CNS stimulants, including amphetamine-containing products and methylphenidate, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy.
Misuse of amphetamines may cause sudden death and serious cardiovascular adverse events.
Attention-deficit/hyperactivity disorder:
Immediate release: Oral: Initial: 5 mg once or twice daily; may increase daily dose based on response and tolerability in 5 to 10 mg increments at intervals ≥1 week up to a usual maximum of 40 mg/day in 1 to 2 divided doses (Bukstein 2020; Spencer 2001). Some experts recommend waiting up to 1 month before increasing dose (Bukstein 2020). Note: Although doses >40 mg/day will rarely be necessary, doses as high as 60 mg/day with close monitoring may be necessary for optimal response in some patients (Bukstein 2020).
Extended release: Oral: Initial: 10 to 20 mg once daily in the morning; may increase daily dose based on response and tolerability in 10 to 20 mg increments at intervals ≥1 week (Bukstein 2020; Weisler 2006). Some experts recommend waiting up to 1 month before increasing dose (Bukstein 2020). Although doses >40 mg/day will rarely be necessary, doses up to 60 mg/day may be necessary for optimal response in some patients, but the frequency and severity of adverse effects are increased with higher doses (Biederman 2005; Bukstein 2020).
Triple-bead extended release: Oral: Initial: 12.5 mg once daily in the morning; may increase daily dose based on response and tolerability in 12.5 mg increments at intervals ≥1 week (Spencer 2008; Wigal 2018; manufacturer's labeling). Some experts recommend waiting up to 1 month before increasing dose (Bukstein 2020). Maximum dose: 50 mg/day.
Narcolepsy, daytime sleepiness (alternative agent): Oral: Initial: 10 mg once daily in the morning; may increase daily dose based on response and tolerability in increments of 10 mg every week until optimal response is obtained; usual dosage range: 20 to 60 mg/day in 1 to 3 divided doses (Thorpy 2015). Some experts recommend initiating therapy with the IR formulation (FDA approved) and transitioning to extended release (off label) once the patient achieves a stable dose. Although the ER formulation is generally dosed once daily, some patients may require a second dose in the early afternoon (Scammell 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Immediate release: There are no dosage adjustments provided in the manufacturer's labeling; use with caution; the potential exists for elimination of amphetamine to be inhibited resulting in prolonged exposure.
Hemodialysis: There are no specific dosage adjustments provided in the manufacturer's labeling; dextroamphetamine is not dialyzable (Ermer 2016).
Extended release: Adderall XR:
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution; the potential exists for elimination of amphetamine to be inhibited resulting in prolonged exposure.
Severe impairment (GFR 15 to <30 mL/minute/1.73 m2): 15 mg once daily in the morning.
ESRD (GFR <15 mL/minute/1.73 m2): Use is not recommended; dextroamphetamine is not dialyzable.
Mydayis:
Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling.
Severe impairment (GFR 15 to <30 mL/minute/1.73 m2): Maximum dose: 25 mg/day
ESRD (GFR <15 mL/minute/1.73 m2): Use is not recommended; dextroamphetamine is not dialyzable
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
(For additional information see "Dextroamphetamine and amphetamine: Pediatric drug information")
Note: Use lowest effective individualized dose; administer first dose as soon as awake; avoid late evening doses
Attention-deficit/hyperactivity disorder: Note: Extended-release products are not interchangeable on a mg-per-mg basis; use precaution to ensure appropriate product specific dosing.
Immediate-release tablets:
Children 3 to 5 years: Oral: Initial 2.5 mg once daily in the morning; increase daily dose by 2.5 mg at weekly intervals until optimal response is obtained; maximum daily dose: 40 mg/day administered in 1 to 2 divided doses per day; use intervals of 4 to 6 hours between doses. Note: Select patients may require daily dose to be given in 3 divided doses per day. Although FDA approved, current guidelines do not recommend dextroamphetamine/amphetamine use in children ≤5 years due to insufficient evidence (AAP 2011).
Children ≥6 years and Adolescents: Oral: Initial: 5 mg once or twice daily; increase daily dose by 5 mg at weekly intervals until optimal response is obtained; usual maximum daily dose: 40 mg/day administered in 1 to 2 divided doses; use intervals of 4 to 6 hours between doses; some patients weighing >50 kg may require and tolerate doses up to 60 mg/day in divided doses with frequent monitoring (AACAP [Pliszka 2007]; Dopheide 2009). Note: Some patients may require daily dose to be administered as 3 divided doses per day.
Extended-release capsules:
Adderall XR:
Initial therapy:
Children 6 to 12 years: Oral: Initial: 5 to 10 mg once daily in the morning; increase daily dose by 5 mg or 10 mg at weekly intervals until optimal response is obtained; usual maximum daily dose: 30 mg/day; some patients weighing >50 kg may require and tolerate doses up to 60 mg/day (AACAP [Pliszka 2007]; Dopheide 2009)
Adolescents 13 to 17 years: Oral: Initial: 10 mg once daily in the morning; may increase to 20 mg daily after 1 week if symptoms are not controlled; usual maximum daily dose: 20 mg/day; some patients weighing >50 kg may require and tolerate doses up to 60 mg/day with frequent monitoring (AACAP [Pliszka 2007]; Dopheide 2009)
Converting Adderall to Adderall XR: Patients taking divided doses of immediate-release Adderall tablets may be switched to extended-release Adderall XR capsule using the same total daily dose (taken once daily); titrate dose at weekly intervals to achieve optimal response.
Mydayis: Note: Do not substitute Mydayis for other amphetamine products on a mg-per-mg basis because of different amphetamine base compositions and differing pharmacokinetic profiles.
Adolescents 13 to 17 years: Oral: Initial: 12.5 mg once daily in the morning; may increase by 12.5 mg increments at weekly intervals; maximum daily dose: 25 mg/day
Narcolepsy:
Children 6 to 12 years: Immediate-release tablets: Oral: Initial: 5 mg daily; increase daily dose by 5 mg at weekly intervals until optimal response is obtained; maximum daily dose: 60 mg/day given in 1 to 3 divided doses per day; use intervals of 4 to 6 hours between doses
Adolescents: Immediate-release tablets: Oral: Initial: 10 mg daily; increase daily dose by 10 mg at weekly intervals until optimal response is obtained; maximum daily dose: 60 mg/day given in 1 to 3 divided doses per day; 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.
Immediate release: Children ≥3 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; use with caution; elimination may be decreased with renal impairment.
Extended release:
Adderall XR: Children ≥6 years and Adolescents ≤17 years:
GFR 15 to <30 mL/minute/1.73 m2: Initial dose: 5 mg once daily; maximum daily dose in children 6 to 12 years: 20 mg/day
GFR <15 mL/minute/1.73 m2: Use not recommended
Mydayis: Adolescents 13 to 17 years:
GFR 15 to <30 mL/minute/1.73 m2: Reduce maximum daily dose to 12.5 mg/day
GFR <15 mL/minute/1.73 m2: Use not recommended
Children ≥3 years and Adolescents: 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; use with caution and start at low end of dosage range.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule Extended Release 24 Hour, Oral:
Adderall XR: 20 mg, 30 mg, 25 mg
Adderall XR: 5 mg, 15 mg, 10 mg [contains fd&c blue #2 (indigotine)]
Mydayis: 37.5 mg
Mydayis: 50 mg [contains fd&c blue #1 (brilliant blue)]
Mydayis: 25 mg, 12.5 mg [contains fd&c blue #2 (indigotine)]
Generic: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 5 mg
Tablet, Oral:
Adderall: 10 mg, 7.5 mg [scored; contains fd&c blue #1 (brill blue) aluminum lake, saccharin sodium]
Adderall: 15 mg, 12.5 mg, 30 mg, 20 mg [scored; contains fd&c yellow #6(sunset yellow)alumin lake, saccharin sodium]
Adderall: 5 mg [scored; contains saccharin sodium]
Generic: 10 mg, 12.5 mg, 15 mg, 20 mg, 30 mg, 5 mg, 7.5 mg
Yes
Products contain equal amounts (by weight) of four salts: dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate, and amphetamine aspartate monohydrate. For example, a 10 mg capsule or tablet contains dextroamphetamine sulfate 2.5 mg, dextroamphetamine saccharate 2.5 mg, amphetamine aspartate monohydrate 2.5 mg, and amphetamine sulfate 2.5 mg.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule Extended Release 24 Hour, Oral:
Adderall XR: 20 mg, 30 mg, 25 mg
Adderall XR: 5 mg, 10 mg, 15 mg [contains fd&c blue #2 (indigotine)]
Generic: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 5 mg
C-II
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Adderall: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/011522s044lbl.pdf#page=15
Adderall XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021303s036lbl.pdf#page=23
Mydayis: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022063s003lbl.pdf#page=22
Administer with or without food. Administer Mydayis consistently either with food or without food.
Immediate release: Administer in 1 to 3 divided doses per day with intervals of 4 to 6 hours between doses. To avoid insomnia, late evening doses should be avoided.
Extended release: To avoid insomnia, afternoon doses should be avoided. Capsule may be swallowed whole or it may be opened and the contents sprinkled on applesauce. Applesauce should be consumed immediately without chewing. Do not divide the contents of the capsule. Do not take less than one capsule per day; a single capsule should not be divided.
Oral:
Immediate-release tablet: Take on awakening; to avoid insomnia, last daily dose should be administered no less than 6 hours before retiring.
Extended-release capsule: Take on awakening. Avoid afternoon doses to prevent insomnia. Swallow capsule whole; do not chew or divide. May be administered with or without food; however, Mydayis should be taken in a consistent manner with regards to food. May open capsule and sprinkle contents on applesauce; consume applesauce/medication mixture immediately; do not store; do not chew sprinkled beads from capsule.
Attention-deficit/hyperactivity disorder: Treatment of attention-deficit/hyperactivity disorder (ADHD) as part of a total treatment program that typically includes other remedial measures (psychological, educational, social) for a stabilizing effect.
Narcolepsy, daytime sleepiness (immediate release only): Treatment of narcolepsy.
Adderall may be confused with Adderall XR, Inderal
Cardiovascular events including acute myocardial infarction (MI), stroke, sudden cardiac death (SCD), increased heart rate, and increased blood pressure have been reported in adult and pediatric patients (Ref). Amphetamine and dextroamphetamine salts, similar to other CNS stimulants, have been associated with sudden cardiac death in children and adolescents with preexisting structural cardiac abnormalities. Available data in patients without congenital heart disease are conflicting (Ref). A large retrospective cohort study showed an overall low incidence and risk of serious cardiovascular events in children and young adults (Ref); similarly, retrospective claims databases have not shown an increase in serious cardiovascular events (MI, sudden death, stroke) with stimulant use in young and middle-aged adults (Ref).
Mechanism : Dose-related; amphetamines increase the mean heart rate and systolic blood pressure by mediating noradrenergic and dopaminergic transmission (Ref). This increase in heart rate and blood pressure can ultimately lead to cardiovascular events such as arrhythmias and/or MI.
Onset: Varied; MI and SCD usually occur within hours (especially in cases of overdose), but arrhythmias usually occur with long-term use (Ref).
Risk factors:
• Higher doses (Ref)
• Prior structural heart disease (Ref)
• Family history of SCD or other cardiovascular diseases (eg, MI, cardiac arrhythmias) (Ref)
• Concomitant use of QTc prolonging medications may increase the risk of arrhythmias
• Strenuous exercise and dehydration (Ref)
Some studies have reported growth retardation in pediatric patients. Decreased height and weight changes have been described in children <12 years receiving long-term treatment (ie, ≥3 years) (Ref). Similarly, statistically significant reductions in total femoral, femoral neck, and lumbar bone mineral density (BMD) were observed in pediatric patients (age range: 8 to 17 years) actively treated with stimulants (including, but not limited to methylphenidate) when compared to matched unmedicated controls; also reported were significantly more subjects in the stimulant-treated group with BMD measurements in the osteopenic range compared to matched controls (38.3% vs 21.6%) (Ref). An association has been observed between cumulative stimulant exposure in childhood and decreased height velocity, decreased adult height, and increased weight in adulthood (Ref). In contrast, a longitudinal cohort-controlled trial reported no difference in peak height velocity and final adult height in subjects with attention-deficit/hyperactivity disorder and/or treated with stimulants (Ref).
Mechanism: Dose- and time-related; possibly due to effects on CNS growth factors and hepatic growth factors and direct cartilage effects. Weight loss may result from appetite suppression, reduced food intake, increased activity, and metabolic shifts (Ref).
Onset: Growth suppression in children: Delayed; appears to occur after months of active treatment (Ref).
Risk factors:
• Higher doses (Ref)
• Duration of treatment/cumulative exposure (Ref)
• Comorbid autism disorder (Ref)
New-onset psychosis or mania and exacerbation of psychotic or manic symptoms (eg, delusional thinking, auditory hallucination and visual hallucination, mania) may occur with neurostimulant use in all ages (Ref); symptoms resemble acute psychosis most commonly observed in schizophrenia (Ref). Amphetamine has also been associated with aggressive behavior or hostility in children; however, a causal relationship has not been established. A study of commercial insurance claims data from 221,846 patients (age: 13 to 25 years) prescribed amphetamines or methylphenidate reported a higher risk of psychosis with amphetamine products compared to methylphenidate (Ref). Studies in adults have suggested that the resolution of the psychotic episode may be incomplete without treatment and may take up to 6 months even if abstinence occurs (Ref).
Mechanism: Psychosis: Amphetamine stimulates the release of dopamine from presynaptic nerve endings and prevents its reuptake. This leads to an increased concentration of dopamine in the neuronal synapse, leading to glutamate dysregulation. Increased dopamine and glutamate dysregulation have been associated with the development of psychotic symptoms (Ref).
Onset: Delayed and varied; a study of commercial insurance claims data from 221,846 patients (age: 13 to 25 years) prescribed amphetamines or methylphenidate reported a mean time of 128 days (IQR: 48 to 333 days) from the time medication was dispensed to the first psychotic episode (Ref). In cases of overdose/intoxication, the onset of symptoms is usually acute and within hours.
Risk factors:
• Preexisting mood or psychotic disorders (Ref)
• Prior history of substance use/abuse (Ref)
• Family history of mood and psychotic disorders (eg, major depression, bipolar disorder, and schizophrenia) (Ref)
• Young age (children, adolescents, and young adults) (Ref)
• Concomitant use of corticosteroids (Ref)
Serotonin syndrome may occur when amphetamines are used in combination with drugs that affect the serotonergic neurotransmitter system in all ages. Early symptoms of serotonin syndrome include tachycardia, shivering, diarrhea, diaphoresis, muscle cramps, agitation, and increased body temperature; these symptoms are usually followed by hypertension, hyperthermia, hyperreflexia, delirium, tremors, and rigidity (Ref). Prompt treatment is needed to minimize risk of adverse outcome, including death (Ref). The incidence of serotonin syndrome from stimulants use is unknown, likely due to under reporting (Ref).
Mechanism: Amphetamines increase serotonin release and inhibit reuptake, which can lead to dangerously high extracellular concentration of serotonin especially when used in combination with other drugs that also increase serotonin concentrations (eg, CYP2D6 inhibitors, serotonin reuptake inhibitors, serotonin-norepinephrine uptake inhibitors) (Ref).
Onset: Rapid; symptoms usually begin within 24 hours of ingestion of the causative agent(s) (Ref).
Risk factors:
• Genetic polymorphism: Poor CYP2D6 metabolizers (Ref)
• Concurrent use of CYP2D6 inhibitors; consult drug interactions database for more information (Ref)
• Concurrent use of serotonergic agents; consult drug interactions database for more information (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are for the extended-release products in children, adolescents, and adults unless otherwise specified.
>10%:
Cardiovascular: Systolic hypertension (adolescents: 7% to 35%; dose related; transient) (table 1)
|
Drug (Dextroamphetamine and Amphetamine) |
Placebo |
Population |
Dose |
Dosage Form |
Number of Patients (Dextroamphetamine and Amphetamine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|---|---|
|
35% |
N/A |
Adolescents |
20 mg |
Extended-release capsules |
23 |
N/A |
N/A |
|
12% |
N/A |
Adolescents |
10 mg |
Extended-release capsules |
17 |
N/A |
N/A |
|
7% |
11% |
Adolescents |
10 or 20 mg/day |
Extended-release capsules |
100 |
64 |
Isolated systolic blood pressure elevations ≥15 mmHg |
Gastrointestinal: Abdominal pain (children and adolescents: 11% to 14%), anorexia (22% to 36%), decreased appetite (adolescents and adults: 22% to 30%), xerostomia (adolescents: 2% to 4%; adults: 23% to 35%)
Nervous system: Headache (adults: 26%), insomnia (8% to 31%)
1% to 10%:
Cardiovascular: Palpitations (adults: 2% to 4%), tachycardia (adults: 6%) (table 2)
|
Drug (Dextroamphetamine and Amphetamine) |
Placebo |
Population |
Dosage Form |
Number of Patients (Dextroamphetamine and Amphetamine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
6% |
3% |
Adults |
Extended-release capsules |
191 |
64 |
Dermatologic: Diaphoresis (adults: 2% to 4%), skin photosensitivity (adults: 2% to 4%)
Endocrine & metabolic: Decreased libido (adults: 2% to 4%), weight loss (4% to 10%)
Gastrointestinal: Bruxism (adults: 2%), constipation (adults: 2% to 4%), diarrhea (adults: 3% to 6%), dyspepsia (children and adolescents: 2% to 4%), nausea (2% to 8%), teeth clenching (adults: ≤4%), tooth infection (adults: ≤4%), upper abdominal pain (adolescents: 4%), vomiting (children and adolescents: 2% to 7%)
Genitourinary: Dysmenorrhea (adults: 2% to 4%), erectile dysfunction (adults: 2%), impotence (adults: 2% to 4%), urinary tract infection (adults: 5%)
Infection: Infection (children and adults: 2% to 4%)
Nervous system: Agitation (adults: 2% to 8%), anxiety (adults: 7% to 8%), depression (adults: 3%), dizziness (2% to 7%), drowsiness (adolescents and adults: 2% to 4%), emotional lability (2% to 9%), fatigue (≤6%), irritability (adolescents: 6%), jitteriness (adults: 2%), nervousness (children and adolescents: 6%), speech disturbance (adults: 2% to 4%), twitching (adults: 2% to 4%)
Neuromuscular & skeletal: Asthenia (≤6%)
Respiratory: Dyspnea (adults: 2% to 4%)
Miscellaneous: Accidental injury (children and adolescents: 2% to 4%), fever (children: 5%)
Frequency not defined:
Cardiovascular: Ischemic bowel disease (intestinal)
Nervous system: Drug abuse, drug dependence
Postmarketing:
Cardiovascular: Acute myocardial infarction (Nissen 2006), increased blood pressure (Nissen 2006), increased heart rate (Nissen 2006), peripheral vascular disease (Syed 2008), Raynaud's phenomenon (Syed 2008)
Dermatologic: Alopecia, dermatillomania, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis (Roberts 2006), urticaria
Endocrine & metabolic: Change in libido, growth retardation (Poulton 2016), pituitary insufficiency (Abdalla 2021)
Gastrointestinal: Unpleasant taste
Genitourinary: Azoospermia (Abdalla 2021), frequent erections, prolonged erection
Hypersensitivity: Anaphylaxis (Fellner 1972), angioedema
Nervous system: Aggressive behavior, auditory hallucination (Fluyau 2019), dysphoria, euphoria, formication, mania (Cressman 2015), outbursts of anger, overstimulation, paresthesia, psychosis (Fluyau 2019), restlessness, talkativeness, tic disorder (Lowe 1982), visual hallucination (Fluyau 2019)
Neuromuscular & skeletal: Dyskinesia (Downes 2005), rhabdomyolysis (Santoro 2013), tremor
Ophthalmic: Blurred vision, mydriasis
Respiratory: Non-cardiogenic pulmonary edema (Khan 2021), respiratory failure (Khan 2021)
Hypersensitivity (eg, angioedema, anaphylaxis) or idiosyncrasy to amphetamine, sympathomimetic amines or any component of the formulation; during or within 14 days following monoamine oxidase inhibitors.
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.
Immediate release, Adderall XR: Additional contraindications: Advanced arteriosclerosis; symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism; glaucoma, agitated states; history of drug abuse.
Concerns related to adverse effects:
• 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, operating machinery, driving).
• 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:
• Cardiovascular disorders: Use with caution in patients with hypertension, ventricular arrhythmia, and other cardiovascular conditions that might be exacerbated by increases in blood pressure or heart rate.
• Hepatic impairment: Use with caution in patients with hepatic impairment; elimination is reduced.
• Bipolar disorder: May precipitate a mixed or manic episode in patients with bipolar illness.
• Renal impairment: Use with caution in patients with renal impairment; elimination is reduced.
• Seizure disorder: Limited information exists regarding stimulant use in seizure disorder. Whereas patients with attention-deficit/hyperactivity disorder (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:
• Older adult: Use caution in this age group due to CNS stimulant adverse effects.
• Pediatric: Pediatric patients 12 years of age and younger experienced high plasma exposure to Mydayis and more adverse reactions, including insomnia and decreased appetite, compared to patients 13 years of age and older.
Other warnings/precautions:
• ADHD treatment: Appropriate use: Recommended to be used as part of a comprehensive treatment program for attention-deficit disorders.
• Appropriate use: Mydayis: Medication errors, including substitution and dispensing errors, may occur, leading to possible overdosage. Do not substitute Mydayis for other amphetamine products on a mg-per-mg basis because of different amphetamine base compositions and differing pharmacokinetic profiles.
• Discontinuation of therapy: Abrupt discontinuation following high doses for prolonged periods results in extreme fatigue, mental depression, and sleep EEG changes; may also result in other symptoms of withdrawal.
Refer to individual components.
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 Amphetamine. 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.
Outcome information related to the use of amphetamine/dextroamphetamine in pregnant women with attention-deficit/hyperactivity disorder is limited (Ornoy 2018).
Data collection to monitor pregnancy outcomes following exposure to amphetamine/dextroamphetamine is ongoing. Health care providers are encouraged to enroll females exposed to amphetamine/dextroamphetamine during pregnancy in the National Pregnancy Registry for Psychostimulants (1-866-961-2388 and/or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications).
Refer to individual monographs for additional information.
Amphetamines are present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.
Refer to individual monographs for additional information.
Cardiac evaluation (including medical or family history of sudden death or ventricular arrhythmia; ECG as indicated) 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 BP 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 (including a history of ethanol or drug abuse) prior to prescribing and signs of misuse, abuse, or addiction throughout treatment (NICE 2018).
Screen for bipolar disorder and risk factors for developing a manic episode prior to treatment; monitor for psychotic or manic symptoms (eg, delusional thinking, hallucinations, mania); monitor for development or worsening of aggressive behavior or hostility.
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.
Note: The immediate-release tablets and ER capsules contain d-amphetamine and l-amphetamine salts in the ratio of 3:1.
Duration of action: Immediate-release tablet: 4 to 6 hours (Dopheide 2009); Adderall XR: 8 to 12 hours (Jain 2017); Mydayis: ≤16 hours
Absorption: Extended release: Food does not affect absorption, but prolongs Tmax of Adderall XR by 2 to 3 hours and Mydayis by 4 to 5 hours.
Half-life elimination:
Children 6 to 12 years: d-amphetamine: 9 hours; l-amphetamine: 11 hours
Adolescents 13 to 17 years: d-amphetamine: 11 hours; l-amphetamine: 13 to 14 hours
Adults: d-amphetamine: 10 hours; l-amphetamine: 13 hours
Metabolism: Hepatic oxidation via cytochrome P450 to 4-hydroxyamphetamine (active) norephedrine (active), and alpha-hydroxy-amphetamine with both active metabolites subsequently oxidized to 4-hydroxy-norephedrine. Cytochrome P450 2D6 is primarily responsible for the formation of 4-hydroxy-amphetamine.
Time to peak: Immediate release: 3 hours; Adderall XR: 7 hours; Mydayis: 7 to 10 hours (children and adolescents 6 to 17 years), 8 hours (adults)
Excretion: Urine (highly dependent on urinary pH); excreted as unchanged amphetamine (30% to 40%, may range from ~1% in alkaline urine to ~75% in acidic urine), and derivatives of alpha-hydroxyamphetamine (50%)
Pediatric: Children eliminated amphetamine faster than adults. The elimination half-life is approximately 1 hour shorter for d-amphetamine and 2 hours shorter for l-amphetamine in children than in adults. However, children had higher systemic exposure to amphetamine (Cmax and AUC) than adults for a given dose of ER capsules, which was attributed to the higher dose administered to children on a mg/kg basis compared with adults. Upon dose normalization on a mg/kg basis, children showed 30% less systemic exposure compared with adults. Patients 6 to 12 years of age experienced higher systemic exposure (72% to 79% higher Cmax and 83% higher AUC), compared with adults.
Weight: Weight is the primary determinant of apparent differences in the pharmacokinetics of d- and l-amphetamine across the age range. Systemic exposure measured by AUC∞ and Cmax decreased with increases in body weight, while apparent oral volume of distribution, apparent oral clearance, and elimination half-life increased with increases in body weight.
Capsule ER 24 Hour Therapy Pack (Adderall XR Oral)
5 mg (per each): $8.55
10 mg (per each): $8.55
15 mg (per each): $8.55
20 mg (per each): $8.55
25 mg (per each): $8.55
30 mg (per each): $8.55
Capsule ER 24 Hour Therapy Pack (Amphetamine-Dextroamphet ER Oral)
5 mg (per each): $0.72 - $7.05
10 mg (per each): $0.72 - $7.05
15 mg (per each): $0.72 - $7.05
20 mg (per each): $0.72 - $7.05
25 mg (per each): $0.72 - $7.05
30 mg (per each): $1.67 - $7.05
Capsule ER 24 Hour Therapy Pack (Mydayis Oral)
12.5 mg (per each): $12.91
25 mg (per each): $12.91
37.5 mg (per each): $12.91
50 mg (per each): $12.91
Tablets (Adderall Oral)
5 mg (per each): $10.75
7.5 mg (per each): $10.75
10 mg (per each): $10.75
12.5 mg (per each): $10.75
15 mg (per each): $10.75
20 mg (per each): $10.75
30 mg (per each): $10.75
Tablets (Amphetamine-Dextroamphetamine Oral)
5 mg (per each): $0.05 - $2.06
7.5 mg (per each): $0.11 - $2.06
10 mg (per each): $0.09 - $2.06
12.5 mg (per each): $0.15 - $2.06
15 mg (per each): $0.12 - $2.06
20 mg (per each): $0.13 - $2.06
30 mg (per each): $0.19 - $2.06
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