetamine; dextroamphetamine, the following GI effects were reported in adults and/or pediatric patients: loss of appetite (30% to 33% of adults, 22% to 36% of adolescents, 22% of children), weight loss (9% to 10% of adults, 5% to 9% of adolescents, 4% of children), vomiting (7% of children), nausea (8% of adults, 8% of adolescents, 5% of children), diarrhea (3% to 6% of adults), teeth grinding (bruxism) (2% of adults), dyspepsia (2% of children), xerostomia (23% to 35% of adults), constipation (2% to 4% of adults), and abdominal pain (4% to 11% of adolescents, 14% of children). Bowel ischemia has been reported during postmarketing use. Dysgeusia has been associated with the use of amphetamines although the frequency has not been determined.[29332] [31563] [62038] Complaints of xerostomia or dysgeusia may be limited by sucking sugarless hard candy, crushed ice, and drinking plenty of water or other fluids. Eating small, frequent meals or snacks may help limit gastrointestinal effects.

Patients with Gilles de la Tourette's syndrome or a family history of this syndrome may have motor or phonetic tics unmasked or exacerbated by the use of stimulants for concomitant ADHD symptoms. Exacerbation of tics may respond to dosage reduction of the amphetamines; in some cases the stimulant may need to be discontinued.[31563]

Growth inhibition is a possible long-term side effect of the use of stimulants in children and adolescents; proposed mechanisms have included the suppression of appetite or an alteration in growth hormone secretion. Some have suggested that the use of drug holidays will allow growth to 'catch-up'. However, drug holidays are typically reserved for children with well-controlled ADHD symptoms, and drug holidays are of unproved value in limiting growth suppression. Growth rebound has been observed after the discontinuation of the stimulants in children and clinical studies do not indicate that amphetamines compromise the attainment of normal adult height and weight. However, practitioners should monitor for this side effect by monitoring height and weight parameters relative to age at the initiation of treatment and periodically during therapy (at minimum yearly). Patients who are not growing or gaining weight as expected may need to have their treatment interrupted.[45900] 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.[31578] [31592] Data obtained on the effects of stimulants on growth suppression in children 7—10 years of age suggested that regularly medicated children (7 days/week) had a temporary average slowing in growth of 2 cm in height and 2.7 kg in weight over 3 years; it is anticipated that chronic amphetamine use may cause similar suppression.[31563]

Like other stimulant medications, amphetamine; dextroamphetamine is associated with cardiovascular adverse effects ranging in severity from mild to fatal. In normal therapeutic doses, amphetamines may induce increases in both systolic and diastolic blood pressure and exacerbate hypertension. In a single dose pharmacokinetic study of adolescents with ADHD (n = 23), increases in systolic blood pressure above the upper 95% CI for age, gender, and stature occurred in 12% of patients given 10 mg of extended-release amphetamine;dextroamphetamine (Adderall XR) and 35% of patients given 20 mg. Maximal increases occurred 2 to 4 hours after dosing, were transient, and were not associated with symptoms. In a second study of adolescents with ADHD treated over a 4-week period, systolic blood pressure increases (15 mmHg or more) occurred in 7% of patients receiving Adderall XR (n = 100) and 11% of patients receiving placebo (n = 64). Diastolic blood pressure increases (8 mmHg or more) occurred in 22% of patients receiving Adderall XR and 25% of patients receiving placebo. In general, stimulant medications cause an average increase in blood pressure of about 2 to 4 mmHg.[29332] A reflex sinus bradycardia, which is not usually clinically significant, may occur. In general, stimulant medications increase heart rate by an average of 3 to 6 bpm, but some patients may experience significantly higher increases. During clinical trial evaluations of extended-release amphetamine; dextroamphetamine in adults, the following cardiac effects were reported more frequently in patients receiving extended-release amphetamine; dextroamphetamine than placebo: tachycardia (6%), increased heart rate (9%), dyspnea (2% to 4%), and palpitations (2% to 4%). Other cardiovascular-related events that have been reported with the use of amphetamines include sudden death, myocardial infarction, stroke (unspecified), and isolated cases of cardiomyopathy with chronic administration. Sudden cardiac death has also been reported in association with CNS stimulant treatment at usual doses in children, adolescents, and adults with structural cardiac abnormalities and other serious heart conditions. Although some structural cardiac abnormalities alone may carry an increased risk of sudden death, stimulant products generally should not be used in children, adolescents, or adults with known structural cardiac abnormalities or other serious heart conditions. All patients should be advised of the risk of serious cardiovascular events (e.g., arrhythmia or arrhythmia exacerbation, tachycardia, hypertension, hypotension) with stimulant use. Patients who develop symptoms such as exertional chest pain (unspecified), unexplained syncope, or other symptoms suggestive of cardiac disease during amphetamine; dextroamphetamine treatment should undergo a prompt cardiac evaluation.[29332] [31563]

During clinical trial evaluations of extended-release amphetamine; dextroamphetamine in adults, the following genitourinary effects were reported more frequently in patients receiving extended-release amphetamine; dextroamphetamine than placebo: dysmenorrhea (2% to 4%), libido decrease (2% to 4%), and impotence (erectile dysfunction) (2% to 4%). Frequent or prolonged erections have occurred during administration of amphetamine derivatives. Similar reactions, including priapism, have been reported during use of other ADHD medications such as methylphenidate and atomoxetine.[51955] [28405] Reported cases of priapism have occurred after a period of time on stimulant therapy and often subsequent to a dose increase. Priapism has also been reported during periods of drug withdrawal (e.g., drug holidays or discontinuation). Prolonged erections in male patients should be promptly reported, as immediate diagnosis and treatment are essential to avoid tissue damage. Amphetamines have been reported to occasionally cause libido increase.[29332] [31563] [62038]

Stimulant medications have the potential to lower the seizure threshold in patients with a prior history of seizures, in patients with a history of EEG abnormalities without a history of seizures, and rarely in patients without a seizure history or EEG abnormalities. Stimulant medications should be discontinued if seizures develop. Seizures are also associated with amphetamine; dextroamphetamine toxicity; carefully evaluate the patient for other signs and symptoms of overdose if seizures occur.[29332]

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. During clinical trial evaluation of extended-release amphetamine; dextroamphetamine in adults, hyperhidrosis and photosensitivity reaction occurred in 2% to 4% of patients receiving extended-release amphetamine; dextroamphetamine and at a greater frequency than placebo. Urticaria, rash (unspecified), and alopecia have also been reported during the administration of amphetamines.[29332] [31563] [62038]

Insomnia is one of the most common centrally-mediated effects of amphetamines. Insomnia will typically resolve within a few days of amphetamine use 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 dosage reduction. During clinical trial evaluations of extended-release amphetamine; dextroamphetamine, the following CNS effects were reported in adults and/or pediatric patients: headache (26% of adults), insomnia (27% to 31% of adults, 8% to 12% of adolescents, 17% of children), dizziness (7% of adults, 4% of adolescents, 2% of children), feeling jittery (2% of adults), asthenia (6% of adults, 2% of children), somnolence/drowsiness (2% to 4% of adults), speech disorder (e.g., stuttering or dysphemia, excessive speech, logorrhea) (2% to 4% of adults), twitching (2% to 4% of adults), and accidental injury (3% of children). Other CNS effects that have been associated with the use of amphetamines include overstimulation, dyskinesia, dysphoria, tremor, euphoria, restlessness, and paresthesias (including formication). Children who become overly preoccupied with a task (over-focused or inflexible) or are described as 'zombie-like' are considered to exhibit supranormalization; these behaviors typically require dosage reduction. Once-daily morning dosing of amphetamine; dextroamphetamine is effective in many children and may also help to limit intolerable adverse reactions.[29332] [31563] [62038]

The sympathetic stimulation of amphetamines blocks aqueous outflow and may cause ocular adverse effects, and raise intraocular pressure (IOP), exacerbating ocular hypertension or glaucoma. Visual impairment such as blurred vision, mydriasis, and accomodation disorder has been reported during use of amphetamines. Patients are encouraged to report any unusual changes in vision promptly for examination and evaluation.[29332] [31563] [62038]

Stimulants used to treat ADHD, including amphetamine; dextroamphetamine, are associated with peripheral vasculopathy. Effects of peripheral vasoconstriction, including Raynaud’s phenomenon, were observed in postmarketing reports 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 ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.[29332] [31563]

Stimulant medications, such as amphetamine; dextroamphetamine, can cause psychotic or manic symptoms (i.e., hallucinations, delusional thinking, or mania) in patients without a prior history of psychosis or mania, and have occurred during use of recommended doses and with toxicity or abuse. 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.[29332] [56750] [56766] 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.[64025] Aggression, hostility, and suicidal ideation or behaviors have also been reported during the use of medications for ADHD.[28405] [29332] [56750] [56766] Although causality to the drugs has not been established and these behaviors are often observed in children and adolescents with ADHD, close monitoring is recommended. If suicide-related events emerge during treatment, consideration should be given to dose reduction or drug discontinuation, especially if symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.[56765] During clinical trial evaluation of extended-release amphetamine; dextroamphetamine, the following psychiatric effects occurred in adults and/or pediatric patients: anxiety (7% to 8% of adults), nervousness (13% of adults, 6% of adolescents, 6% of children), irritability (6% of adolescents), emotional lability (2% to 4% of adults, 9% of children), depression (3% of adults), and agitation (2% to 8% of adults). Other psychiatric effects that have been associated with the use of amphetamine; dextroamphetamine include anger and dermatillomania. Patients and their caregivers should be advised to promptly report any changes in mood or behavior. Discontinuation of the drug may be required if psychiatric symptoms are persistent or severe. Abrupt discontinuation of amphetamines after chronic administration may unmask severe depression, suicidal ideation, anxiety, agoraphobia, dysphoria, psychomotor agitation, or symptoms of overactive behaviors.[62038] [29332] [31563]

Toxic effects of amphetamines are more variable in children than in adults and appear to occur over a wide dosage range. Signs of excessive dosages or acute overdose may include: anxiety, headache, euphoria, hyperactivity, agitation, confusion, delirium, paranoia, hallucinations, tremor, paresthesias, palpitations, sinus tachycardia, hypertension, chest pain (unspecified), nausea, vomiting, diaphoresis, mydriasis, dyspnea, tachypnea, hyperthermia, and hyperreflexia. Minor manifestations of any of these symptoms during prescription use indicate a need for dosage reduction or discontinuation. Severe manifestations of amphetamine overdose include cardiac arrhythmias, refractory hypotension, myocardial infarction, circulatory collapse, ischemic stroke, rhabdomyolysis, seizures, acute renal failure (unspecified), fulminant hyperthermia, coma, and death. Symptoms of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and psychosis indistinguishable from schizophrenia. Some severe manifestations of toxicity may also occur during therapeutic use of amphetamines, such as rhabdomyolysis, seizures, cardiac arrhythmias, and psychosis; however, they are most often associated with sympathomimetic toxicity. The product labeling for amphetamines includes a boxed warning stating that misuse of amphetamines may cause sudden death or serious cardiovascular adverse events.[28488] [29332] [31563] [31971] [31972] [59447] [61065] [62090]

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. Serotonin syndrome may occur when amphetamines are combined with other medications (e.g., SSRIs) that enhance serotonin activity within the CNS or following overdose. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., agitation, delirium, hallucinations, coma), and in rare cases, death. Th use of amphetamines with potent CYP2D6 inhibitors, such as paroxetine or fluoxetine, may also increase the risk through inhibition of amphetamine metabolism and an increase in systemic exposure. If serotonin syndrome becomes evident during treatment, the amphetamine and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.[62038]

Psychological dependence, physiological dependence, and tolerance may occur with amphetamine; dextroamphetamine therapy. Abrupt discontinuation or a significant dose reduction of CNS stimulants after prolonged use may produce withdrawal symptoms that include dysphoria, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation. Signs and symptoms of chronic amphetamine abuse include severe dermatoses, marked insomnia, irritability, hyperactivity, personality changes, and psychosis with features indiscriminate from schizophrenia.[29332] [31563]

Patients receiving extended-release amphetamine; dextroamphetamine salts in clinical trials experienced fever (5% of children), infection (3% of children), viral infection (1% of adolescent patients) and urinary tract infection (5% of adults). Other infections occurring in 2% to 4% of adults receiving extended-release amphetamine; dextroamphetamine and at a greater frequency than placebo included tooth infection (dental caries).[29332] [62038]

Central nervous system (CNS) stimulants, such as amphetamines; dextroamphetamine, have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction.[29332] [31563] [68987] Amphetamine; dextroamphetamine has a high potential for abuse and is contraindicated in patients with a history of substance abuse; evaluate these patients for a personal or family history of abuse or dependence on alcohol (alcoholism), prescription medications, or street drugs.[29332] [31563] Assess each individual's risk for abuse, misuse, or addiction before prescribing a CNS stimulant, and monitor for the development of these behaviors or conditions throughout treatment.[29332] [31563] [68987] 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.[57647] Prescribing and dispensing the smallest appropriate quantity may help to minimize abuse, misuse, and overdosage.[31563] 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.[68987] 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.[29332] [31563] [68987]

Amphetamine; dextroamphetamine combinations are contraindicated in patients in an agitated state. Stimulants such as amphetamine; dextroamphetamine should be used cautiously in those with bipolar disorder and/or mania due to the potential for manic episodes to occur in such patients. An assessment should be performed prior to initiation of therapy to determine the risk for bipolar disorder in patients presenting with symptoms of depression. Due to its toxic effects in overdose, amphetamine; dextroamphetamine should only be used in those with major depression or suicidal ideation when absolutely necessary. Aggression, hostility, and suicidal ideation or behaviors have been reported in both clinical trials and post-marketing experience with ADHD medications.[28405] [28518] [43863] [56750] [56766] Although causality has not been established and these behaviors may be inherent to ADHD, close monitoring is recommended. Patients and their caregivers should be advised to promptly report any changes in mood or behavior. If suicide-related events emerge during treatment, consideration should be given to dose reduction or drug discontinuation, especially if symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.[56765] In psychotic individuals (e.g., schizophrenia), amphetamines may exacerbate behavioral disturbances, psychosis, or thought disorders.[31563]

Amphetamine; dextroamphetamine is contraindicated in patients with symptomatic cardiovascular disease, advanced atherosclerosis, and moderate to severe hypertension. However, patients with even mild hypertension or tachycardia should be closely monitored while taking amphetamines. Use stimulant medications with caution in patients for whom an elevation in blood pressure or heart rate may be clinically significant. Stimulant medications cause a modest increase in average blood pressure (approximately 2 to 4 mmHg) and average heart rate (approximately 3 to 6 bpm); however, some individuals may have larger increases. Elevated blood pressure may require a dose reduction, discontinuation, and/or initiation of appropriate antihypertensive medication. Periodic blood pressure and heart rate monitoring is recommended in all patients taking stimulant medications.[31563] Adolescents with ADHD were enrolled in a 4-week controlled comparative trial of Adderall XR vs. placebo; 7 of 64 (11%) placebo-treated patients and 7 of 100 (7%) patients receiving Adderall XR had elevations in systolic blood pressures > 15 mmHg. Dose-related blood pressure elevations have also been noted in single dose studies. All increases were transient, appeared maximal at 2 to 4 hours post dose and were not associated with symptoms.

Amphetamine; dextroamphetamine is contraindicated in patients with symptomatic cardiac disease, advanced arteriosclerosis, and moderate to severe hypertension.[31563] The FDA recommends that, in general, stimulant medications not be used in patients with known serious cardiac structural abnormalities, a history of acute myocardial infarction, aortic stenosis, prosthetic heart valves, valvular heart disease, cardiomyopathy, ventricular dysfunction or heart failure, cardiac arrhythmias, coronary artery disease, or other serious cardiac problems.[46636] Stimulant medications may increase blood pressure or heart rate in some individuals; more serious cardiac effects have also been associated with stimulant use. Sudden unexplained death (SUD) and myocardial infarction have occurred in adults receiving stimulants at standard dosages for attention-deficit hyperactivity-disorder (ADHD). Sudden death has also been associated with stimulant medications at usual doses in pediatrics with structural cardiac abnormalities or other serious heart problems.[31563] A large retrospective cohort study including over 1.2 million children and young adults 2 to 24 years of age did not find an increased risk of serious cardiovascular events 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). Similar results were seen when current users of ADHD drugs were compared to former users and when current users with severe underlying cardiovascular disease were included in the analysis. The authors concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out.[46635] The American Heart Association (AHA) states that it is reasonable to consider the use of these medications 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.[34206] 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 sec, or heart rate or blood pressure more than 2 SD above the mean for age. All patients being considered for treatment with stimulant medications should have a careful history taken, including assessment for a family history of sudden death or ventricular arrhythmias, 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 is reasonable to obtain a baseline ECG as a part of the initial evaluation.[34206] If a child or adolescent has any significant findings on physical examination, ECG, or family history, consult a pediatric cardiologist before initiating the stimulant medication. Once the medication is started, a repeat ECG may be helpful if the original ECG was obtained before the child was 12 years old, if cardiac symptoms develop, or there is a change in family history.

Stroke has occurred in adults receiving stimulants such as amphetamine; dextroamphetamine at usual doses for ADHD [31563]; therefore, those with cerebrovascular disease should be closely monitored. Stimulant medications may increase blood pressure or heart rate in some individuals.

Children 3 years of age and older have been successfully treated for attention-deficit hyperactivity-disorder (ADHD) with amphetamines. It should be noted that not all children with ADHD will require medication; non-drug measures are often instituted concurrently with drug therapy. Amphetamines are not recommended for use in children and infants younger than 3 years of ageThe efficacy of stimulant therapy in children with ADHD is substantiated by a large body of evidence.[31567] [31586] [31588] [31589] However, do not use the Mydayis extended-release capsule formulation in children younger than 13 years of age, as safety and efficacy are not established, and a higher rate of adverse reactions was noted with this dosage form during clinical trials compared with adolescents.[62038] Safety and efficacy of Adderall XR (and generic equivalents) ha ve been established in pediatric patients 6 years and older.[29332] However, the efficacy of stimulant therapy in children with ADHD is substantiated by a large body of evidence. Monitoring of the effectiveness of stimulant therapy by the health care prescriber, parents, and teachers is important; periodic reassessment of the need for medication is recommended. Appropriate stimulant therapy should not suppress normal emotions or intellectual ability in the child or adolescent; the occurrence of certain side effects may indicate a need for dosage reduction. In psychotic children, amphetamines may exacerbate behavioral disturbances, psychosis, or thought disorders. New onset psychotic or manic symptoms may develop in children and adolescents receiving therapeutic doses of stimulants. Discontinuation of therapy may be required. Although a direct causal relationship has not been established, aggressive behavior and hostility have been reported during use of some stimulants for ADHD in children. It is recommended to monitor for signs of aggression or worsening of pre-existing aggressive behavior when treatment is initiated. Amphetamines are associated with a reduced appetite and weight loss. Over time weight will increase but not to the amount expected based on CDC normative values. 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.[45900] In one controlled trial in adolescents, the mean weight change from baseline within the initial 4 weeks of therapy was -1.1 pounds and -2.8 pounds, respectively, for patients receiving 10 mg and 20 mg Adderall XR. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment.[29332] Data obtained on the effects of the stimulants on growth suppression in children 7 to 10 years of age suggested that regularly medicated children (7 days/week) had a temporary average slowing in growth of 2 cm in height and 2.7 kg in weight over 3 years. The long-term effects of stimulants on brain development and physical growth in children are unknown. Sudden death has been reported in association with CNS stimulant treatment at usual doses in children with structural cardiac abnormalities or other serious heart problems (i.e., aortic stenosis, cardiomyopathy, congenital heart disease, prosthetic heart valves, valvular heart disease, ventricular dysfunction). Some case reports have involved concomitant medications, such as tricyclic antidepressants.[31971] [31972] A large retrospective cohort study including over 1.2 million children and young adults 2 to 24 years of age did not find an increased risk of serious cardiovascular events, including sudden cardiac death, 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). The authors concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out.[46635] Although some structural cardiac abnormalities alone may carry an increased risk of sudden death, stimulant products generally should not be used in patients with known structural cardiac abnormalities or other serious heart conditions.[31563] [46636] Exceptions to this warning do exist, but careful screening and monitoring is recommended by the American Heart Association.[34206]

Amphetamine; dextroamphetamine is contraindicated for use patients with hyperthyroidism, including thyrotoxicosis, since sympathomimetic stimulation may induce cardiac arrhythmias or other side effects.[29332] [31563]

Amphetamine; dextroamphetamine is contraindicated in patients with glaucoma. The sympathetic stimulation of amphetamines blocks aqueous outflow and raises intraocular pressure. Occasionally, visual disturbance, such as blurred vision and accommodation difficulties, have been reported in individuals without ocular disease while they are taking amphetamine; dextroamphetamine. Patients should report any new visual disturbance as ophthalmic evaluation may be needed.[29332] [31563]

Amphetamines are excreted in human breast milk by the lactating mother. Limited data from published literature have indicated a resulting infant dose of 2% to 13.8% of the maternal weight-adjusted dosage and a milk to plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant. Long-term neurodevelopmental effects on infants are unknown. Large dosages of dextroamphetamine might interfere with milk production, especially in women whose lactation is not well established. Due to the potential for serious adverse reactions in nursing infants (cardiovascular reactions, blood pressure and heart rate increase, suppression of growth, and peripheral vasculopathy), breast-feeding is not recommended during the use of amphetamines.[62038] Methylphenidate may be considered an alternative to amphetamine agents in women who are breast-feeding an infant, although the medical use of stimulant medications has not been formally evaluated during lactation. The AAP previously considered amphetamines, when used as drugs of abuse, to be contraindicated in breast-feeding due to concerns of irritability and poor sleeping pattern in the infant.[27500] If breast-feeding cannot be avoided during administration of a stimulant, the nursing infant should be monitored for signs of central nervous system hyperactivity, including decreased appetite, insomnia, and irritability. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

Amphetamine; dextroamphetamine products should only be used during pregnancy if the expected benefit to the mother clearly outweighs the potential fetal risk; the limited available data from published literature and postmarketing reports during human pregnancy are not sufficient to inform a drug-associated risk for major birth defects and miscarriage; however, there may be risks to the fetus associated with the use of CNS stimulants during pregnancy.[62038] [63187] [31563] There are limited published literature and postmarketing reports on the use of amphetamines during pregnancy. Most early data was derived from studies of illicit drug use, which may be complicated by comorbid substance abuse or ingestion of higher doses of amphetamines than what is typically prescribed.[65048] [69068] Amphetamines can cause vasoconstriction and can thereby decrease placental perfusion. This vasoconstriction can also lead to hypertension in the mother. In addition, amphetamines can stimulate uterine contractions, increasing the risk of premature delivery and low birth weight.[69116] Non-teratogenic effects are known to occur in neonates who are born to mothers dependent on amphetamines. These have included increased incidences of premature births, low birth weights and length, lower occipitofrontal circumference, and physical withdrawal symptoms (e.g., abnormal sleep patterns, poor feeding, tremor, agitation, fatigue, and hypertonia).[62038] [63187] [31563] In one prospective comparison study, neonates exposed to cocaine, methamphetamine, or a combination of cocaine and narcotic in utero had a 35.1% incidence of cranial abnormalities (i.e., intraventricular hemorrhage, echodensities known to be associated with necrosis, and cavitary lesions) compared to a 5.3% incidence in normal newborns as assessed by cranial ultrasonography. The authors speculated that the ultrasonographic abnormalities were probably related to the vasoconstrictive properties of the drugs.[48418] There is one case of a neonate born with a severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia following maternal exposure to dextroamphetamine sulfate and lovastatin during the first trimester of pregnancy.[28488] However, more recent data demonstrate that risks associated with the use of prescription amphetamine products may be lower than initially thought.[69111] Among 671 mother-child pairs enrolled in the Collaborative Perinatal Project who had first trimester exposure to amphetamines and 1,898 mother-child pairs with amphetamine exposures at any time during pregnancy, there was no evidence suggesting a relationship to large categories of major or minor malformations.[48419] Similarly, a large cohort study of pregnancy outcomes in the United States and 5 Nordic countries were compared to assess for the risks of major congenital malformations and cardiac effects in infants exposed to stimulants in utero. Of the 5,571 women who filled a prescription for amphetamine during the first trimester, 253 (4.54%) were diagnosed with malformations. In infants who were not exposed, 62,966 (3.5%) of the nearly 1.8 million infants developed malformations. After adjusting for underlying psychiatric disorders and other potential confounders, no increased risks were observed for amphetamine use compared to controls.[69191] The National Pregnancy Registry for ADHD medications is dedicated to evaluating the safety of ADHD medication exposure during pregnancy. Healthcare providers are encouraged to register patients at https://womensmentalhealth.org/research/pregnancyregistry/adhd-medications/ or by calling 1-866-961-2388.

Amphetamine; dextroamphetamine may precipitate motor or phonetic tics in those with Tourette's syndrome. Some patients with Tourette's syndrome may actually benefit from stimulant therapy; administer under close supervision.

The use of amphetamine; dextroamphetamine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Patients should not perform such tasks, including driving or operating machinery, until they are aware of how this medication affects them.[31563] [29332]

Use amphetamine; dextroamphetamine with caution in patients with a history of a seizure disorder because the seizure threshold can be reduced, particularly during excess CNS stimulation (i.e., amphetamine overdosage). The effects of amphetamines on the seizure threshold, in normal therapeutic dosages, are less clear. Seizure threshold may be reduced in those with EEG abnormalities and rarely in patients without a seizure history or EEG abnormalities. If seizures occur, discontinuation of therapy is recommended.

The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of amphetamines and other sympathomimetic drugs.

Amphetamines lower the seizure threshold. 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.

Psychological dependence, physiological dependence, and tolerance may occur with amphetamine; dextroamphetamine therapy. Abrupt discontinuation or a significant dose reduction of CNS stimulants after prolonged use may produce withdrawal symptoms that include dysphoria, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation. Consider monitoring for withdrawal symptoms after significant dose reduction or discontinuation after prolonged use.[29332] [31563] [68987]

Amphetamine; dextroamphetamine has not been systematically studied in the geriatric population for use in ADHD or narcolepsy.[29332] [31563] [62038] Stimulant medications are used as the treatments of choice in the adult patient over 50 years of age with ADHD when behavioral and lifestyle modifications alone have failed to improve concerns associated with inattention, such as task focus and completion, or organization and time management. Medication should be titrated with low doses initially and with a slow increase.[60888] Debilitated or geriatric patients may be more susceptible to the CNS and sympathomimetic side effects of the amphetamines; use with caution in the older adult. Side effects of amphetamines or other stimulants are usually mild but may include mood or behavior changes, tremor, insomnia, increased blood pressure, headache, or gastroesophageal reflux or other GI complaints. Adults should have their blood pressure and heart rate checked at baseline and periodically during treatment. If treatment is considered necessary, periodically re-evaluate the long-term usefulness of the drug for the individual patient.[60888]

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.[29332]

Use amphetamine; dextroamphetamine with caution in patients with significant hepatic disease or renal impairment. The elimination of amphetamine; dextroamphetamine is dependent on hepatic metabolism, urinary pH and urinary flow rates, as well as active secretion. Both hepatic disease and renal impairment have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. Amphetamine; dextroamphetamine extended-release product dosages should be reduced in patients with an eGFR less than 30 mL/minute/1.73 m², and use of these dosage forms in patients with renal failure (end-stage renal disease) is not recommended.[29332] [31563] [62038]

Amphetamine; dextroamphetamine is contraindicated in patients who have received 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, serotonin syndrome, and a variety of toxic neurologic effects; these events can be fatal. Increased risk for serotonin syndrome also may occur when amphetamines are co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans, and others), and may also occur during overdosage situations. If serotonin syndrome occurs, discontinue amphetamine; dextroamphetamine and all other serotonergic agents, and initiate supportive treatment.[29332] [31563] [62038]

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.[29332]

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 increase their susceptibility to the adverse effects of stimulants. In addition, the abuse potential of stimulants in weight loss induction should be considered in patients with an eating disorder. The use of sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. Amphetamine; dextroamphetamine is not indicated or recommended for obesity treatment.[56717]