Lisdexamfetamine

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Lisdexamfetamine
Lisdexamfetamine-Structural Formula V.1.svg
Lisdexamfetamine.gif
Systematic (IUPAC) name
(2S)-2,6-Diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Clinical data
Trade names Tyvense, Elvanse, Venvanse, Vyvanse
AHFS/Drugs.com monograph
MedlinePlus a607047
Licence data US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status Controlled (S8) (AU) Schedule I (CA) POM (UK) Schedule II (US)
Routes Oral
Pharmacokinetic data
Bioavailability 28%
Metabolism Gastro-intestinal (initial); Hepatic (extensively CYP2D6) after conversion to dextroamphetamine
Half-life < 1 hour (prodrug molecule), 10-13 hours (dextroamphetamine)
Excretion Renal: ~2%
Identifiers
CAS number 608137-32-2 YesY
ATC code N06BA12
PubChem CID 11597698
DrugBank DB01255
ChemSpider 9772458 YesY
UNII H645GUL8KJ YesY
ChEMBL CHEMBL1201222 N
Synonyms (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide

(2S)-2,6-Bis(azanyl)-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Chemical data
Formula C15H25N3O 
Mol. mass 263.378 g/mol
 N (what is this?)  (verify)
30mg Vyvanse capsules

Lisdexamfetamine dimesylate (L-lysine-dextroamphetamine dimesylate) is a psychostimulant prodrug of the phenethylamine and amphetamine chemical classes. Its molecular structure consists of dextroamphetamine coupled with the essential amino acid L-lysine. Lisdexamfetamine itself is inactive and acts as a prodrug to dextroamphetamine upon cleavage of the lysine portion of the molecule.

Lisdexamfetamine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children six to twelve years and in adults as a part of a treatment program that may include other measures (i.e., psychological, educational, social). The safety and the efficacy of lisdexamfetamine dimesylate in people three to five years old have not been established.[1]

Lisdexamfetamine is also being investigated for possible treatment of major depressive disorder, cognitive impairment associated with schizophrenia, excessive daytime sleepiness, and binge eating disorder.[2]

Medical uses[edit]

Lisdexamfetamine is used primarily, in addition to other treatment, for attention deficit hyperactivity disorder (ADHD).[3]

Pregnancy[edit]

Lisdexamfetamine is a pregnancy category C drug. No adequate studies have been performed to test the use of Vyvanse during pregnancy. It is known that amphetamine use during pregnancy can lead to adverse outcomes including preterm delivery and low birth weight.[4] Animal studies have shown that in-utero exposure to amphetamines can lead to behavioral effects such as learning and memory deficits, altered locomotor activity, and changes in sexual function.[5]

Breast feeding[edit]

Amphetamines are able to pass from the bloodstream into human milk. The long term effects of amphetamine exposure from breastfeeding are unknown.

Geriatrics[edit]

Individuals over the age of 65 were not commonly tested in clinical trials of Lisdexamfetamine. Therefore, there is insufficient data to determine how older individuals respond. People over the age of 65 should start on the low end of dosing schedules due to the prevalence of decreased hepatic function, decreased renal function, and comorbidities in this population.[5]

Side effects[edit]

Psychosis[edit]

Abuse of amphetamines can result in a stimulant psychosis which may present with a variety of symptoms (e.g., paranoia, hallucinations, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine induced psychosis[6] states that about 5-15% of users fail to recover completely.[7] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[6]

Although rare, amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[8]

Most common[edit]

[5]

Severe reactions[edit]

[5]

  • Abuse/dependence
  • Cardiovascular events including sudden death, stroke, and heart attack
  • Hypertension
  • Tachycardia
  • Growth suppression in the pediatric population
  • Peripheral vasculopathy

Contraindications[edit]

Vyvanse is contraindicated in patients with hypersensitivity to amphetamine products and can cause anaphylaxis, angioedema, urticaria, and Stevens-Johnson syndrome. It is also contraindicated in in patients who have ingested medications of the monoamine oxidase inhibitors class (MAOIs)within the last 14 days.[5]

Drug interactions[edit]

Acidifying Agents: Drugs that acidify the urine, such as ascorbic acid, increase urinary excretion of amphetamines thus decreasing the half-life time of Vyvanse in the body.[5]

Alkalinizing Agents: Drugs that alkalinize the urine, such as sodium bicarbonate, decrease urinary excretion of amphetamines thus increasing the half-life time of Vyvanse in the body.[5]

Monoamine Oxidase Inhibitors: Concomitant use of MAOIs and central nervous system stimulants such as Vyvanse can cause hypertensize crisis.[5]

Pharmacology[edit]

Lisdexamfetamine is a therapeutically inactive prodrug molecule that is converted in the body to the active component dextroamphetamine, of the amphetamine class. After oral ingestion, lisdexamfetamine is broken down by enzymes to form L-lysine, a naturally occurring essential amino acid, and active dextroamphetamine, which is responsible for the drug’s activity. The conversion of LDX to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times.[9]

Amphetamines are noncatecholamine, sympathomimetic amines that cause the release of catecholamines (primarily dopamine and norepinephrine) from their storage sites in the presynaptic nerve terminals.[10] Amphetamines are also known to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and therefore increase their availability into the extraneuronal space.[11] Although the precise mechanism of action by which amphetamines improve the symptoms of ADHD remains unknown, it is thought that amphetamines decrease ADHD symptoms due to their effects on the central nervous system.

Lisdexamphetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to obtain dextroamphetamine from LDX.[9] As opposed to Adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamic salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.[12][13] Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.[9]

History[edit]

Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Shire Pharmaceuticals shortly before lisdexamfetamine began being marketed.

It was developed for the intention of creating a longer-lasting and less-easily-abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells increases its duration of action, regardless of the route of ingestion.[14] The drug lisdexamfetamine dimesylate is the first prodrug of its kind.

On April 23, 2008, Vyvanse received FDA approval for the adult population.[15] In a randomized, double-blind, four-week phase III trial in adult patients with ADHD, dosages of 30, 50 or 70 mg/day of oral lisdexamfetamine caused a significantly greater improvement in ADHD-Rating Scale total score than placebo.[16]

On February 19, 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.[17]

On February 8, 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD.[18]

In February 2014, Shire announced that two late-stage clinical trials had shown that Vyvanse was not an effective treatment for depression.[19]

Trade names[edit]

Lisdexamfetamine is sold as Tyvense (IE), Elvanse (UK), Venvanse (BR), Vyvanse (CA, US))

References[edit]

  1. ^ "Lisdexamfetamine dimesylate (generic)." Brown University Psychopharmacology Update 19.7 (2008): 1-2. Academic Search Premier. EBSCO. Web. 12 September 2010.
  2. ^ http://www.shire.com/shireplc/en/rd/pipeline
  3. ^ "Lisdexamfetamine Dimesylate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  4. ^ Oei, JL; et al (Oct 2012). "Amphetamines, the pregnant woman and her children: a review". The Journal of Perinatology 32 (10): 737–747. PMID 22652562. 
  5. ^ a b c d e f g h "Vyvanse Drug Insert". Shire. Retrieved 19 April 2014. 
  6. ^ a b Shoptaw SJ, Kao U, Ling W (2009). "Treatment for amphetamine psychosis (Review)". Cochrane Database of Systematic Reviews (1). 
  7. ^ Hofmann FG. A handbook on drug and alcohol abuse: the biomedical aspects. 2nd Edition. New York: Oxford University Press, 1983.
  8. ^ Berman, SM.; Kuczenski, R.; McCracken, JT.; London, ED. (Feb 2009). "Potential adverse effects of amphetamine treatment on brain and behavior: a review.". Mol Psychiatry 14 (2): 123–42. doi:10.1038/mp.2008.90. PMC 2670101. PMID 18698321. 
  9. ^ a b c Jasinski, DR and S Krishnan. "Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse." Journal of Psychopharmacology 23, no. 4 (2009) 419-427. doi:10.1177/0269881109103113 PMID 19329547.
  10. ^ "Lisdexamphetamine". Lexicomp. Retrieved 19 April 2014. 
  11. ^ Katherine A. Lyseng-Williamson. "Lisdexamfetamine dimesylate: a guide to its use in attention-deficit hyperactivity disorder." Drugs & Therapy Perspectives 26, no. 10 (2010): 1-5.
  12. ^ Identification. "Lisdexamfetamine". Drugbank. Retrieved 13 October 2013. 
  13. ^ "Adderall XR Prescribing Information". United States Food and Drug Administration. pp. 1–18. Retrieved 7 October 2013. 
  14. ^ Lisdexamfetamine Dimesylate: A Prodrug Stimulant for the Treatment of ADHD in Children and Adults
  15. ^ FDA Adult Approval of Vyvanse - FDA Label and Approval History
  16. ^ Weber J, Siddiqui, MA. [1].CNSDrugs 2009; 23(5): 419-425. doi:10.2165/00023210-200923050-00005.
  17. ^ Health Canada Notice of Compliance - Vyvanse. February 19, 2009, retrieved on March 9, 2009.
  18. ^ [2]. February 8, 2012, retrieved on February 9, 2012.
  19. ^ Hirschler, Ben (7 February 2014). "UPDATE 2-Shire scraps Vyvanse for depression after failed trials". Reuters. Retrieved 13 February 2014.