Amphetamines have a high potential for abuse and dependence. Administration of amphetamines for prolonged periods of time may lead to drug dependence and must be avoided. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Particular attention should be paid to the possibility of subjects obtaining amphetamines for non-therapeutic use or distribution to others, and the drugs should be prescribed or dispensed sparingly.
Misuse of amphetamine may cause sudden death and serious cardiovascular adverse events.
Note: Individualize and titrate to lowest effect dose.
Attention-deficit/hyperactivity disorder (ADHD): Note: Do not substitute extended-release formulations for other amphetamine products (immediate or extended release) on a mg-per-mg basis since base composition and pharmacokinetic profiles are not similar.
Immediate release:
Orally disintegrating tablet (eg, Evekeo ODT):
Children 3 to 5 years: Oral: Initial: 2.5 mg once daily; increase daily dose in 2.5 mg increments at weekly intervals until optimal response is obtained; first dose should be given at awakening; if additional daily doses necessary, separate dose(s) by 4- to 6-hour intervals. Maximum dose not specified; in children ≥6 years, daily doses >40 mg/day are rarely necessary.
Children ≥6 years and Adolescents ≤17 years: Oral: Initial: 5 mg once or twice daily; increase daily dose in 2.5 to 5 mg increments at weekly intervals until optimal response is obtained; first dose should be given at awakening; if additional daily doses necessary, separate dose(s) by 4- to 6-hour intervals. Maximum dose not specified; daily doses >40 mg/day are rarely necessary.
Tablet (eg, Evekeo):
Children 3 to 5 years: Oral: Initial: 2.5 mg once daily; increase daily dose in 2.5 mg increments at weekly intervals until optimal response is obtained; first dose should be given at awakening; if additional daily doses necessary, separate dose(s) by 4- to 6-hour intervals. Maximum dose not specified; in children ≥6 years, daily doses >40 mg/day are rarely necessary.
Children ≥6 years and Adolescents: Oral: Initial: 5 mg once or twice daily; increase daily dose in 5 mg increments at weekly intervals until optimal response is obtained; first doses should be given at awakening; if additional daily doses necessary, separate dose(s) by 4- to 6-hour intervals. Only in rare cases will it be necessary to exceed 40 mg daily.
Extended release:
Orally disintegrating tablet (Adzenys XR-ODT): Children ≥6 years and Adolescents: Oral: Initial: 6.3 mg once daily in the morning; may increase in 3.1 or 6.3 mg increments at weekly intervals until optimal response or age-based maximum dose reached. Maximum daily dose: Ages 6 to 12 years: 18.8 mg/day; ages 13 to 18 years: 12.5 mg/day.
To convert Adderall XR (mixed salt of single entity amphetamine product) to Adzenys XR-ODT, the following conversions may be applied:
Adderall XR (current once-daily dose) |
Adzenys XR-ODT (initial once-daily dose) |
---|---|
5 mg |
3.1 mg |
10 mg |
6.3 mg |
15 mg |
9.4 mg |
20 mg |
12.5 mg |
25 mg |
15.7 mg |
30 mg |
18.8 mg |
To convert other amphetamine products to Adzenys XR-ODT: Discontinue that treatment, and then initiate and titrate Adzenys XR-ODT as per the recommended dosing schedule.
Oral suspension:
Adzenys XR: Children ≥6 years and Adolescents: Oral: Initial: 6.3 mg once daily in the morning; may increase in 3.1 or 6.3 mg increments at weekly intervals until optimal response or age-based maximum dose reached. Maximum daily dose: Ages 6 to 12 years: 18.8 mg/day; ages 13 to 18 years: 12.5 mg/day.
To convert Adderall XR (mixed salt of single entity amphetamine product) to Adzenys ER, the following conversions may be applied:
Adderall XR (current once-daily dose) |
Adzenys ER (initial once-daily dose) |
---|---|
5 mg |
3.1 mg |
10 mg |
6.3 mg |
15 mg |
9.4 mg |
20 mg |
12.5 mg |
25 mg |
15.7 mg |
30 mg |
18.8 mg |
To convert other amphetamine products to Adzenys ER: Discontinue that treatment, and then initiate and titrate Adzenys ER as per the recommended dosing schedule.
Dyanavel XR: Children ≥6 years and Adolescents: Oral: Initial: 2.5 or 5 mg once daily in the morning; may increase in 2.5 to 10 mg/day increments every 4 to 7 days until optimal response is obtained; maximum daily dose: 20 mg/day. Note: Dyanavel XR oral suspension and tablet formulations are bioequivalent and may be substituted on a mg:mg basis.
Tablet: Dyanavel XR: Children ≥6 years and Adolescents: Oral: Initial: 2.5 or 5 mg once daily in the morning; may increase in 2.5 to 10 mg/day increments every 4 to 7 days until optimal response is obtained; maximum daily dose: 20 mg/day. Note: Dyanavel XR oral suspension and tablet formulations are bioequivalent and may be substituted on a mg:mg basis. The 5 mg tablet is scored and may be cut.
Exogenous obesity: Immediate-release tablet (eg, Evekeo): Children ≥12 years and Adolescents: Oral: Initial: 5 to 10 mg once daily; titrate in 5 to 10 mg increments (at a minimum of weekly intervals); maximum daily dose: 30 mg/day in divided doses.
Narcolepsy: Immediate-release tablet:
Children 6 to 12 years: Oral: Initial: 5 mg once daily; increase daily dose in 5 mg increments at weekly intervals until optimal response is obtained; first doses should be given at awakening; additional daily doses (5 or 10 mg) may be necessary and should be separated by 4- to 6-hour intervals; usual daily dosage range: 5 to 60 mg daily in divided doses.
Children ≥12 years and Adolescents: Oral: Initial: 10 mg once daily; increase daily dose in 10 mg increments at weekly intervals until optimal response is obtained; first doses should be given at awakening; additional daily doses (5 or 10 mg) may be necessary and should be separated by 4- to 6-hour intervals; usual daily dosage range: 5 to 60 mg daily in divided doses.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution; elimination may be decreased with renal impairment.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution; elimination may be decreased with hepatic impairment.
(For additional information see "Amphetamine (single-ingredient pharmaceutical): Drug information")
Note: Administer at the lowest effective dose.
Attention-deficit/hyperactivity disorder:
ER orally disintegrating tablet: Oral: 12.5 mg once daily.
Conversion: Do not substitute ER formulation for other amphetamine formulations on a mg-per-mg basis.
Converting from Adderall XR to Adzenys XR-ODT: Initial dose of Adzenys XR-ODT should be determined by the current dose of Adderall XR as follows:
Current Adderall XR dose of 5 mg once daily: Initial Adzenys XR-ODT dose of 3.1 mg once daily.
Current Adderall XR dose of 10 mg once daily: Initial Adzenys XR-ODT dose of 6.3 mg once daily.
Current Adderall XR dose of 15 mg once daily: Initial Adzenys XR-ODT dose of 9.4 mg once daily.
Current Adderall XR dose of 20 mg once daily: Initial Adzenys XR-ODT dose of 12.5 mg once daily.
Current Adderall XR dose of 25 mg once daily: Initial Adzenys XR-ODT dose of 15.7 mg once daily.
Current Adderall XR dose of 30 mg once daily: Initial Adzenys XR-ODT dose of 18.8 mg once daily.
Converting from all other amphetamine formulations to Adzenys XR-ODT: Discontinue that treatment and titrate Adzenys XR-ODT as per the recommended dosing schedule.
ER suspension:
Adzenys ER: Oral: 12.5 mg once daily.
Conversion: Do not substitute for other amphetamine formulations on a mg-per-mg basis.
Converting from Adderall XR to Adzenys ER: Initial dose of Adzenys ER should be determined by the current dose of Adderall XR as follows:
Current Adderall XR dose of 5 mg once daily: Initial Adzenys ER dose of 3.1 mg once daily.
Current Adderall XR dose of 10 mg once daily: Initial Adzenys ER dose of 6.3 mg once daily.
Current Adderall XR dose of 15 mg once daily: Initial Adzenys ER dose of 9.4 mg once daily.
Current Adderall XR dose of 20 mg once daily: Initial Adzenys ER dose of 12.5 mg once daily.
Current Adderall XR dose of 25 mg once daily: Initial Adzenys ER dose of 15.7 mg once daily.
Current Adderall XR dose of 30 mg once daily: Initial Adzenys ER dose of 18.8 mg once daily.
Converting from all other amphetamine formulations to Adzenys ER: Discontinue that treatment and titrate Adzenys ER as per the recommended dosing schedule.
Dyanavel XR: Oral: Initial: 2.5 or 5 mg once daily; may increase in 2.5 to 10 mg/day increments every 4 to 7 days until optimal response is obtained (maximum: 20 mg/day).
Note: Dyanavel XR suspension can be converted to Dyanavel XR tablet on a mg-per-mg basis. Do not substitute for other amphetamine products on a mg-per-mg basis since base composition and pharmacokinetic profiles are not similar. If switching from other amphetamine products, discontinue that treatment, and titrate as per the recommended dosing schedule.
ER tablet:
Dyanavel XR: Oral: Initial: 2.5 or 5 mg once daily; may increase in 2.5 to 10 mg/day increments every 4 to 7 days until optimal response is obtained (maximum: 20 mg/day).
Note: Dyanavel XR tablet can be converted to Dyanavel XR suspension on a mg-per-mg basis.
Narcolepsy: IR tablet: Oral: Initial: 10 mg once daily; increase daily dose in 10 mg increments at weekly intervals until optimal response is obtained; usual dosage range: 5 to 60 mg/day in divided doses.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; however, because the drug is renally eliminated, renal dysfunction has the potential to result in prolonged exposure.
There are no dosage adjustments provided in the manufacturer’s labeling; however, because the drug is hepatically metabolized, hepatic dysfunction has the potential to result in prolonged exposure.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Suspension Extended Release, Oral:
Adzenys ER: 1.25 mg/mL (450 mL [DSC]) [contains fd&c yellow #6 (sunset yellow), methylparaben, polyethylene glycol, propylene glycol, propylparaben; orange flavor]
Generic: 1.25 mg/mL (450 mL [DSC])
Suspension Extended Release, Oral, as base:
Dyanavel XR: 2.5 mg/mL (464 mL) [contains methylparaben, polysorbate 80, propylparaben]
Tablet, Oral, as sulfate:
Evekeo: 5 mg [scored]
Evekeo: 10 mg [scored; contains brilliant blue fcf (fd&c blue #1)]
Generic: 5 mg, 10 mg
Tablet Disintegrating, Oral, as sulfate:
Evekeo ODT: 5 mg, 10 mg, 15 mg, 20 mg
Tablet Extended Release Disintegrating, Oral, as base:
Adzenys XR-ODT: 3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, 18.8 mg
May be product dependent
Dyanavel XR extended-release tablets: FDA approved November 2021; availability anticipated in the first quarter of 2022. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.
C-II
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Adzenys ER: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204325s000lbl.pdf#page=26
Dyanavel XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210526s000lbl.pdf#page=20
Evekeo ODT: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209905s000lbl.pdf#page=15
Oral: For attention-deficit/hyperactivity disorder and narcolepsy, administer the first dose in the morning with or without food.
Immediate release: Administer additional doses at intervals of 4 to 6 hours. Avoid late evening dosing.
Orally disintegrating tablet (Evekeo ODT): Do not remove from blister until ready to administer. Using dry hands, push tablet through foil. Remove tablet and immediately place on tongue and allow to disintegrate; may actively move around between tongue and roof of mouth until disintegrates. Swallow with saliva. Do not chew or crush tablet.
Extended release:
Orally disintegrating tablet (Adzenys XR-ODT): Do not remove from blister until ready to administer. Using dry hands, peel backing off the blister; do not push tablet through foil. Remove tablet and immediately place on tongue and allow to disintegrate. Swallow with saliva. Do not chew or crush tablet.
Oral suspension (Adzenys ER, Dyanavel XR): Shake suspension well before administration; use provided oral dosing dispenser or other calibrated device to measure dose. Administer directly into mouth from dispenser (do not add to food or mix with liquids); wash dispenser after each use.
Tablet (Dyanavel XR): May be chewed or swallowed whole; scored tablets (5 mg) may be cut.
Oral:
ER orally disintegrating tablet: Administer in the morning with or without food. Do not remove from blister until ready to administer. Using dry hands, peel backing off the blister; do not push tablet through foil. Remove tablet and immediately place on tongue and allow to disintegrate. Swallow with saliva. Do not chew or crush tablet.
ER suspension: Administer in the morning with or without food; use the oral dosing dispenser provided. Administer directly into mouth from dispenser (do not add to food or mix with liquids); wash dispenser after each use. Shake bottle well prior to administration.
ER tablet: Administer in the morning with or without food. May be chewed, swallowed whole, or divided into equal halves at the scored line.
IR orally disintegrating tablet: Do not remove from blister until ready to administer. Using dry hands, push tablet through foil. Remove tablet and immediately place on tongue and allow to disintegrate; may actively move around between tongue and roof of mouth until disintegrates. Swallow with saliva. Do not chew or crush tablet.
IR tablet: Administer with or without food. Administer the first dose on awakening; administer additional doses at intervals of 4 to 6 hours. Avoid late evening dosing.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF). Store orally disintegrating tablet blister packages in travel case or plastic sleeve provided.
Immediate release:
Orally disintegrating tablet (Evekeo ODT): Treatment of attention-deficit/hyperactivity disorder (ADHD) (FDA approved in ages 3 through 17 years).
Tablet (Evekeo): Treatment of ADHD (FDA approved in ages ≥3 years through adolescence); narcolepsy (FDA approved in ages ≥6 years and adults); exogenous obesity (FDA approved in ages ≥12 years and adults).
Extended release:
Orally disintegrating tablet (Adzenys XR-ODT): Treatment of ADHD (FDA approved in ages ≥6 years and adults).
Oral suspension (Adzenys ER, Dyanavel XR): Treatment of ADHD (FDA approved in ages ≥6 years and adults).
Tablet (Dyanavel XR): Treatment of ADHD (FDA approved in ages ≥6 years and adults).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Gastrointestinal: Abdominal pain (3%), decreased appetite (4%), upper abdominal pain
Nervous system: Emotional lability (3%), insomnia (4%)
Respiratory: Allergic rhinitis, epistaxis
Miscellaneous: Accidental injury (3%)
Frequency not defined:
Cardiovascular: Acute myocardial infarction, cardiomyopathy (with chronic use), increased blood pressure, ischemic bowel disease (intestinal), palpitations, tachycardia
Dermatologic: Alopecia, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Change in libido, weight loss
Gastrointestinal: Anorexia, constipation, diarrhea, unpleasant taste, xerostomia
Genitourinary: Frequent erections, impotence, prolonged erection
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction
Nervous system: Aggressive behavior, depression, dizziness, drug abuse, drug dependence, dysphoria, euphoria, exacerbation of Gilles de la Tourette’s syndrome, exacerbation of tics, exacerbation of vocal tics, fatigue, headache, irritability, overstimulation, outbursts of anger, psychosis, restlessness, talkativeness, tic disorder
Neuromuscular & skeletal: Dyskinesia, rhabdomyolysis, tremor
Ophthalmic: Blurred vision, mydriasis
Postmarketing:
Cardiovascular: Peripheral vascular disease (including digital ulceration, Raynaud's disease, or soft tissue breakdown)
Dermatological: Dermatillomania
Gastrointestinal: Bruxism
Nervous system: Paresthesia (including formication)
Hypersensitivity to amphetamine or any component of the formulation, anaphylactic reactions and angioedema have been reported; use during or within 14 days following MAO inhibitor (including linezolid or intravenous methylene blue).
Evekeo immediate-release tablet: Additional contraindications: Hypersensitivity or idiosyncrasy to amphetamine, other sympathomimetic amines, or any component of the formulation; advanced arteriosclerosis; symptomatic cardiovascular disease; moderate to severe hypertension; hyperthyroidism; agitated states; history of drug abuse; use during or within 14 days following MAO inhibitor.
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: [US Boxed Warning; Immediate release]: Misuse may cause serious cardiovascular events including sudden death. 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 the 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: May impair the ability to engage in potentially hazardous activities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Hypersensitivity: Angioedema and anaphylactic reactions have been reported.
• Hypertension/tachycardia: May occur; monitor blood pressure and heart rate in all patients.
• 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 (Syed 2008).
• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) may occur when amphetamine 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 amphetamine. Concomitant use with monoamine oxidase inhibitors is contraindicated. If concomitant use of amphetamine with serotonergic drugs or CYP2D6 inhibitors is indicated, initiate amphetamine at a low dose and monitor patient closely for signs and symptoms of SS. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.
• Visual disturbance: Difficulty in accommodation and blurred vision has been reported with the use of stimulants.
Disease-related concerns:
• Abuse potential: [US Boxed Warning]: Potential for drug abuse and dependency exists; prolonged use may lead to drug dependency and must be avoided. Assess the risk for abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Consider the possibility of patients obtaining amphetamines for non-therapeutic use or distribution to others; prescribe sparingly. Use of immediate-release formulation is contraindicated in patients with history of drug abuse. Write prescriptions 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). May be associated with aggressive behavior or hostility (causal relationship not established); monitor for development or worsening of these behaviors.
• 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).
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. Monitor weight during therapy; treatment interruption may be necessary in patients who are not increasing in height or gaining weight as expected.
Dosage form specific issues:
• Intestinal necrosis: Adzenys ER: Cases of intestinal necrosis, including some deaths, have been reported with the concomitant use of sodium polystyrene sulfonate and sorbitol, two of the inactive ingredients in Adzenys ER. In these cases, patients were administered sodium polystyrene sulfonate at doses greater than 200 times the amount present in Adzenys ER, however no absolute safe levels for the interaction of sodium polystyrene sulfonate and sorbitol have been established.
Other warnings/precautions:
• Discontinuation of therapy: Abrupt discontinuation following high doses or for prolonged periods may result in symptoms of 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% 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).
Use of stimulants in children has been associated with growth suppression; monitor growth; treatment interruption may be needed. Appetite suppression may occur; monitor weight during therapy, particularly in children. 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 pediatric patients 8 to 17 years actively treated with stimulants, significant reductions in total femoral, femoral neck, and lumbar bone mineral density (BMD) were observed compared to matched unmedicated cohorts; 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%) (Howard 2017). A longitudinal cohort-controlled trial reported no different in peak height velocity and final adult height in subjects with ADHD and/or treated with stimulants (Harstad 2014).
Substrate of CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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
Antihistamines: Amphetamines may diminish the sedative effect of Antihistamines. Risk C: Monitor therapy
Antihypertensive Agents: Amphetamines may diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Antipsychotic Agents: May diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Ascorbic Acid: May decrease the serum concentration of Amphetamines. 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
Ethosuximide: Amphetamines may diminish the therapeutic effect of Ethosuximide. Amphetamines may decrease the serum concentration of Ethosuximide. 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 Amphetamine. 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
PHENobarbital: Amphetamines may decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy
Phenytoin: Amphetamines may decrease the serum concentration of Phenytoin. 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
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.
Information related to use of amphetamine in pregnancy is limited (Maurovich-Horvat 2013). The majority of human data are 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). Newborns should be monitored for agitation, irritability, excessive drowsiness, or feeding difficulties
Data collection to monitor pregnancy outcomes following exposure to amphetamine is ongoing. Healthcare providers are encouraged to enroll females exposed to amphetamine during pregnancy in the National Pregnancy Registry for Psychostimulants (1-866-961-2388 and/or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/).
Prior to initiation of therapy, assess medical history and family history of sudden death or ventricular arrhythmia, and 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 symptom of cardiac disease during treatment. For children already taking a stimulant, it is reasonable to evaluate medical and family history, review physical examination, and order ECG if not done prior to initiation (Vetter 2008).
Monitor growth (weight and height in children; baseline and periodically during therapy); other parameters to monitor periodically during therapy: CBC with differential and platelet count, liver enzymes, blood pressure and heart rate (baseline, following dose increases, and periodically during treatment), appetite, and sleep patterns; observe for abnormal movements. Patients should be reevaluated at appropriate intervals to assess continued need of the medication. Observe for signs/symptoms of new or worsening aggression or hostility, depression, delusional thinking, hallucinations, or mania. Monitor for visual disturbances. Observe for digital changes suggestive of peripheral vasculopathy (eg, Raynaud phenomenon). Monitor for signs of misuse, abuse, addiction, and diversion.
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. The anorexigenic effect is probably secondary to the CNS-stimulating effect; the site of action is probably the hypothalamic feeding center.
Note: Alkaline urine pH will result in reduced renal elimination of amphetamine and acidic urine pH will result in increased renal elimination. Decreased renal elimination in the context of alkaline urine pH may be more pronounced when renal elimination is already decreased.
Duration of action: Oral:
Immediate-release tablet: Evekeo: 4 to 6 hours (Jain 2017).
Extended-release orally-disintegrating tablet: Adzenys XR-ODT: 10 to 12 hours.
Absorption: Oral:
Immediate-release tablet: Rapid (de la Torre 2004).
Immediate-release orally-disintegrating tablet: Evekeo ODT: Cmax and AUC comparable to equivalent immediate-release dose.
Distribution: Oral: Immediate-release tablet: Vd: 3 to 4 L/kg (de la Torre 2004).
Protein binding: Oral: Immediate-release tablet: 16% (de la Torre 2004).
Metabolism: Hepatic via oxidation, deamination, and CYP2D6.
Bioavailability: Oral:
Immediate-release tablet: Good (de la Torre 2004).
Extended release:
Dyanavel XR suspension:
Relative to equivalent dose of immediate-release mixed amphetamine salts: 106% of d-amphetamine and 111% for l-amphetamine.
Relative to equivalent dose of extended-release mixed amphetamine salts: 94% of d-amphetamine and l-amphetamine.
Dyanavel XR tablet: Relative to equivalent dose of Dyanavel XR suspension: 105% of d-amphetamine and 106% of l-amphetamine.
Half-life elimination: Oral:
Immediate-release tablet: 12 hours (de la Torre 2004).
Immediate-release orally-disintegrating tablet: Evekeo ODT: Adults: d-amphetamine 10 hours and l-amphetamine 11.7 hours.
Extended-release orally-disintegrating tablet: Adzenys XR-ODT:
Children 6 to 12 years: d-amphetamine 9 to 10 hours and l-amphetamine 10 to 11 hours.
Adults: d-amphetamine 11 hours and l-amphetamine 14 hours.
Extended-release suspension:
Adzenys ER:
Children 6 to 12 years: d-amphetamine 12.7 hours (mean) and l-amphetamine 15.3 hours.
Adults: d-amphetamine 11.4 hours and l-amphetamine 14.1 hours.
Dyanavel XR:
Children: d-amphetamine 10.43 ± 2.01 hours and l-amphetamine 12.14 ± 3.15 hours.
Adults: d-amphetamine 12.36 ± 2.95 hours and l-amphetamine 15.12 ± 4.4 hours.
Extended-release tablet: Dyanavel XR: Mean: Adults: d-amphetamine 13.5 hours and l-amphetamine 17.3 hours.
Time to peak, serum: Oral:
Immediate-release tablet: Within 4 hours (de la Torre 2004).
Immediate-release orally-disintegrating tablet: Evekeo ODT: Median time d-amphetamine and l-amphetamine 3.5 hours (with water) and 3 hours (without water); increased with food in adults.
Extended-release orally-disintegrating tablet: Adzenys XR-ODT: Median time d-amphetamine 5 hours (7 hours with food) and l-amphetamine ~5.25 hours (7.75 hours with food).
Extended-release suspension:
Adzenys ER suspension: d-amphetamine and l-amphetamine: 5 hours (median) with or without food.
Dyanavel XR suspension:
Children: Median time d-amphetamine 3.9 hours and l-amphetamine 4.5 hours.
Adults: 4 (2 to 7) hours.
Extended-release tablet: d-amphetamine and l-amphetamine: 5 hours (median; range 2 to 9 hours) without food.
Excretion: Urine (30% to 40% unchanged; ~50% as metabolites).
Body weight: Systemic exposure and maximum concentration of d- and l-amphetamine decrease as body weight increases; volume of distribution, clearance, and half-life increase as body weight increases.
Adzenys ER and XR-ODT contain d-amphetamine and l-amphetamine in a 3:1 ratio, containing ~ equal amounts of immediate-release and extended-release amphetamine.
Evekeo immediate release contains d-amphetamine and l-amphetamine in a 1:1 ratio.
Dyanavel XR contains d-amphetamine and l-amphetamine in a 3.2:1 ratio containing immediate-release and extended-release components.
Treatment of ADHD should include "drug holidays" or periodic discontinuation of medication in order to assess the patient's requirements, decrease tolerance, and limit suppression of linear growth and weight. Medications used to treat ADHD should be part of a total treatment program that may include other components, such as psychological, educational, and social measures.
Suspension Extended Release (Dyanavel XR Oral)
2.5 mg/mL (per mL): $3.47
Tablet Extended Release Dispersible (Adzenys XR-ODT Oral)
3.1 mg (per each): $17.42
6.3 mg (per each): $17.42
9.4 mg (per each): $17.42
12.5 mg (per each): $17.42
15.7 mg (per each): $17.42
18.8 mg (per each): $17.42
Tablet, orally-disintegrating (Evekeo ODT Oral)
5 mg (per each): $8.25
10 mg (per each): $8.25
15 mg (per each): $8.25
20 mg (per each): $8.25
Tablets (Amphetamine Sulfate Oral)
5 mg (per each): $1.51 - $8.70
10 mg (per each): $1.51 - $8.70
Tablets (Evekeo Oral)
5 mg (per each): $8.25
10 mg (per each): $8.25
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