Introduction
Lisdexamfetamine dimesylate is a central nervous system (CNS) stimulant prodrug approved by the FDA in 2007. It is classified as a Schedule II controlled substance due to its high potential for abuse and dependence. Lisdexamfetamine is a therapeutically inactive prodrug that is converted to dextroamphetamine, the active moiety, following oral administration.
Mechanism of Action
Lisdexamfetamine itself is pharmacologically inactive. Following oral ingestion, it is hydrolyzed in the blood primarily by red blood cells to L-lysine and dextroamphetamine. Dextroamphetamine exerts its therapeutic effects primarily by increasing extracellular levels of dopamine and norepinephrine in the CNS through multiple mechanisms:
- Facilitating release of catecholamines from nerve terminals
- Blocking reuptake of dopamine and norepinephrine transporters
- Weak inhibition of monoamine oxidase
The prodrug design results in a slower onset of action and potentially reduced abuse liability compared to immediate-release amphetamine formulations.
Indications
FDA-approved indications:
- Attention-Deficit/Hyperactivity Disorder (ADHD) in patients 6 years and older
- Moderate to severe Binge Eating Disorder (BED) in adults
Off-label uses (require careful risk-benefit assessment):
- Treatment-resistant depression (as adjunctive therapy)
- Narcolepsy
- Cognitive enhancement in certain neurological conditions
Dosage and Administration
ADHD:- Initial dose: 30 mg once daily in morning
- Titration: May increase by 10-20 mg weekly
- Maximum dose: 70 mg/day (children) or 70 mg/day (adults)
- Initial dose: 30 mg once daily
- Titration: May increase by 20 mg weekly
- Maximum dose: 70 mg/day
- Renal impairment: Use caution; consider reduced dosing
- Hepatic impairment: Use caution; no specific dosing recommendations
- Geriatric patients: Initiate at lower doses
- Pediatric patients: Dosing based on weight for children under 6 years
Pharmacokinetics
Absorption: Rapidly absorbed from GI tract; peak concentrations of dextroamphetamine occur approximately 3.5 hours post-dose Distribution: Volume of distribution: ~3-4 L/kg; protein binding: 15-40% Metabolism: Hydrolyzed by red blood cells to dextroamphetamine and L-lysine; not significantly metabolized by CYP enzymes Elimination: Renal excretion (96%); elimination half-life of dextroamphetamine: 10-13 hours Food effects: No significant effect on absorptionContraindications
- Known hypersensitivity to amphetamine products
- Advanced arteriosclerosis
- Symptomatic cardiovascular disease
- Moderate to severe hypertension
- Hyperthyroidism
- Glaucoma
- Agitated states
- History of drug abuse
- During or within 14 days following MAOI therapy
Warnings and Precautions
Black Box Warnings:- High potential for abuse and dependence
- Serious cardiovascular risks including sudden death, stroke, and myocardial infarction
- Psychiatric adverse reactions (psychosis, mania, aggression)
- Growth suppression in pediatric patients
- Peripheral vasculopathy including Raynaud's phenomenon
- Serotonin syndrome risk (particularly with other serotonergic drugs)
- Motor and verbal tics exacerbation or onset
Drug Interactions
Contraindicated combinations:- MAO inhibitors (risk of hypertensive crisis)
- Alkalinizing agents (sodium bicarbonate, acetazolamide): Increase amphetamine concentrations
- Acidifying agents (ammonium chloride, ascorbic acid): Decrease amphetamine concentrations
- SSRIs/SNRIs: Increased risk of serotonin syndrome
- Antihypertensive agents: Reduced efficacy
- CYP2D6 inhibitors: May increase amphetamine exposure
Adverse Effects
Common (≥5%):- Insomnia (19-27%)
- Dry mouth (12-26%)
- Decreased appetite (27-39%)
- Headache (12-19%)
- Irritability (10-12%)
- Nausea (6-12%)
- Cardiovascular events (MI, stroke, sudden death)
- Psychiatric events (psychosis, mania)
- Peripheral vasculopathy
- Serotonin syndrome
- Priapism
Monitoring Parameters
Baseline:- Comprehensive cardiovascular assessment
- Blood pressure and heart rate
- Height and weight (pediatric patients)
- Psychiatric history assessment
- Substance use history
- Blood pressure and heart rate at each dose adjustment and periodically during treatment
- Height and weight growth charts in pediatric patients (every 3-6 months)
- Monitoring for signs of misuse, abuse, or diversion
- Psychiatric symptom assessment
- Evaluation for development of peripheral vasculopathy
Patient Education
- Take medication early in day to prevent insomnia
- Do not crush, chew, or break capsules
- Report any chest pain, shortness of breath, or fainting
- Monitor for new or worsening psychiatric symptoms
- Understand risk of dependence and abuse potential
- Avoid alcohol during treatment
- Inform all healthcare providers about lisdexamfetamine use
- Store securely to prevent misuse by others
- Do not suddenly stop medication without medical supervision
References
1. FDA Prescribing Information: Vyvanse (lisdexamfetamine dimesylate) 2. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13th Edition 3. Stahl SM. Stahl's Essential Psychopharmacology, 4th Edition 4. Biederman J, et al. Efficacy and safety of lisdexamfetamine dimesylate in children with ADHD. J Am Acad Child Adolesc Psychiatry. 2007 5. McElroy SL, et al. Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder. JAMA Psychiatry. 2015 6. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Lisdexamfetamine monograph 7. UpToDate: Lisdexamfetamine drug information 8. American Psychiatric Association: Practice Guideline for the Treatment of Patients with ADHD