Amphetamines have a high potential for abuse. Administration of amphetamines for prolonged periods of time may lead to drug dependence and must be avoided. Pay particular attention to the possibility of subjects obtaining amphetamines for nontherapeutic use or distribution to others; prescribe and dispense the drugs sparingly.
Misuse of amphetamines may cause sudden death and serious cardiovascular adverse reactions.
Attention-deficit/hyperactivity disorder: Topical: Initial: 9 mg per 9 hours transdermal system applied 2 hours before effect is desired and removed within 9 hours after application; may increase as needed based on clinical response and tolerability up to a maximum dose of the 18 mg per 9 hours transdermal system; apply no more than 1 transdermal system in a 24-hour period.
Switching to transdermal system from other stimulant therapy: Discontinue the other stimulant and initiate transdermal system with 9 mg per 9 hours.
Narcolepsy: Oral:
Extended release (capsule): Initial: 10 mg once daily; may increase dose based on response and tolerability in 10 mg increments at intervals ≥1 week; usual dosage: 5 to 60 mg/day once daily or in divided doses.
Immediate release (solution, tablet): Initial: 10 mg once daily; may increase dose based on response and tolerability in 10 mg increments at intervals ≥1 week; usual dosage: 5 to 60 mg/day in 2 to 3 divided doses; use intervals of 4 to 6 hours between doses.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Oral products: There are no dosage adjustments provided in the manufacturer's labeling.
Transdermal patch:
GFR 15 to <30 mL/minute/1.73 m2: Maximum dose: 13.5 mg per 9 hours transdermal system applied 2 hours before effect is desired and removed within 9 hours after application.
GFR <15 mL/minute/1.73 m2: Maximum dose: 9 mg per 9 hours transdermal system applied 2 hours before effect is desired and removed within 9 hours after application.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Dextroamphetamine: Pediatric drug information")
Note: Use lowest effective individualized dose; administer first dose as soon as awake; avoid late evening doses. Dextroamphetamine transdermal system is not bioequivalent with other amphetamine products due to differing base compositions and pharmacokinetic profiles and should not be substituted on a mg:mg basis.
Attention-deficit/hyperactivity disorder (ADHD):
Oral:
Immediate-release tablets; oral solution (eg, ProCentra, Zenzedi):
Children 3 to 5 years: Oral: Initial: 2.5 mg once daily in the morning; increase daily dose by 2.5 mg increments at weekly intervals until optimal response is obtained; maximum daily dose: 40 mg/day in 2 to 3 divided doses; use intervals of 4 to 6 hours between doses. Note: Although FDA approved, current guidelines do not recommend use in children ≤5 years of age due to insufficient evidence (AAP 2011).
Children ≥6 years and Adolescents: Oral: Initial: 5 mg once or twice daily with first dose in the morning; increase daily dose by 5 mg increments at weekly intervals until optimal response is obtained, usual range 5 to 20 mg/day; maximum daily dose: 40 mg/day in 2 to 3 divided doses; use intervals of 4 to 6 hours between doses.
Extended-/sustained-release capsules (eg, Dexedrine Spansules): Children ≥6 years and Adolescents: Oral: Initial: 5 mg once or twice daily with first dose in the morning; increase daily dose by 5 mg increments at weekly intervals until optimal response is obtained, usual range: 5 to 20 mg/day; maximum daily dose: 40 mg/day in 1 to 2 divided doses; use intervals of 6 to 8 hours between doses; in patients >50 kg, a maximum daily dose of 60 mg/day in divided doses has been used (AACAP [Pliszka 2007]; Dopheide 2009).
Transdermal (Xelstrym): The dextroamphetamine transdermal system Xelstrym is available in multiple strengths which describe the total amount of drug delivered over a 9-hour period and applied no more than every 24 hours.
Children ≥6 years and Adolescents <18 years: Topical: Initial: 4.5 mg/9 hours transdermal system applied 2 hours before effect is desired and removed within 9 hours after application; may titrate in 4.5 mg increments at weekly intervals based on clinical response and tolerability up to a maximum dose of the 18 mg/9 hours transdermal system; apply no more than 1 transdermal system in a 24-hour period.
Adolescents ≥18 years: Topical: Initial: 9 mg/9 hours transdermal system applied 2 hours before effect is desired and removed within 9 hours after application; may titrate as needed based on clinical response and tolerability up to a maximum dose of the 18 mg/9 hours transdermal system; apply no more than 1 transdermal system in a 24-hour period.
Switching to transdermal system from other stimulant therapy: Discontinue that medication (eg, other stimulant, amphetamine) and initiate transdermal system with titration schedule.
Narcolepsy (hypersomnia):
Note: Stimulants are recommended for management of daytime sleepiness associated with hypersomnia; alternative therapy is recommended for management of cataplexy if present (Kotagal 2018).
Immediate-release tablets, oral solution:
Children 6 to 12 years: Oral: Initial: 5 mg daily; may increase at 5 mg increments at weekly intervals until optimal response is obtained; maximum daily dose: 60 mg/day in 1 to 3 divided doses: use intervals of 4 to 6 hours between doses (Kotagal 2018; manufacturer's labeling).
Adolescents: Oral: Initial: 10 mg daily; may increase at 10 mg increments at weekly intervals until optimal response is obtained; maximum daily dose: 60 mg/day in 1 to 3 divided doses; use intervals of 4 to 6 hours between doses (Kotagal 2018; manufacturer's labeling).
Extended-/sustained-release capsules:
Children 6 to 12 years: Oral: Initial: 5 mg daily; may increase at 5 mg increments at weekly intervals until optimal response is obtained; maximum daily dose: 60 mg/day in 1 to 2 divided doses; use intervals of 6 to 8 hours between doses (Kotagal 2018; manufacturer's labeling).
Adolescents: Oral: Initial: 10 mg daily; may increase at 10 mg increments at weekly intervals until optimal response is obtained; maximum daily dose: 60 mg/day in 1 to 2 divided doses; use intervals of 6 to 8 hours between doses (Kotagal 2018; manufacturer's labeling).
Obesity secondary to hypothalamic-pituitary dysfunction: Limited data available (Bereket 2012):
Immediate-release tablet; oral solution: Children ≥6 years and Adolescents: Oral: Initial: 5 mg once daily in the morning; may increase daily dose at 2.5 mg increments at weekly intervals until optimal response is obtained; additional daily doses may be given before lunch and dinner if necessary; maximum single dose reported: 7.5 mg/dose; maximum daily dose: 20 mg/day in divided doses; dosing based on experience in pediatric patients (n=17) following postsurgical resection for management of craniopharyngioma reported in 2 open-labeled trials and a case series (n=7); weight stabilization was reported in all 3 groups with some patients reporting moderate to significant weight loss (Denzer 2019; Ismail 2006; Mason 2002)
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Oral: There are no dosage adjustments provided in the manufacturer's labeling; use with caution; elimination may be decreased with renal impairment. Hemodialysis: Not dialyzable.
Transdermal: Based on pharmacokinetic modeling data.
Children ≥6 years and Adolescents:
GFR 15 to <30 mL/minute/1.73 m2: Maximum dose: 13.5 mg/9 hours transdermal system.
GFR <15 mL/minute/1.73 m2: Maximum dose: 9 mg/9 hours transdermal system.
Hemodialysis: Not dialyzable.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution; elimination may be decreased with hepatic impairment.
Refer to adult dosing; start at lowest dose. Use with caution.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule Extended Release 24 Hour, Oral, as sulfate:
Dexedrine: 5 mg [DSC] [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Dexedrine: 5 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Dexedrine: 10 mg [DSC] [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Dexedrine: 10 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Dexedrine: 15 mg [DSC] [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Dexedrine: 15 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Generic: 5 mg, 10 mg, 15 mg
Patch, Transdermal:
Xelstrym: 4.5 mg/9 hr (1 ea, 30 ea); 9 mg/9 hr (1 ea, 30 ea); 13.5 mg/9 hr (1 ea, 30 ea); 18 mg/9 hr (1 ea, 30 ea)
Solution, Oral, as sulfate:
ProCentra: 5 mg/5 mL (473 mL) [contains benzoic acid, saccharin sodium; bubble-gum flavor]
Generic: 5 mg/5 mL (473 mL)
Tablet, Oral, as sulfate:
Zenzedi: 2.5 mg
Zenzedi: 5 mg [contains fd&c yellow #6 (sunset yellow)]
Zenzedi: 5 mg [DSC] [scored; contains fd&c yellow #6 (sunset yellow)]
Zenzedi: 7.5 mg [contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]
Zenzedi: 10 mg [contains fd&c blue #2 (indigotine), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
Zenzedi: 10 mg [DSC] [scored; contains fd&c blue #2 (indigotine), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
Zenzedi: 15 mg [contains fd&c blue #1 (brilliant blue), fd&c blue #2 (indigotine), fd&c red #40 (allura red ac dye)]
Zenzedi: 20 mg [contains fd&c blue #1 (brilliant blue)]
Zenzedi: 30 mg [contains quinoline yellow (d&c yellow #10)]
Generic: 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule Extended Release 24 Hour, Oral, as sulfate:
Dexedrine: 10 mg, 15 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Generic: 10 mg, 15 mg
Tablet, Oral, as sulfate:
Dexedrine: 5 mg [contains fd&c yellow #5 (tartrazine), fd&c yellow #6 (sunset yellow)]
Generic: 5 mg
Xelstrym transdermal system: FDA approved March 2022; availability anticipated in the second half of 2022.
C-II
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Dexedrine Spansule: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/017078s054lbl.pdf#page=14
ProCentra: http://fscpediatrics.com/pdf/Pages%20ProCentra%20med%20guide.pdf
Zenzedi: http://dailymed.nlm.nih.gov/dailymed/medguide.cfm?setid=d6394df5-f2c9-47eb-b57e-f3e9cfd94f84
Oral: Administer initial dose upon awakening; do not administer doses late in the evening due to potential for insomnia. Do not crush or chew ER formulations.
Topical: Transdermal patch: Apply to clean, dry, hairless, non-oily, intact skin of the upper arm, upper back, chest, flank, or hip; avoid areas of tight clothing (eg, waistbands, straps). Select a different application site with each new patch. Press patch firmly with palm of hand and smooth patch to ensure proper adherence. Avoid exposure of application site to external heat source (eg, electric blankets, hair dryers, heat lamps, heating pads, hot tubs, saunas, heated water beds), which may increase the amount of drug absorbed. Do not use a patch that has been damaged or torn; do not cut patch. Check patch regularly to ensure it is completely sticking to the application site; if patch edges lift, smooth patient down and press firmly with palm of hand (do not reapply with dressings, tape, or other adhesives). If patch dislodges, may replace with new patch (to different site) but total wear time should not exceed 9 hours. Wash hands with soap and water after handling; do not use hand sanitizer. Avoid touching the sticky side of the patch. If patch removal is difficult, an oil-based product (eg, petroleum jelly, olive oil) may be applied to the patch edges to aid removal; never apply acetone-based products (eg, nail polish remover) to patch. Dispose of used patch by folding adhesive side onto itself, and discard in an appropriate lidded container; do not flush down the toilet. An oil-based product (eg, petroleum jelly, olive oil) or soap and water may be used to remove any remaining adhesive glue on the skin.
Bariatric surgery: Capsule, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER capsule cannot be opened due to biphasic release mechanism. Switch to IR formulation (tablet or oral solution).
Oral: Administer initial dose upon awakening; do not administer doses late in the evening due to potential for insomnia. Do not crush or chew extended-/sustained-release preparations.
Topical: Transdermal system: Remove from protective pouch and immediately apply to either the hip, upper arm, chest, upper back, or flank area. Application site used should be hairless (or nearly hairless), dry, intact, clean, and void of any lotions, gels, or oils. A different application site should be used for each dose. Avoid touching the adhesive during application. If contact made with adhesive, wash hands with soap immediately. A single transdermal system should be removed within 9 hours of application and no more than 1 system should be applied within a 24-hour period. Application site should not be covered with dressing, nor should any adhesives be used on the system. If patch edges lift, re-apply by firmly pressing and smoothing edges. If the transdermal system falls off, re-apply a new patch and do not extend wear time past 9 hours from initial transdermal system application. To avoid increased rate and extent of drug absorption, avoid exposing applied transdermal system to heat sources (electric blankets, heating pads, hair dryers, heated water beds, etc). To discard, fold the system in half so that the adhesive side of system adheres to itself and place in a lidded container. Do not flush the system down the toilet.
Attention-deficit/hyperactivity disorder: Treatment of attention-deficit/hyperactivity disorder as part of a total treatment program that typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in pediatric patients 3 to 16 years (IR tablet, oral solution) or 6 to 16 years (ER capsule); treatment of attention-deficit/hyperactivity disorder in adults and pediatric patients ≥6 years of age (transdermal patch).
Narcolepsy: Treatment of narcolepsy (excludes transdermal patch).
Dexedrine may be confused with dextran, Excedrin
Dextroamphetamine may be confused with dexamethasone
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for transdermal administration in pediatrics, unless otherwise noted. Reported incidences were higher during initial titration.
>10%:
Gastrointestinal: Decreased appetite (12%)
Hematologic & oncologic: Decreased neutrophils (14%)
Local: Application-site reaction (including application-site burning, application-site edema, application-site erythema, application-site irritation [94%], application-site pain, application-site pruritus, local discomfort [application-site: 69%])
1% to 10%:
Cardiovascular: Increased blood pressure (2%), increased heart rate (2%; including tachycardia)
Gastrointestinal: Abdominal pain (4%), nausea (3%), vomiting (4%)
Hematologic & oncologic: Decreased white blood cell count (10%)
Nervous system: Emotional lability (3%), headache (6%), insomnia (8%), irritability (2%), tic disorder (2%)
Frequency not defined (any formulation or population):
Cardiovascular: Palpitations
Dermatologic: Alopecia, urticaria
Endocrine & metabolic: Change in libido, weight loss
Gastrointestinal: Anorexia, constipation, diarrhea, mesenteric ischemia, unpleasant taste, xerostomia
Genitourinary: Frequent erections, impotence, prolonged erection
Nervous system: Dizziness, drug abuse, drug dependence, dysphoria, euphoria, exacerbation of tics (including exacerbation of Gilles de la Tourette syndrome, exacerbation of vocal tics and motor tics), overstimulation, psychosis, restlessness, tremor
Neuromuscular & skeletal: Dyskinesia, rhabdomyolysis
Postmarketing (any formulation or population): Cardiovascular: Peripheral vascular disease (including Raynaud disease)
Oral products: Hypersensitivity (eg, angioedema, anaphylaxis) or idiosyncrasy to amphetamine, dextroamphetamine, other sympathomimetic amines, or any component of the formulation; advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension; hyperthyroidism; glaucoma; agitated states; history of drug abuse; during or within 14 days of stopping monoamine oxidase inhibitor (MAOI) therapy (including MAOIs such as linezolid or intravenous methylene blue).
Transdermal patch: Known hypersensitivity (eg, angioedema, anaphylaxis, Stevens-Johnson syndrome, urticaria) to dextroamphetamine, other amphetamine products, or any component of the formulation; during or within 14 days of stopping MAOI therapy (including MAOIs such as linezolid or intravenous methylene blue).
Canadian labeling: Additional contraindications (not in US labeling): Anxiety; tension; motor tics or a family history of Tourette syndrome diagnosis (verbal tics).
Documentation of allergenic cross-reactivity for amphetamines is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Cardiovascular events: Use has been associated with serious cardiovascular events including sudden death in patients with preexisting structural cardiac abnormalities or other serious heart problems (sudden death in children and adolescents; sudden death, stroke and MI in adults). Consistent with other studies, a large retrospective cohort study involving 1,200,438 children, adolescents, and young adults (aged 2 to 24 years) prescribed methylphenidate, dexmethylphenidate, dextroamphetamines, amphetamine salts, pemoline, or atomoxetine found no evidence that current use of an ADHD medication increased risk for sudden cardiac death, acute MI, or stroke (Cooper 2011). Stimulants should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, Marfan syndrome, or other serious cardiac problems. Some products are contraindicated in patients with moderate or severe hypertension. Prior to initiating stimulant, assess medical history and family history of sudden death or ventricular arrhythmia; conduct a physical exam to assess for cardiac disease; patients should receive further evaluation if findings suggest cardiac disease, such as ECG and echocardiogram. Promptly conduct cardiac evaluation in patients who develop exertional chest pain, unexplained syncope, or any other symptoms of cardiac disease during stimulant treatment.
• CNS effects: Amphetamines may impair the ability to engage in potentially hazardous activities; patients must be cautioned about performing tasks that require mental alertness (eg, driving, operating machinery).
• Peripheral vasculopathy: Stimulants are associated with peripheral vasculopathy, including Raynaud phenomenon; signs/symptoms are usually mild and intermittent, and generally improve with dose reduction or discontinuation. Peripheral vasculopathy effects have been observed at different times, at therapeutic doses, and in all age groups. Digital ulceration and/or soft tissue breakdown have been observed rarely; monitor for digital changes during therapy and seek further evaluation (eg, rheumatology) if necessary.
• Visual disturbance: Difficulty in accommodation and blurred vision has been reported with the use of stimulants.
Disease-related concerns:
• Abuse potential: Potential for drug dependency exists; prolonged use may lead to drug dependency. Use is contraindicated in patients with history of ethanol or drug abuse. Prescriptions should be written for the smallest quantity consistent with good patient care to minimize possibility of overdose.
• Cardiovascular disease: CNS stimulants may increase heart rate and blood pressure; in pediatric patients, the observed mean increase in heart rate was 3 to 6 bpm and blood pressure was 2 to 4 mm Hg. Use with caution in patients with hypertension, heart failure, recent MI, ventricular arrhythmia, and other cardiovascular conditions that might be exacerbated by increases in blood pressure or heart rate. Some products are contraindicated in patients with moderate to severe hypertension or hyperthyroidism.
• Psychiatric disorders: Use with caution in patients with preexisting psychosis (may exacerbate symptoms of behavior and thought disorder) or bipolar disorder (may induce mixed/manic episode). New-onset psychosis or mania may occur with stimulant use. Patients should be screened for bipolar disorder and risk factors for developing a manic episode prior to treatment; consider discontinuation if psychotic or manic symptoms (eg, delusional thinking, hallucinations, mania) occur. May be associated with aggressive behavior or hostility (causal relationship not established); monitor for development or worsening of these behaviors.
• Renal impairment: Use with caution in patients with renal impairment; elimination of amphetamines may be reduced.
• Seizure disorder: Limited information exists regarding stimulant use in seizure disorder. Whereas patients with ADHD are at an increased risk for seizure activity compared to the general population, a retrospective study using drug claims data showed that the use of stimulant medications was associated with a lower risk (Cortese 2013; Wiggs 2018). Manufacturers of some stimulants recommend discontinuing therapy if seizures occur.
• Tourette syndrome/tics: Use with caution in patients with Tourette syndrome or other tic disorders. Stimulants may exacerbate tics (motor and phonic) and Tourette syndrome; however, evidence demonstrating increased tics is limited. Evaluate for tics and Tourette syndrome prior to therapy initiation (AACAP [Murphy 2013, Pliszka 2007]).
Concurrent drug therapy issues:
• Serotonin syndrome: Potentially life-threatening serotonin syndrome may occur when dextroamphetamine is used in combination with other serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, St. John's wort, tryptophan), agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors), or CYP2D6 inhibitors that impair metabolism of dextroamphetamine. Concomitant use with monoamine oxidase inhibitors is contraindicated. If concomitant use of dextroamphetamine with serotonergic drugs or CYP2D6 inhibitors is indicated, initiate dextroamphetamine at a low dose and monitor patient closely for signs and symptoms of serotonin syndrome. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.
Special populations:
• Pediatric: Appetite suppression may occur, particularly in children. Use of stimulants has been associated with weight loss and slowing of growth rate; monitor growth rate and weight during treatment. Treatment interruption may be necessary in patients who are not increasing in height or gaining weight as expected.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.
• Transdermal patch: Localized contact sensitization to the transdermal system has been reported; in these patients, allergic reactions (eg, generalized rash, urticaria, angioedema) have also occurred following subsequent substitution of oral therapy. Application site reactions (eg, burning, discomfort, edema, erythema, pain, pruritus, swelling) may occur; change application site daily to minimize occurrence. Do not expose to direct external heat sources (eg, electric blankets, hair dryers, heating pads, heated water beds).
Other warnings/precautions:
• ADHD treatment: Appropriate use: Recommended to be used as part of a comprehensive treatment program for attention-deficit disorders.
• Discontinuation of therapy: Abrupt discontinuation following high doses or for prolonged periods may result in symptoms for withdrawal.
CNS stimulant treatment has been associated with sudden death in children and adolescents with preexisting structural cardiac abnormalities; one study reported methylphenidate increased risk for arrhythmia and MI in youth without congenital heart disease (Shin 2016) and a retrospective case-control study reported an association with stimulants and sudden unexplained death in youth (Gould 2009). However, as noted in reviews (Martinez-Raga 2013; Westover 2012) several large studies have not found an association between prescription stimulants and cardiovascular events; though most retrospective studies were large (n=55,383 to 2,131,953), some had statistical power or methodological limitations (Westover 2012). A large retrospective cohort study involving 1,200,438 children and young adults (aged 2 to 24 years) prescribed ADHD medication (methylphenidate, dexmethylphenidate, dextroamphetamines, amphetamine salts, pemoline, or atomoxetine) found no evidence that ADHD medication was associated with an increased risk of serious cardiovascular events (ie, acute MI, sudden cardiac death, stroke) in current (adjusted hazard ratio: 0.75; 95% confidence interval [CI]: 0.31 to 1.85) or former (adjusted hazard ratio: 1.03; 95% CI: 0.57 to 1.89) users compared with nonusers, nor in current compared with former users. Results were similar with multiple alternative analyses to assess for bias or study assumptions. While point estimates of relative risks for ADHD drugs did not demonstrate increased risk, the upper limit of the 95% CI suggested a doubling of the risk could not be ruled out, although absolute magnitude of increased risk would be low. Data on any individual medication, other than methylphenidate, were too sparse for separate regression analyses (Cooper 2011). Prior to treatment with medications for ADHD, the American Heart Association and the American Academy of Pediatrics recommend that all children and adolescents diagnosed with ADHD have a thorough cardiovascular assessment, including patient and family health histories, determination of all medications used (prescribed and over-the-counter), and a physical examination focused on cardiovascular disease risk factors. An ECG is not mandatory but is reasonable to consider prior to stimulant medication therapy. Prompt evaluation and appropriate referral and testing, if warranted, should occur if any cardiac symptoms present (Vetter 2008).
Evaluation of the effect of stimulants on growth in ADHD diagnosed children <12 years receiving treatment for at least 3 years with stimulants has shown decreased height and weight changes over time compared to age matched control; height: 4.7 to 5.5 cm/year compared to 6.3 cm/year and 2.1 to 3.3 kg/year compared to 4.4 kg/year (Poulton 2016). In 5,315 pediatric patients (age range: 8 to 17 years) actively treated with stimulants (methylphenidate, dexmethylphenidate, dextroamphetamine, atomoxetine, lisdexamfetamine), significant reductions in total femoral, femoral neck, and lumbar bone mineral density (BMD) were observed compared to matched unmedicated controls (n=1,967); also reported were significantly more subjects in the stimulant-treated group with BMD measurements in the osteopenic range compared to matched cohorts (38.3% to 21.6%); of note, there was no data on duration of medication treatment, dosing, or therapy changes (Howard 2017). A longitudinal cohort-controlled trial reported no difference in peak height velocity and final adult height in subjects with ADHD and/or treated with stimulants (Harstad 2014). With the transdermal system, patients <6 years of age showed more long-term weight loss compared to patients ≥6 years of age.
Substrate of CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Risk X: Avoid combination
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Alkalinizing Agents: May decrease the excretion of Amphetamines. Management: Consider alternatives to using amphetamines and alkalinizing agents in combination. If these agents must be used together, patients should be monitored closely for excessive amphetamine effects. Risk D: Consider therapy modification
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Ammonium Chloride: May decrease the serum concentration of Amphetamines. This effect is likely due to an enhanced excretion of amphetamines in the urine. Risk C: Monitor therapy
Antacids: May decrease the excretion of Amphetamines. Risk C: Monitor therapy
Antihypertensive Agents: Amphetamines may diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Antipsychotic Agents: May enhance the adverse/toxic effect of Amphetamines. Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy
Antipsychotic Agents: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy
Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May decrease the excretion of Amphetamines. Risk C: Monitor therapy
Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities (including serotonin syndrome) if used with a moderate CYP2D6 inhibitor. Initiate amphetamine therapy at lower doses, monitor frequently, and adjust doses as needed. Discontinue amphetamines if serotoinin syndrome occurs Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities (including serotonin syndrome) if used with a strong CYP2D6 inhibitor. Initiate amphetamine therapy at lower doses, monitor frequently, and adjust doses as needed. Discontinue amphetamines if serotoinin syndrome occurs. Risk C: Monitor therapy
Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Risk C: Monitor therapy
Esketamine: May enhance the hypertensive effect of CNS Stimulants. Risk C: Monitor therapy
Gastrointestinal Acidifying Agents: May decrease the serum concentration of Amphetamines. Risk C: Monitor therapy
Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Inhibitors of the Proton Pump (PPIs and PCABs): May increase the absorption of Dextroamphetamine. Specifically, the dextroamphetamine absorption rate from mixed amphetamine salt extended release (XR) capsules may be increased in the first hours after dosing. Risk C: Monitor therapy
Iobenguane Radiopharmaceutical Products: Amphetamines may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid combination
Iobenguane Radiopharmaceutical Products: CNS Stimulants may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid combination
Ioflupane I 123: Amphetamines may diminish the diagnostic effect of Ioflupane I 123. Risk C: Monitor therapy
Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Kratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combination
Methenamine: May decrease the serum concentration of Amphetamines. This effect is likely due to an enhanced excretion of amphetamines in the urine. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of Amphetamines. While linezolid and tedizolid may interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Risk X: Avoid combination
Multivitamins/Fluoride (with ADE): May decrease the serum concentration of Amphetamines. More specifically, the ascorbic acid (vitamin C) in many multivitamins may decrease amphetamine concentrations. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Amphetamines. Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Amphetamines. Specifically, vitamin C may impair absorption of amphetamines. Risk C: Monitor therapy
Opioid Agonists: Amphetamines may enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Quinolones: Amphetamines may enhance the cardiotoxic effect of Quinolones. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Amphetamines may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities, including serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust dose as needed. Risk C: Monitor therapy
Serotonergic Agents (High Risk): Amphetamines may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
Solriamfetol: CNS Stimulants may enhance the hypertensive effect of Solriamfetol. CNS Stimulants may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the adverse/toxic effect of Amphetamines. Tricyclic Antidepressants may potentiate the cardiovascular effects of Amphetamines. Amphetamines may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased cardiovascular effects when these agents are combined. Risk C: Monitor therapy
Urinary Acidifying Agents: May decrease the serum concentration of Amphetamines. Risk C: Monitor therapy
Amphetamine serum levels may be reduced if taken with acidic food, juices, or vitamin C. Management: Monitor response when taken concurrently.
The majority of human data is based on illicit amphetamine/methamphetamine exposure and not from therapeutic maternal use (Golub 2005). Use of amphetamines during pregnancy may lead to an increased risk of premature birth and low birth weight; newborns may experience symptoms of withdrawal. Behavioral problems may also occur later in childhood (LaGasse 2012).
Dextroamphetamine is present in breast milk.
The relative infant dose (RID) of dextroamphetamine ranged from 3.9% to 13.8% in a study when compared to a weight-adjusted maternal dose of 15 to 45 mg/day.
In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).
The RID of dextroamphetamine was calculated using average milk concentrations of 0.066 to 0.313 mcg/mL, providing an absolute infant dose via breast milk of 10 to 47 mcg/kg/day (median: 21 mcg/kg/day). This milk concentration was obtained following maternal administration of dextroamphetamine 15 to 45 mg/day (average: 18 mg/day) in divided doses to four women. Dextroamphetamine was detected in the plasma of two of the three infants tested. Adverse events were not reported in the breastfed infants (Ilett 2007).
The majority of human data is based on illicit amphetamine/methamphetamine exposure and not from therapeutic maternal use (Golub 2005). Increased irritability, agitation, and crying have been reported in breastfeeding infants. As a class, amphetamines may also decrease milk supply (ACOG 2011). Breastfeeding is not recommended (AAP 2012)
Cardiac evaluation should be completed at baseline and on any patient who develops exertional chest pain, unexplained syncope, and any symptom of cardiac disease during treatment with stimulants. Monitor blood pressure and heart rate (baseline, following dose increases and periodically during treatment); growth rate (height and weight) and appetite in children; weight in adults; signs of peripheral vasculopathy (eg, digital changes); sleep and behavioral changes. Assess for risk of abuse prior to prescribing and signs of misuse, abuse, or addiction throughout treatment (NICE 2018).
Amphetamines are noncatecholamine, sympathomimetic amines that promote release of catecholamines (primarily dopamine and norepinephrine) from their storage sites in the presynaptic nerve terminals. A less significant mechanism may include their ability to block the reuptake of catecholamines by competitive inhibition.
Duration of action:
Oral: Immediate release: 4 to 6 hours; extended release: 8 hours (Dopheide 2009).
Transdermal: 9 hours.
Metabolism: Hepatic to some degree by CYP2D6.
Half-life elimination:
Oral: Adults: ~12 hours.
Transdermal: Pediatric and Adult patients: 6.4 to 11.5 hours.
Time to peak, serum:
Oral: Immediate release: ~3 hours; Sustained release: ~8 hours.
Transdermal: Initial application: 6 to 9 hours; repeat application: 6 hours.
Excretion: Urine; urinary excretion is pH dependent and is increased with acid urine (low pH).
Capsule ER 24 Hour Therapy Pack (Dexedrine Oral)
10 mg (per each): $28.13
15 mg (per each): $28.13
Capsule ER 24 Hour Therapy Pack (Dextroamphetamine Sulfate ER Oral)
5 mg (per each): $4.05
10 mg (per each): $5.06
15 mg (per each): $6.45
Solution (Dextroamphetamine Sulfate Oral)
5 mg/5 mL (per mL): $1.82
Solution (ProCentra Oral)
5 mg/5 mL (per mL): $2.03
Tablets (Dextroamphetamine Sulfate Oral)
5 mg (per each): $2.90
10 mg (per each): $3.15
15 mg (per each): $7.50
20 mg (per each): $7.50
30 mg (per each): $7.50
Tablets (Zenzedi Oral)
2.5 mg (per each): $8.82
5 mg (per each): $8.82
7.5 mg (per each): $8.82
10 mg (per each): $8.82
15 mg (per each): $8.82
20 mg (per each): $8.82
30 mg (per each): $8.82
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