LISDEXAMFETAMINE DIMESYLATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LISDEXAMFETAMINE DIMESYLATE (LISDEXAMFETAMINE DIMESYLATE).
Lisdexamfetamine is a prodrug of dextroamphetamine, which blocks the reuptake of norepinephrine and dopamine from the synaptic cleft and increases their release into the extraneuronal space.
| Metabolism | Lisdexamfetamine is metabolized primarily by enzymatic hydrolysis in the blood to dextroamphetamine and L-lysine. Dextroamphetamine is further metabolized via CYP2D6 to 4-hydroxyamphetamine, which is then glucuronidated or sulfated. |
| Excretion | Primarily renal: approximately 95% of the dose is excreted in urine, with about 70% as intact lisdexamfetamine, 20% as dextroamphetamine and its metabolites (hippuric acid, benzoic acid), and minimal biliary/fecal elimination (<5%). |
| Half-life | Terminal elimination half-life of lisdexamfetamine is approximately 1 hour (prodrug conversion), while dextroamphetamine (active moiety) has a half-life of 10-12 hours in adults. In children, half-life is slightly shorter (9-11 hours). Clinically, once-daily dosing provides symptom control for ADHD. |
| Protein binding | Lisdexamfetamine is 20-30% bound to plasma proteins (primarily albumin). Dextroamphetamine is approximately 20-25% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Lisdexamfetamine: Vd ~ 4.5 L/kg; Dextroamphetamine: Vd ~ 5-6 L/kg. Large Vd indicates extensive tissue distribution, including brain penetration. |
| Bioavailability | Oral bioavailability of lisdexamfetamine is approximately 96% for lisdexamfetamine itself, but the conversion to dextroamphetamine is rate-limited; the AUC of dextroamphetamine is comparable to that of an equimolar dose of immediate-release amphetamine. |
| Onset of Action | After oral administration, onset of clinical effect (improvement in attention) is typically within 0.5 to 1.5 hours for lisdexamfetamine, due to rate-limited conversion to dextroamphetamine. Immediate-release amphetamine salts have onset in 0.5 hours. |
| Duration of Action | Duration of clinical effect is approximately 10-12 hours in adults and 8-10 hours in children for ADHD symptoms. Due to the prodrug design, effects are smoother and less variable compared to immediate-release amphetamine. |
| Molecular Weight | 455.6 |
30–70 mg orally once daily in the morning.
| Dosage form | CAPSULE |
| Renal impairment | eGFR 15–29 mL/min: maximum 50 mg/day. eGFR <15 mL/min or dialysis: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: maximum 50 mg/day. Child-Pugh C: not recommended. |
| Pediatric use | 6–17 years: initial 30 mg orally once daily; may increase by 10 or 20 mg weekly to a maximum of 70 mg/day. |
| Geriatric use | Limited data; initiate at low end of dosing range (30 mg/day) due to potential for increased sensitivity and comorbidities. |
| 1st trimester | Limited human data; risk of major congenital malformations not significantly increased based on small studies. However, stimulant use in pregnancy may increase risk of preeclampsia and preterm birth. Use only if benefit outweighs risk. |
| 2nd trimester | Limited human data; possible risk of fetal growth restriction and preterm birth. Monitor fetal growth. Use only if clearly needed. |
| 3rd trimester | Neonatal withdrawal syndrome reported with late pregnancy use (including irritability, feeding difficulties, poor weight gain). Consider tapering prior to delivery if possible. |
Clinical note
Comprehensive clinical and safety monograph for LISDEXAMFETAMINE DIMESYLATE (LISDEXAMFETAMINE DIMESYLATE).
| Placental transfer | Lisdexamfetamine is a prodrug converted to dextroamphetamine, which is known to cross the placenta. Animal studies show placental transfer; human data limited but expected due to low molecular weight and lipophilicity. |
| Breastfeeding |
■ FDA Black Box Warning
WARNING: ABUSE AND DEPENDENCE. CNS stimulants, including lisdexamfetamine, 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.
| Serious Effects |
Advanced arteriosclerosisSymptomatic cardiovascular diseaseModerate to severe hypertensionHyperthyroidismGlaucomaAgitated statesHistory of drug abuseConcurrent use or within 14 days of MAOIsHypersensitivity to sympathomimetic amines
| Precautions | Serious cardiovascular events: sudden death, stroke, myocardial infarction in adults with pre-existing structural cardiac abnormalities or other serious heart problems; increased blood pressure and heart rate., Psychiatric adverse reactions: exacerbation of pre-existing psychosis, induction of manic/mixed episodes in bipolar disorder, new psychotic or manic symptoms, and aggression., Long-term suppression of growth in pediatric patients, requiring monitoring of height and weight., Potential for peripheral vasculopathy including Raynaud's phenomenon., Seizures: may lower seizure threshold in patients with prior history, EEG abnormalities, or in those with no prior seizures., Serotonin syndrome risk, particularly with concomitant serotonergic drugs. |
Loading safety data…
| Lisdexamfetamine is excreted into breast milk in low concentrations. Relative infant dose estimated at 3-6% of maternal weight-adjusted dose. Monitor infant for irritability, poor feeding, and insomnia. Avoid breastfeeding if maternal doses are high or if infant is premature or has cardiac conditions. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Insufficient human data; animal studies show no teratogenicity at clinically relevant doses. First trimester: no known structural anomalies. Second and third trimesters: risk of fetal growth restriction, preterm delivery, and neonatal withdrawal syndrome (jitteriness, irritability, poor feeding). Use only if maternal benefit outweighs risks. |
| Fetal Monitoring | Maternal: blood pressure, heart rate, weight, and signs of abuse/dependence. Fetal: serial growth ultrasounds (every 4-6 weeks) and nonstress testing in third trimester if growth restriction suspected. Neonatal: monitor for withdrawal symptoms for 48-72 hours after delivery. |
| Fertility Effects | No adequate studies; animal studies show no impaired fertility at clinical doses. Theoretical risk of hypothalamic-pituitary-adrenal axis suppression affecting ovulation. No evidence of irreversible effects. |
| Food/Dietary |
| Avoid high-fat meals as they may increase absorption and peak concentration; take consistently with or without food. Avoid acidic food/drinks (e.g., grapefruit juice, cola) within 1 hour of administration as they may reduce absorption. Avoid alcohol; may increase CNS depression or cardiac effects. |
| Clinical Pearls | Lisdexamfetamine is a prodrug converted to dextroamphetamine; onset is delayed (1-2 hours) compared to immediate-release amphetamines. Avoid concurrent use with MAOIs; risk of hypertensive crisis. Monitor for growth suppression in children; use drug holidays if possible. Abuse potential exists but lower than immediate-release stimulants due to prodrug mechanism. Adjust dose in severe renal impairment (GFR <30 mL/min). |
| Patient Advice | Take exactly as prescribed; do not crush, chew, or open capsule—swallow whole or mix contents with soft food like yogurt. · Avoid taking in the evening or late afternoon to prevent insomnia; typically taken once daily in the morning. · Report any chest pain, palpitations, shortness of breath, or signs of serotonin syndrome (agitation, hallucinations, rapid heart rate). · Do not use within 14 days of MAOIs (e.g., phenelzine, tranylcypromine). · May cause dizziness or blurred vision; avoid driving until you know how the drug affects you. |