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Lisdexamfetamine

PubChem CID
11597698
Structure
Lisdexamfetamine_small.png
Lisdexamfetamine_3D_Structure.png
Molecular Formula
Synonyms
  • Lisdexamfetamine
  • 608137-32-2
  • lisdexamphetamine
  • Lisdexamfetamine [INN]
  • UNII-H645GUL8KJ
Molecular Weight
263.38 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2006-10-26
  • Modify:
    2024-12-28
Description
Lisdexamfetamine is an amino acid amide.
Lisdexamfetamine is a prodrug of [dextroamphetamine], a central nervous system stimulant known as d-amphetamine, covalently attached to the naturally occurring amino acid L-lysine. Lisdexamfetamine is the first chemically formulated prodrug stimulant and was first approved by the FDA in April 2008. It was also approved by Health Canada in February 2009. Lisdexamfetamine works to treat attention deficit hyperactivity disorder and binge eating disorder by blocking dopamine and norepinephrine reuptake and increasing their levels in the extraneuronal space.
Lisdexamfetamine is a Central Nervous System Stimulant. The physiologic effect of lisdexamfetamine is by means of Central Nervous System Stimulation.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Lisdexamfetamine.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C15H25N3O/c1-12(11-13-7-3-2-4-8-13)18-15(19)14(17)9-5-6-10-16/h2-4,7-8,12,14H,5-6,9-11,16-17H2,1H3,(H,18,19)/t12-,14-/m0/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

VOBHXZCDAVEXEY-JSGCOSHPSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C[C@@H](CC1=CC=CC=C1)NC(=O)[C@H](CCCCN)N
Computed by OEChem 2.3.0 (PubChem release 2021.10.14)

2.2 Molecular Formula

C15H25N3O
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 UNII

2.3.3 ChEBI ID

2.3.4 ChEMBL ID

2.3.5 DrugBank ID

2.3.6 DSSTox Substance ID

2.3.7 HMDB ID

2.3.8 KEGG ID

2.3.9 Metabolomics Workbench ID

2.3.10 NCI Thesaurus Code

2.3.11 Nikkaji Number

2.3.12 Pharos Ligand ID

2.3.13 RXCUI

2.3.14 Wikidata

2.3.15 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Dimesylate, Lis-dexamfetamine
  • Dimesylate, Lisdexamfetamine
  • elvanse
  • Lis dexamfetamine Dimesylate
  • lis-dexamfetamine dimesylate
  • lisdexamfetamine
  • lisdexamfetamine dimesylate
  • NRP 104
  • NRP-104
  • NRP104
  • Vyvanse

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
263.38 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
1.2
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
8
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
263.199762429 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
263.199762429 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
81.1Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
19
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
252
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Golden-colored solid from methanol
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1026

3.2.3 Melting Point

191-193
120-122 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1026

3.2.4 Flash Point

9.7 °C; 49.5 °F (closed cup)
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

3.2.5 Solubility

792mg/mL
White to off-white powder. MP 120-122 °C. Solubility in water: 792 mg/mL /Lisdexamfetamine dimethanesulfonate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1026
8.77e-02 g/L

3.2.6 LogP

3.2.7 Stability / Shelf Life

Stable under recommended storage conditions.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

3.2.8 Dissociation Constants

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds
S58 | PSYCHOCANNAB | Synthetic Cannabinoids and Psychoactive Compounds | DOI:10.5281/zenodo.3247723
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Adrenergic Agents; Central Nervous System Stimulants; Dopamine Agents; Sympathomimetics; Wakefulness-Promoting Agents

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 GC-MS

1 of 2
Source of Spectrum
SWG-33-3935-0
Copyright
Copyright © 2020-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Technique
GC/MS
Source of Spectrum
DigiLab GmbH (C) 2024
Copyright
Copyright © 2024 DigiLab GmbH and Wiley-VCH GmbH. All Rights Reserved.
Thumbnail
Thumbnail

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Lisdexamfetamine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients six years and older. It is also indicated to treat moderate to severe binge eating disorder (BED) in adults. It is approved for use in the US and Canada.

7.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Adrenergic Agents; Central Nervous System Stimulants; Dopamine Agents; Sympathomimetics; Wakefulness-Promoting Agents

7.3 FDA National Drug Code Directory

7.4 Drug Labels

Drug and label

7.5 Clinical Trials

7.5.1 ClinicalTrials.gov

7.5.2 EU Clinical Trials Register

7.6 DEA Drug and Chemical Information

7.6.1 DEA Controlled Substances

Non-Proprietary Name
LISDEXAMFETAMINE
DEA Substances Act Schedule
Schedule II

7.7 Therapeutic Uses

Attention Deficit Disorder with Hyperactivity
National Library of Medicine's Medical Subject Headings. Lisdexamfetamine. Online file (MeSH, 2015). Available from, as of November 20, 2015: https://www.nlm.nih.gov/mesh/MBrowser.html
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Lisdexamfetamine is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of September 30, 2015: https://clinicaltrials.gov/search/intervention=nrp+104+OR+lisdexamfetamine
Vyvanse is indicated for the treatment of: Attention Deficit Hyperactivity Disorder (ADHD) and moderate to severe binge eating disorder (BED). /Included in US product label/
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
EXPL THER Attention deficits are often among the most persistent and debilitating impairments resulting from traumatic brain injury (TBI). This study examined the effects of lisdexamfetamine dimesylate (Vyvanse) in treating attention deficits due to moderate-to-severe TBI. It was the first study of lisdexamfetamine dimesylate with this population and, in fact, was the first controlled trial in this area examining a stimulant medication option other than methylphenidate. This was a 12-week, randomized, double-blind, placebo-controlled, cross-over trial. A total of 22 rigorously selected cases were enrolled, 13 of whom completed the trial. They were 16-42 years of age and had newly acquired attention deficits persisting for 6-34 months post-injury. They were assessed on a broad range of neuropsychological and behavioural measures at baseline, 6-weeks and at 12-weeks. Positive treatment effects were found involving selective measures of sustained attention, working memory, response speed stability and endurance and in aspects of executive functioning. No major problems with safety or tolerability were observed. Some moderating treatment effects were found from a broad range of pre-treatment subject characteristics and injury variables examined. Avenues for further research and treatment applications in this area are discussed.
Tramontana MG et al; Brain Inj 28 (11): 1461-72 (2014)
EXPL THER Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment's efficacy in decreasing cocaine consumption is unknown. This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0-0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32-3.2mg/kg/day, i.m.) or d-amphetamine (0.032-0.1mg/kg/hr, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine's efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.
Banks ML et al; Int J Neuropsychopharmacol 18(8) pii: pyv009 (2015).

7.8 Drug Warnings

/BOX WARNING/ CNS stimulants (amphetamines and methylphenidate-containing products), including Vyvanse, 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.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in children and adolescents with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Vyvanse treatment.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
Risk of prematurity, low birth weight, and withdrawal symptoms (e.g., dysphoria, lassitude, agitation) in infants born to dependent women.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2535
Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Other reactions include arrhythmias, hypertension or hypotension, circulatory collapse, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
For more Drug Warnings (Complete) data for Lisdexamfetamine (21 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Once administered, lisdexamfetamine is converted to its active metabolite, dextroamphetamine, which is taken up by the brain. Dextroamphetamine blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.

8.2 MeSH Pharmacological Classification

Central Nervous System Stimulants
A loosely defined group of drugs that tend to increase behavioral alertness, agitation, or excitation. They work by a variety of mechanisms, but usually not by direct excitation of neurons. The many drugs that have such actions as side effects to their main therapeutic use are not included here. (See all compounds classified as Central Nervous System Stimulants.)
Dopamine Uptake Inhibitors
Drugs that block the transport of DOPAMINE into axon terminals or into storage vesicles within terminals. Most of the ADRENERGIC UPTAKE INHIBITORS also inhibit dopamine uptake. (See all compounds classified as Dopamine Uptake Inhibitors.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
H645GUL8KJ
Active Moiety
LISDEXAMFETAMINE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Central Nervous System Stimulant
Pharmacological Classes
Physiologic Effects [PE] - Central Nervous System Stimulation
FDA Pharmacology Summary
Lisdexamfetamine is a Central Nervous System Stimulant. The physiologic effect of lisdexamfetamine is by means of Central Nervous System Stimulation.
2 of 2
Non-Proprietary Name
LISDEXAMFETAMINE
Pharmacological Classes
Central Nervous System Stimulation [PE]; Central Nervous System Stimulant [EPC]

8.4 ATC Code

N - Nervous system

N06 - Psychoanaleptics

N06B - Psychostimulants, agents used for adhd and nootropics

N06BA - Centrally acting sympathomimetics

N06BA12 - Lisdexamfetamine

8.5 Absorption, Distribution and Excretion

Absorption
After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract. Following single-dose oral administration of lisdexamfetamine in pediatric patients with ADHD under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at approximately one hour and 3.5 hours post-dose, respectively. Weight/Dose normalized AUC and Cmax values were the same in pediatric patients as the adults. Food prolongs Tmax by approximately one hour and may decrease the exposure (Cmax and AUC) of dextroamphetamine.
Route of Elimination
Following oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate in six healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine, and only 0.3% recovered in the feces over 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine.
Volume of Distribution
Dextroamphetamine, the active metabolite of lisdexamfetamine, easily crosses the blood-brain barrier.
After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
Following the oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate to 6 healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine and only 0.3% recovered in the feces over a period of 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine. Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non-quantifiable by 8 hours after administration.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
/MILK/ Distributed into milk ... .
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2535

8.6 Metabolism / Metabolites

Lisdexamfetamine dimesylate is hydrolyzed by red blood cells to dextroamphetamine and l-lysine primarily in the blood. Substantial hydrolysis occurs even at low hematocrit levels. Dextroamphetamine can further be metabolized to form other metabolites, such as hippuric acid. Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.
The metabolic route of lisdexamfetamine is unusual because after absorption into the bloodstream it is metabolized by red blood cells to yield d-amphetamine and the natural amino acid, L-lysine, by rate- limited, enzymatic hydrolysis.
Heal DJ et al; J Psychopharmacol 27(6): 479-96 (2013).
Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells. In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamfetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
These studies investigated the absorption and metabolic conversion of lisdexamfetamine dimesylate (LDX), a prodrug stimulant that requires conversion to d-amphetamine for activity. Oral absorption of LDX was assessed in rat portal and jugular blood, and perfusion of LDX into isolated intestinal segments of anesthetized rats was used to assess regional absorption. Carrier-mediated transport of LDX was investigated in Caco-2 cells and Chinese hamster ovary (CHO) cells expressing human peptide transporter-1 (PEPT1). LDX metabolism was studied in rat and human tissue homogenates and human blood fractions. LDX was approximately10-fold higher in portal blood versus systemic blood. LDX and d-amphetamine were detected in blood following perfusion of the rat small intestine but not the colon. Transport of LDX in Caco-2 cells had permeability apparently similar to cephalexin and was reduced with concurrent PEPT1 inhibitor. Affinity for PEPT1 was also demonstrated in PEPT1-transfected CHO cells. LDX metabolism occurred primarily in whole blood (rat and human), only with red blood cells. Slow hydrolysis in liver and kidney homogenates was probably due to residual blood. The carrier-mediated absorption of intact LDX, likely by the high-capacity PEPT1 transporter, and subsequent metabolism to d-amphetamine in a high-capacity system in blood (ie, red blood cells) may contribute to the consistent, reproducible pharmacokinetic profile of LDX.
Pennick M; Neuropsychiatr Dis Treat 6: 317-327 (2010)

8.7 Biological Half-Life

Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non-quantifiable by 8 hours after administration. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in volunteers ages six years and older. The plasma elimination half-life of dextroamphetamine was approximately 8.6 to 9.5 hours in pediatric patients six to 12 years and 10 to 11.3 hours in healthy adults.
The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in studies of lisdexamfetamine dimesylate in volunteers.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad

8.8 Mechanism of Action

Lisdexamfetamine is a prodrug of dextroamphetamine, which is a noncatecholamine sympathomimetic amine with CNS stimulant activity. Dextroamphetamine is a known inhibitor of the dopamine transporter (DAT), noradrenaline transporter (NET) and vesicular monoamine transporter 2 (VMAT2), with a weaker affinity for the serotonin transporter (SERT). It is also a weak monoamine oxidase (MAO) inhibitor. Dextroamphetamine ultimately blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases catecholamine availability in the extracellular space. The exact mode of therapeutic action of lisdexamfetamine in ADHD and BED has not been fully elucidated; however, the clinical effects of lisdexamfetamine are believed to be linked to the pharmacological actions of dextroamphetamine.
Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad

8.9 Human Metabolite Information

8.9.1 Cellular Locations

Membrane

9 Use and Manufacturing

9.1 Uses

EPA CPDat Chemical and Product Categories
The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products, Scientific Data, volume 5, Article number: 180125 (2018), DOI:10.1038/sdata.2018.125
MEDICATION
Attention Deficit Disorder with Hyperactivity
National Library of Medicine's Medical Subject Headings. Lisdexamfetamine. Online file (MeSH, 2015). Available from, as of November 20, 2015: https://www.nlm.nih.gov/mesh/MBrowser.html
Lisdexamfetamine, its salts, isomers, and salts of its isomers (DEA Code Number: 1205) are Schedule II controlled substances.
21 CFR 1308.12(d) (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of October 7, 2015: https://www.ecfr.gov
Schedule II Controlled Substance: (A) The drug or other substance has a high potential for abuse; (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence.
US Department of Justice/Office of Diversion Control; Schedule of Controlled Substances. Available from, as of October 7, 2015: https://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm

9.2 Methods of Manufacturing

Preparation: T. Mickle et al., World Intellectual Property Organization patent 05032474; eidem, USA patent 0505461 (both 2005 to New River Pharm.)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1026

9.3 Formulations / Preparations

Table: Lisdexamfetamine Dimesylate Preparations
Route of Administration
Oral
Dosage Form
Capsules
Strength
20 mg
Brand or Generic Form (Manufacturer)
Vyvanse, C-II (Shire)
Route of Administration
Oral
Dosage Form
Capsules
Strength
30 mg
Brand or Generic Form (Manufacturer)
Vyvanse, C-II (Shire)
Route of Administration
Oral
Dosage Form
Capsules
Strength
40 mg
Brand or Generic Form (Manufacturer)
Vyvanse, C-II (Shire)
Route of Administration
Oral
Dosage Form
Capsules
Strength
50 mg
Brand or Generic Form (Manufacturer)
Vyvanse, C-II (Shire)
Route of Administration
Oral
Dosage Form
Capsules
Strength
60 mg
Brand or Generic Form (Manufacturer)
Vyvanse, C-II (Shire)
Route of Administration
Oral
Dosage Form
Capsules
Strength
70 mg
Brand or Generic Form (Manufacturer)
Vyvanse, C-II (Shire)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2536

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

Pictogram(s)
Flammable
Acute Toxic
Health Hazard
Signal
Danger
GHS Hazard Statements

H225: Highly Flammable liquid and vapor [Danger Flammable liquids]

H301: Toxic if swallowed [Danger Acute toxicity, oral]

H311: Toxic in contact with skin [Danger Acute toxicity, dermal]

H331: Toxic if inhaled [Danger Acute toxicity, inhalation]

H370: Causes damage to organs [Danger Specific target organ toxicity, single exposure]

Precautionary Statement Codes

P210, P233, P240, P241, P242, P243, P260, P261, P262, P264, P270, P271, P280, P301+P316, P302+P352, P303+P361+P353, P304+P340, P308+P316, P316, P321, P330, P361+P364, P370+P378, P403+P233, P403+P235, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

10.2 Safety and Hazard Properties

10.2.1 Explosive Limits and Potential

Upper explosion limit: 36 %(V); Lower explosion limit: 6 %(V)
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

10.3 Fire Fighting

10.3.1 Fire Fighting Procedures

Use water spray to cool unopened containers.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html
Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html
Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

10.4 Accidental Release Measures

10.4.1 Cleanup Methods

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapors accumulating to form explosive concentrations. Vapors can accumulate in low areas. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

10.4.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Burn in a chemical incinerator equipped with an afterburner and scrubber but exert extra care in igniting as this material is highly flammable. Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Contaminated packaging: Dispose of as unused product.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

10.4.3 Preventive Measures

Conditions to avoid: Heat, flames and sparks. Extremes of temperature and direct sunlight.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html
Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapor or mist. Use explosion-proof equipment. Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

10.5 Handling and Storage

10.5.1 Storage Conditions

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Recommended storage temperature -20 degrees C
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

10.6 Exposure Control and Personal Protection

10.6.1 Personal Protective Equipment (PPE)

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU)..
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Complete suit protecting against chemicals, Flame retardant antistatic protective clothing., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html
Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

10.7 Stability and Reactivity

10.7.1 Hazardous Reactivities and Incompatibilities

Incompatible materials: Acids, Oxidizing agents, Alkali metals, Strong oxidizing agents, Strong acids, Acid chlorides, Acid anhydrides, Reducing agents, Strong reducing agents, and Phosphorus halides.
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html
Possibility of hazardous reactions: Vapors may form explosive mixture with air
Sigma-Aldrich; Material Safety Data Sheet for Lisdexamfetamine dimesylate, Product Number: L026, Version 5.3 (Revision Date 08/14/2014). Available from, as of October 30, 2015: https://www.sigmaaldrich.com/safety-center.html

10.8 Regulatory Information

10.8.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including lisdexamfetamine dimesylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Lisdexamfetamine dimesylate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of September 30, 2015: https://www.fda.gov/cder/ob/
Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... (d) Stimulants. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a stimulant effect on the central nervous system: Lisdexamfetamine, its salts, isomers, and salts of its isomers (DEA Code Number: 1205) is included on this list.
21 CFR 1308.12(d) (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of October 7, 2015: https://www.ecfr.gov

11 Toxicity

11.1 Toxicological Information

11.1.1 Toxicity Summary

IDENTIFICATION AND USE: Lisdexamfetamine (trade name: Vynase) is a prescription medication, taken in oral capsules, indicated for the treatment of attention deficit hyperactivity disorder (ADHD) and moderate to severe binge eating disorder. It is listed as a Schedule II controlled substance by the US Drug Enforcement Agency. HUMAN EXPOSURE AND TOXICITY: In a single case report, accidental ingestion of Vynase resulted in symptoms of serotonin syndrome. Adverse events reported in epidemiological studies include acute chorea, agitation, tachycardia, abuse/misuse, decreased appetite, decreased weight, irritability, insomnia, headache, upper abdominal pain, and initial insomnia. Lisdexamfetamine, like many other CNS stimulants, carries a high potential for misuse and chemical dependence, especially in children and adolescents. An additional risk for children and adolescents is temporary growth suppression (in cases where Lisdexamfetamine is administered for more than 12 months). Additionally, it may impair the ability to engage in certain potentially hazardous activities (operating machinery or vehicles), it may exacerbate Tourette's syndrome associated motor and phonic tics, may precipitate mixed or manic episodes in ADHD patients with comorbid bipolar disorder, it may also exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder, and may cause visual disturbances. Lisdexamfetamine may also lower the threshold for seizure activity, regardless of whether or not the patient has a prior history of seizures. Additional risks include increases in blood pressure, tachycardia, sudden death and cardiovascular events (notably in patients who abuse Lisdexamfetamine). Lisdexamfetamine is a prodrug that requires conversion to d-amphetamine (d-AMPH) for bioactivity. The metabolic route of lisdexamfetamine is unusual because after absorption into the bloodstream it is metabolized by red blood cells to yield d-amphetamine and the natural amino acid, L-lysine, by rate- limited, enzymatic hydrolysis. ANIMAL STUDIES: In rodents, high doses of lisdexamfetamine have produced chronic, irreversible nerve damage. In rats, subchronic exposure has produced increased locomotor behavior (hyperlocomotion).

11.1.2 Drug Induced Liver Injury

Compound
lisdexamfetamine
DILI Annotation
Ambiguous DILI-concern
Severity Grade
3
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

11.1.3 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Lisdexamfetamine is a prodrug of dextroamphetamine. In dosages prescribed for medical indications, some evidence indicates that dextroamphetamine might not affect nursing infants adversely. The effect of dextroamphetamine in milk on the neurological development of the infant has not been well studied. It is possible that large dosages of dextroamphetamine might interfere with milk production, especially in women whose lactation is not well established. Therapeutic dosages of amphetamine can be used during nursing with monitoring of the infant for irritability, insomnia, and feeding difficulty. Breastfeeding is generally discouraged in mothers who are actively abusing amphetamines.

◉ Effects in Breastfed Infants

The author of a 1973 newsletter reported a personal communication from the drug manufacturer which stated that of 103 nursing mothers treated with dextroamphetamine (dosage unspecified) for postpartum depression, no infant showed any evidence of stimulation or insomnia.

Four mothers averaging 5.5 months postpartum (range 3.3 to 10 months) were taking dextroamphetamine in an average dosage of 18 mg daily (range 15 to 45 mg daily in 2 to 4 divided doses) for attention deficit hyperactivity disorder. Their infants had been breastfed (extent not stated) since birth. The infants all had weights between the 10th and 75th percentiles for their age, normal progress, and no adverse effects according to their pediatricians. Denver developmental ages for 2 of the infants were 100% and 117% of normal.

In a prospective study, lactating women taking either lisdexamfetamine (Vyvanse®, Shire; n = 6) or mixed racemic amphetamine salts (n = 7) for attention deficit hyperactivity disorder were followed by telephone for several months to 5 years. Seven had also taken one of the drugs during pregnancy. At an average age of follow-up of 18 months, 5 of their 13 infants (5 fully breastfed) had experienced an adverse reaction possibly related to amphetamine in milk; 1 infant had somnolence, 3 had crying or restlessness, and 4 had colic or constipation. Four of these 5 were only partially breastfed from birth onward. All infants had normal Denver developmental scale and pediatric quality of life scores. The authors concluded that therapeutic used of amphetamines is likely compatible with breastfeeding.

◉ Effects on Lactation and Breastmilk

In 2 papers by the same authors, 20 women with normal physiologic hyperprolactinemia were studied on days 2 or 3 postpartum. Eight received dextroamphetamine 7.5 mg intravenously, 6 received 15 mg intravenously and 6 who served as controls received intravenous saline. The 7.5 mg dose reduced serum prolactin by 25 to 32% compared to control, but the difference was not statistically significant. The 15 mg dose significantly decreased serum prolactin by 30 to 37% at times after the infusion. No assessment of milk production was presented. The authors also quoted data from another study showing that a 20 mg oral dose of dextroamphetamine produced a sustained suppression of serum prolactin by 40% in postpartum women. The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed.

In a retrospective Australian study, mothers who used intravenous amphetamines during pregnancy were less likely to be breastfeeding their newborn infants at discharge than mothers who abused other drugs (27% vs 42%). The cause of this difference was not determined.

11.1.4 Interactions

Amphetamines may antagonize the hypotensive effects of antihypertensives.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2536
Amphetamines may counteract the sedative effects of antihistamines.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2536
Enhanced activity of tricyclic antidepressants; desipramine or protriptyline cause striking and sustained increases in the concentration of dextroamphetamine in the brain; cardiovascular effects can be potentiated.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2536
Decreased urinary excretion of amphetamines with concomitant use of alkalinizing agents (carbonic anhydrase inhibitors, sodium bicarbonate).
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2536
For more Interactions (Complete) data for Lisdexamfetamine (15 total), please visit the HSDB record page.

11.1.5 Antidote and Emergency Treatment

A 6-year-old girl displayed symptoms of serotonin syndrome after accidental ingestion of Vyvanse (lisdexamfetamine dimesylate). Dexmedetomidine was administered because of persistent neuromuscular hyperactivity and severe agitation despite initial therapy with benzodiazepines. Some children show a paradoxical reaction to benzodiazepines, and dexmedetomidine has a possible role in the treatment of serotonin syndrome.
Akingbola OA et al; Am J Crit Care 21(6): 456-9 (2012).
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1
For more Antidote and Emergency Treatment (Complete) data for Lisdexamfetamine (8 total), please visit the HSDB record page.

11.1.6 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in children and adolescents with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Vyvanse treatment.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
/SIGNS AND SYMPTOMS/ Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Other reactions include arrhythmias, hypertension or hypotension, circulatory collapse, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma. /Amphetamine/
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
/CASE REPORTS/ Amphetamine-derived medications are being prescribed with increasing frequency to younger pediatric patients to treat attention deficit hyperactivity disorder. Although choreiform movements were reported in adults with amphetamine abuse and in those under therapeutic treatment for attention deficit hyperactivity disorder, previous literature concerning the pediatric population is sparse. We describe two children who developed chorea after ingesting amphetamine-derived medications prescribed to treat attention deficit hyperactivity disorder. Patient 1, a 10-year-old boy, accidently received an extra dose of lisdexamfetamine dimesylate the night before the onset of acute chorea involving his arms, legs, and trunk. Patient 2, an 8-month-old boy, accidentally ingested his stepbrother's mixed amphetamine salts (Adderall XR) and developed acute chorea. Benzodiazepines, diphenhydramine, benztropine, and opioids did not suppress the chorea in either case. The 10-year-old received haloperidol, which significantly improved his abnormal findings, and he returned to baseline in approximately 48 hours. The 8-month-old was observed in the pediatric intensive care unit, and his signs resolved by 72 hours. Our cases demonstrate that choreiform movements of sustained duration can occur in children with acute supratherapeutic ingestions of amphetamine-derived medications.
Ford JB et al; Pediatr Neurol 47(3): 216-8 (2012).
/EPIDEMIOLOGY STUDIES/ Lisdexamfetamine dimesylate (LDX) is the first prodrug stimulant and is indicated for the treatment of attention-deficit/hyperactivity disorder. A single-center, double-blind, randomized, placebo-controlled, 6-period crossover study evaluated the abuse potential of single oral doses of 50, 100 (equivalent to 40 mg d-amphetamine), and 150 mg LDX, 40 mg d-amphetamine and 200 mg diethylpropion in 36 individuals with a history of stimulant abuse. On the primary abuse liability measure, maximum change of the Drug Rating Questionnaire-Subject Liking Scale compared with placebo, d-amphetamine and diethylpropion showed significant differences of 4.5 and 4.0 units, respectively (P < 0.001 for both vs placebo). LDX, administered at 50, 100 and 150 mg, showed nonsignificant differences of 2.0 and 2.1 units, respectively, at the two lower doses but a significant (P < 0.001 vs placebo) difference of 6.1 units at the highest dose. Subjects significantly favored d-amphetamine 40 mg versus LDX 100 mg (2.4 units difference; P < 0.05). There was no significant difference in liking scores between d-amphetamine 40 mg and LDX 150 mg. Drug Rating Questionnaire-Subject Feel-Drug-Effect score was significantly lower for 100 mg LDX than for 40 mg d-amphetamine. There were no statistically significant differences between LDX and diethylpropion hydrochloride, a Schedule IV amphetamine-like stimulant, on abuse-related liking scores. Cardiovascular responses of LDX and d-amphetamine were similar at equivalent doses. In conclusion, at an equivalent amount of amphetamine base taken orally, LDX 100 mg had attenuated responses on measures of abuse liability compared with immediate-release d-amphetamine 40 mg. Abuse-related liking scores of LDX at a dose corresponding to a 50% higher amphetamine base (LDX 150 mg) were similar to d-amphetamine 40 mg.
Jasinski DR et al; J Psychopharmacol 23 (4): 419-27 (2009)
For more Human Toxicity Excerpts (Complete) data for Lisdexamfetamine (10 total), please visit the HSDB record page.

11.1.7 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ Acute administration of high doses of amphetamine (d- or d,l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown. /d-, l- amphetamine/
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Lisdexamfetamine dimesylate (LDX) is a prodrug that requires conversion to d-amphetamine (d-AMPH) for bioactivity. Treatment with d-AMPH induces hyperlocomotion and is regarded as a putative animal model of bipolar mania. Therefore, we sought to determine the behavioral and oxidative stress alterations induced by sub-chronic LDX administration as well as their reversal and prevention by lithium in rats. A significant increment in locomotor behavior was induced by LDX (10 and 30 mg/kg). To determine Li effects against LDX-induced alterations, in the reversal protocol rats received LDX (10 or 30 mg/kg) or saline for 14 days. Between days 8 and 14 animals received Li (47.5 mg/kg, i.p.) or saline. In the prevention paradigm, rats were pretreated with Li or saline prior to LDX administration. Glutathione (GSH) levels and lipid peroxidation was determined in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) of rats. Lithium prevented LDX-induced hyperlocomotion at the doses of 10 and 30 mg/kg, but only reversed LDX-induced hyperlocomotion at dose of 10mg/kg. In addition, both doses of LDX decreased GSH content (in ST and PFC), while Li was able to reverse and prevent these alterations mainly in the PFC. LDX (10 and 30 mg/kg) increased lipid peroxidation which was reversed and prevented by Li. In conclusion, LDX-induced hyperlocomotion along with associated increments in oxidative stress show promise as an alternative animal model of mania.
Macedo DS et al; Prog Neuropsychopharmacol Biol Psychiatry 43: 230-7 (2013).
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenicity was found in studies in which d-, l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. /d-,l- amphetamine/
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Lisdexamfetamine dimesylate had no apparent effects on embryofetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 40 and 120 mg/kg/day, respectively. These doses are approximately 4 and 27 times, respectively, the maximum recommended human dose of 70 mg/day given to adolescents, on a mg/sq m body surface area basis.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
For more Non-Human Toxicity Excerpts (Complete) data for Lisdexamfetamine (8 total), please visit the HSDB record page.

11.1.8 Populations at Special Risk

Sudden death has been reported in children and adolescents with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Vyvanse treatment.
NIH; DailyMed. Current Medication Information for Vyvanse (Lisdexamfetamine Dimesylate) Capsule (Updated: April 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad
Contraindicated in patients with advanced arteriosclerosis, cardiovascular disease, moderate to severe hypertension, hyperthyroidism, hypersensitivity or idiosyncrasy to sympathomimetic amines, glaucoma, or a history of substance abuse. Not to be used in agitated patients.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2535
Possible lowering of seizure threshold in patients with history of seizures, in those with prior EEG abnormalities but no history of seizures, and, very rarely, in those without history of seizures and with no prior evidence of EEG abnormalities.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2535
May exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2535
May precipitate mixed or manic episodes in ADHD patients with comorbid bipolar disorder.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2535

11.2 Ecological Information

11.2.1 Environmental Fate / Exposure Summary

Lisdexamfetamine's production and administration as a medication may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 1.3X10-7 mm Hg at 25 °C indicates lisdexamfetamine will exist in both the vapor and particulate phases the particulate phase in the atmosphere. Vapor-phase lisdexamfetamine will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 1 hr. Particulate-phase lisdexamfetamine will be removed from the atmosphere by wet and dry deposition. Lisdexamfetamine contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, lisdexamfetamine is expected to have slight mobility based upon an estimated Koc of 4900. The estimated pKa1, pKa2 and pKa3 of lisdexamfetamine are 8.43, 10.21 and 15.89, respectively, indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.3X10-15 atm-cu m/mole. Lisdexamfetamine is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data in soil or water were not available. If released into water, lisdexamfetamine is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces iis not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is expected to be an important environmental fate process since this compound contains functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to lisdexamfetamine may occur through inhalation and dermal contact with this compound at workplaces where lisdexamfetamine is produced or used. The general public is not likely to be exposed to lisdexamfetamine unless by direct medical treatment. (SRC)

11.2.2 Artificial Pollution Sources

Lisdexamfetamine's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1026 (2013)

11.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 4900(SRC), determined from a structure estimation method(2), indicates that lisdexamfetamine is expected to have slight mobility in soil(SRC). The estimated pKa1, pKa2 and pKa3 of lisdexamfetamine are 8.43, 10.21 and 15.89(3), respectively, indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of lisdexamfetamine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.3X10-15 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Lisdexamfetamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Royal Soc Chem; ChemSpider. Lisdexamfetamine. (608137-32-2). Available from, as of Oct 19, 2015: https://www.chemspider.com/Search.aspx
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 4900(SRC), determined from a structure estimation method(2), indicates that lisdexamfetamine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.3X10-15 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 1.27(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2015).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(5) Franke C et al; Chemosphere 29: 1501-14 (1994)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), lisdexamfetamine, which has an estimated vapor pressure of 1.3X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase lisdexamfetamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1 hr(SRC), calculated from its rate constant of 9.8X10-11 cu cm/molecule-sec at 25 °C(SRC). Particulate-phase lisdexamfetamine may be removed from the air by wet and dry deposition(SRC). Lisdexamfetamine contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

11.2.4 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of lisdexamfetamine with photochemically-produced hydroxyl radicals has been estimated as 9.8X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about one hour at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Lisdexamfetamine is expected to undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(2). Lisdexamfetamine contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

11.2.5 Environmental Bioconcentration

An estimated BCF of 3 was calculated in fish for lisdexamfetamine(SRC), using an estimated log Kow of 1.27(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 19, 2016: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm/
(2) Franke C et al; Chemosphere 29: 1501-14 (1994)

11.2.6 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of lisdexamfetamine can be estimated to be 4900(SRC). According to a classification scheme(2), this estimated Koc value suggests that lisdexamfetamine is expected to have slight mobility in soil. The estimated pKa1, pKa2 and pKa3 of lisdexamfetamine are 8.43, 10.21 and 15.89(3), respectively, indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) Royal Soc Chem; ChemSpider. Lisdexamfetamine. (608137-32-2). Available from, as of Oct 19, 2015: https://www.chemspider.com/Search.aspx
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

11.2.7 Volatilization from Water / Soil

The Henry's Law constant for lisdexamfetamine is estimated as 2.X10-15 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that lisdexamfetamine is expected to be essentially nonvolatile from water and moist soil surfaces(2). Lisdexamfetamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-17 mm Hg(SRC), determined from a fragment constant method(3).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

11.2.8 Environmental Water Concentrations

While data specific to lisdexamfetamine were not located(SRC, 2015), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are, therefore, discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).
(1) Heberer T; Tox Lett 131: 5-17 (2002)
(2) Koplin DW et al; Environ Sci Toxicol 36: 1202-211 (2002)

11.2.9 Probable Routes of Human Exposure

Occupational exposure to lisdexamfetamine may occur through inhalation and dermal contact with this compound at workplaces where lisdexamfetamine is produced or used. The general public is not likely to be exposed to lisdexamfetamine unless by direct medical treatment. (SRC)

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Chemical Co-Occurrences in Literature

13.5 Chemical-Gene Co-Occurrences in Literature

13.6 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 Chemical Co-Occurrences in Patents

14.4 Chemical-Disease Co-Occurrences in Patents

14.5 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Chemical-Target Interactions

15.2 Drug-Drug Interactions

15.3 Drug-Food Interactions

  • Avoid antacids. Urinary excretion of lisdexamfetamine is elevated when the urine is more acidic. Antacids like sodium bicarbonate alkalinize the urine; therefore, they may reduce lisdexamfetamine elimination.
  • Limit foods and supplements high in vitamin C. Urinary excretion of lisdexamfetamine is elevated when the urine is more acidic. Vitamin C acidifies the urine and, therefore, may increase lisdexamfetamine elimination.
  • Take with or without food. Food prolongs Tmax by approximately one hour, but does not significantly affect drug exposure.

16 Biological Test Results

16.1 BioAssay Results

17 Classification

17.1 MeSH Tree

17.2 NCI Thesaurus Tree

17.3 ChEBI Ontology

17.4 KEGG: ATC

17.5 KEGG: Target-based Classification of Drugs

17.6 WHO ATC Classification System

17.7 FDA Pharm Classes

17.8 ChemIDplus

17.9 EPA CPDat Classification

17.10 NORMAN Suspect List Exchange Classification

17.11 EPA DSSTox Classification

17.12 MolGenie Organic Chemistry Ontology

18 Information Sources

  1. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
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  3. DrugBank
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  5. FDA Global Substance Registration System (GSRS)
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  6. Hazardous Substances Data Bank (HSDB)
  7. Human Metabolome Database (HMDB)
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  8. ChEBI
  9. FDA Pharm Classes
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  12. ChEMBL
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    http://www.ebi.ac.uk/Information/termsofuse.html
  13. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  14. DailyMed
  15. Drug Induced Liver Injury Rank (DILIrank) Dataset
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  16. Therapeutic Target Database (TTD)
  17. Drugs and Lactation Database (LactMed)
  18. EPA Chemical and Products Database (CPDat)
  19. EU Clinical Trials Register
  20. National Drug Code (NDC) Directory
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  21. Japan Chemical Substance Dictionary (Nikkaji)
  22. KEGG
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    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  23. Metabolomics Workbench
  24. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  25. NORMAN Suspect List Exchange
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    https://creativecommons.org/licenses/by/4.0/
    LISDEXAMFETAMINE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  26. Pharos
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    https://pharos.nih.gov/about
  27. SpectraBase
  28. Springer Nature
  29. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    https://www.nlm.nih.gov/copyright.html
    Central Nervous System Stimulants
    https://www.ncbi.nlm.nih.gov/mesh/68000697
  33. PubChem
  34. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  35. PATENTSCOPE (WIPO)
  36. NCBI
CONTENTS