Dextroamphetamine

Indications

• FDA-approved for attention-deficit/hyperactivity disorder, with immediate-release tablets labeled from age 3 and Spansule capsules from age 6.
• FDA-approved for narcolepsy in patients age 6 years and older, typically at 5-60 mg/day in divided doses titrated to symptom control.
• Xelstrym transdermal system is approved for ADHD in patients age 6 and older and is the only amphetamine patch on the US market.
• Preferred over mixed salts by some prescribers when the levo isomer appears to drive jitteriness, irritability, or cardiovascular effects.
• Used off-label for treatment-resistant depression augmentation and for apathy or fatigue in palliative care and medically ill adults.
• Used off-label for idiopathic hypersomnia and residual sleepiness in treated obstructive sleep apnea when modafinil is ineffective.

Mechanism of action

• Enters presynaptic terminals through the dopamine and norepinephrine transporters and reverses their direction, releasing stored catecholamines.
• Disrupts vesicular monoamine transporter 2 storage, moving monoamines into the cytoplasm where they become available for carrier-mediated efflux.
• Weak monoamine oxidase inhibition further raises cytoplasmic catecholamine concentration and prolongs the released signal.
• Contains only the dextro isomer, which is more dopaminergic and roughly twice as potent as the levo isomer at central sites.
• The resulting prefrontal catecholamine surge improves attention and impulse control, while nucleus accumbens effects create reinforcement risk.

Pharmacokinetics

• Immediate-release Tmax is about 3 hours and Spansule Tmax about 8 hours, giving roughly 4-6 and 8 hours of clinical coverage respectively.
• Elimination half-life is 10-12 hours in adults and closer to 9 hours in children, so twice-daily immediate-release dosing is typical.
• Metabolized by CYP2D6 to 4-hydroxyamphetamine and by side-chain deamination, with a substantial fraction excreted unchanged in urine.
• Excretion is highly pH dependent: alkaline urine prolongs the half-life sharply while acidification can shorten it to as little as 7 hours.
• The Xelstrym patch avoids first-pass effects and delivers steadily over a 9-hour wear time, with effect declining over 2 hours after removal.

Dosing

• ADHD in patients 6 and older: start 5 mg PO once or twice daily, increase by 5 mg/day at weekly intervals; doses above 40 mg/day are rarely useful.
• Children 3-5 years: start 2.5 mg PO daily and increase by 2.5 mg/day weekly, recognizing that drug treatment at this age is a second-line step.
• Dexedrine Spansule: 5-30 mg PO once daily in the morning, replacing divided immediate-release dosing when a smoother curve is wanted.
• Narcolepsy: 5-60 mg/day PO in divided doses; give the first dose on waking and additional doses at 4-6 hour intervals.
• Xelstrym: start 9 mg/9 h applied to hip, upper arm, chest, upper back, or flank 2 hours before effect is needed; maximum 18 mg per 9 hours.
• No taper is required, though stopping high chronic doses abruptly causes fatigue, hypersomnia, hyperphagia, and depressed mood for several days.

Adverse effects

• Appetite suppression, weight loss, insomnia, dry mouth, headache, and irritability are the dominant dose-limiting effects in practice.
• Blood pressure and heart rate rise modestly, but new hypertension, palpitations, or exertional chest pain require reassessment or discontinuation.
• Emotional blunting, anxiety, and end-of-dose rebound irritability are common complaints that often reflect dose or timing rather than nonresponse.
• Psychosis, mania, aggression, or new tics can emerge at usual doses and are indications to stop the stimulant rather than to add treatment.
• Peripheral vasculopathy including Raynaud phenomenon, priapism in males, and rare sudden cardiac death in structural heart disease are labeled risks.
• Xelstrym adds application-site reactions and permanent skin hypopigmentation at the site, which is a labeled dermatologic warning.

Monitoring

• Baseline weight, height, blood pressure, pulse, cardiac and family sudden-death history, and screening for psychosis, tics, and substance misuse.
• Recheck pulse, blood pressure, and weight each visit, plotting growth at least every 6 months in children on continuous treatment.
• Use validated ADHD or sleepiness scales such as ADHD-RS-5 or the Epworth scale at baseline and after every dose change.
• Screen for insomnia, evening rebound, and appetite pattern, which usually direct formulation and dosing time more than dose size.
• Check the prescription drug monitoring program at each refill and ask directly about diversion, nonoral use, and early refill requests.

Interactions

• Contraindicated within 14 days of an MAOI, including phenelzine, tranylcypromine, selegiline, and linezolid, because of hypertensive crisis risk.
• Urinary alkalinizers such as sodium bicarbonate and acetazolamide raise levels, and acidifying agents including ascorbic acid lower them.
• CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion, and quinidine raise amphetamine exposure and per the label add serotonin syndrome risk.
• Additive cardiovascular effects with decongestants, thyroid hormone, other stimulants, and SNRIs; avoid stacking stimulants without a clear plan.
• Amphetamines antagonize guanethidine-type antihypertensives and can precipitate arrhythmia when combined with halogenated general anesthetics.

Special populations

• Pregnancy: observational data link amphetamine use to lower birth weight and preterm birth; use only when the benefit clearly outweighs the risk.
• Lactation: dextroamphetamine concentrates in breast milk with a relative infant dose near 2-14 percent, so watch for infant irritability and poor feeding.
• Pediatric: labeled from age 3, but behavioral parent training should precede medication in preschoolers and doses must be weight-appropriate.
• Geriatric: use the lowest effective dose, avoid in uncontrolled hypertension or recent myocardial infarction, and watch for delirium and weight loss.
• Renal impairment: clearance falls with declining eGFR, so cap the dose in severe impairment and avoid use in end-stage renal disease.

Clinical pearls

• Alkaline urine can double amphetamine exposure; ask about bicarbonate, antacids, and acetazolamide.
• One Spansule often replaces twice-daily immediate-release dosing with less midday rebound.
• Xelstrym can leave permanent skin lightening at the site; rotate sites and warn patients up front.