Lisdexamfetamine


Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used as a treatment for attention deficit hyperactivity disorder in both children and adults, and for moderate-to-severe binge eating disorder in adults. A prodrug of dextroamphetamine, lisdexamfetamine is taken by mouth. Its effects generally begin within 90 minutes and last for up to 14 hours.
Common side effects of lisdexamfetamine include loss of appetite, anxiety, diarrhea, trouble sleeping, irritability, and nausea. Rare but serious side effects include mania, sudden cardiac death in those with underlying heart problems, and psychosis. It has a high potential for substance abuse. Serotonin syndrome may occur if used with certain other medications. Its use during pregnancy may result in harm to the fetus, and use during breastfeeding is not recommended by the manufacturer as dextroamphetamine can pass through the breastmilk.
Lisdexamfetamine is an inactive prodrug that is formed by the condensation of L-lysine, a naturally occurring amino acid, and dextroamphetamine. In the body, metabolic action reverses this process to release the active agent, the central nervous system stimulant dextroamphetamine.
Lisdexamfetamine was approved for medical use in the United States in 2007 and in the European Union in 2012. In 2023, it was the 76th most commonly prescribed medication in the United States, with more than 9million prescriptions. It is a Class B controlled substance in the United Kingdom, a Schedule 8 controlled drug in Australia, and a Schedule II controlled substance in the United States.

Uses

Medical

Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder and binge eating disorder. It has similar uses as those of other pharmaceutical amphetamines, such as the treatment of narcolepsy. Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine for ADHD. According to a 2019 systematic review, lisdexamfetamine was the most effective treatment for adult ADHD.

Available forms

Lisdexamfetamine is available as the dimesylate salt in the form of both oral capsules and chewable tablets. A dose of 50 mg of lisdexamfetamine dimesylate is approximately equimolar to a 20 mg dose of dextroamphetamine sulfate or to 15 mg dextroamphetamine free-base in terms of the amount of dextroamphetamine contained. Lisdexamfetamine capsules can be swallowed intact, or they can be opened and mixed into water, yogurt, or applesauce and consumed in that manner.

Contraindications

Pharmaceutical lisdexamfetamine is contraindicated in people with hypersensitivity to amphetamine products or any of the formulation's inactive ingredients. It is also contraindicated in patients who have used a monoamine oxidase inhibitor within the last 14 days. Amphetamine products are contraindicated by the United States Food and Drug Administration in people with a history of drug abuse, heart disease, or severe agitation or anxiety, or in those currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension. However, a European consensus statement on adult ADHD noted that stimulants do not worsen substance misuse in adults with ADHD and comorbid substance use disorder and should not be avoided in these individuals. In any case, the statement noted that immediate-release stimulants should be avoided in those with both ADHD and substance use disorder and that slower-release stimulant formulations like methylphenidate and lisdexamfetamine should be preferred due to their lower misuse potential. Prescribing information approved by the Australian Therapeutic Goods Administration further contraindicates anorexia.

Adverse effects

Products containing lisdexamfetamine have a comparable drug safety profile to those containing amphetamine. The major side effects of lisdexamfetamine in short-term clinical trials have included decreased appetite, insomnia, dry mouth, weight loss, irritability, upper abdominal pain, nausea, vomiting, diarrhea, constipation, increased heart rate, anxiety, dizziness, and feeling jittery. Rates of side effects may vary in adults, adolescents, and children. Rare but serious side effects of lisdexamfetamine may include mania, sudden cardiac death in those with underlying heart problems, stimulant psychosis, and serotonin syndrome.

Interactions

Pharmacology

Mechanism of action

Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound that is responsible for the drug's activity. After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine. The half-life of this conversion is roughly 1 hour. The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times. Studies show a linear relationship between peak plasma concentration of dextroamphetamine and lisdexamfetamine dose up to lisdexamfetamine doses of 250 mg.
The optical isomers of amphetamine, i.e., dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular [monoamine transporter 2] inhibitors that can enter monoamine neurons; this allows them to release monoamine neurotransmitters from their storage sites in the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.
Lisdexamfetamine was developed to provide a long-duration 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 in the bloodstream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. Lisdexamfetamine is a single-enantiomer dextroamphetamine formula similar to Dexedrine but opposed to other amphetamine based pharmaceuticals such as Adderall, which contains both dextroamphetamine and levoamphetamine at a 3:1 ratio, or racemic mixtures like Evekeo and the presently discontinued Benzedrine which are amphetamine salts with a 1:1 enantiomer ratio. Studies conducted show that lisdexamfetamine 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%.

Chemistry

Lisdexamfetamine is a substituted amphetamine with an amide linkage formed by the condensation of dextroamphetamine with the carboxylate group of the essential amino acid L-lysine. The reaction occurs with retention of stereochemistry, so the product lisdexamfetamine exists as a single stereoisomer. There are many possible names for lisdexamfetamine based on IUPAC nomenclature, but it is usually named as or. The condensation reaction occurs with loss of water:
Amine functional groups are vulnerable to oxidation in air and so pharmaceuticals containing them are usually formulated as salts where this moiety has been protonated. This increases stability, water solubility, and, by converting a molecular compound to an ionic compound, increases the melting point and thereby ensures a solid product. In the case of lisdexamfetamine, this is achieved by reacting with two equivalents of methanesulfonic acid to produce the dimesylate salt, a water-soluble powder with a white to off-white color.

Comparison to other formulations

Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. The following table compares the drug to other amphetamine pharmaceuticals.

History

Lisdexamfetamine was developed by Robert Oberlender at New River Pharmaceuticals, under the name NRP104, before being bought by Takeda Pharmaceuticals through its acquisition of Shire Pharmaceuticals, prior to market release. It was developed to create a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells delays its onset of action, regardless of the route of administration.
In February 2007, the US Food and Drug Administration approved lisdexamfetamine for the treatment of ADHD. In August 2009, Health Canada approved the marketing of lisdexamfetamine for prescription use.
In January 2015, lisdexamfetamine was approved by the FDA for the treatment of binge eating disorder in adults.
The FDA gave tentative approval to generic formulations of lisdexamfetamine in 2015. The expiration date for patent protection of lisdexamfetamine in the US was 24 February 2023. The Canadian patent expired 20 years from the filing date of 1 June 2004.
Production quotas for 2016 in the United States were 29,750 kg.

Society and culture

Name

[Image:Elvanse.jpg|thumb|Elvanse Adult capsules 50mg and 70mg laid on the packaging (German)]
Lisdexamfetamine is the International Nonproprietary Name and is a contraction of L-lysine-dextroamphetamine.
As of November 2020, lisdexamfetamine is sold under the following brand names: Aduvanz, Elvanse, Juneve, Samexid, Tyvense, Venvanse, and Vyvanse.

Research

Depression

Amphetamine was used to treat depression starting in the 1930s and has been described as the first antidepressant. In clinical studies in the 1970s and 1980s, psychostimulants, including amphetamine and methylphenidate, were found to transiently improve mood in a majority of people with depression and to increase psychomotor activation in almost all individuals.
Some clinical trials that used lisdexamfetamine as an add-on therapy with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor for treatment-resistant depression indicated that this is no more effective than the use of an SSRI or SNRI alone. Other studies indicated that psychostimulants potentiated antidepressants, and were under-prescribed for treatment-resistant depression. In those studies, patients showed significant improvement in energy, mood, and psychomotor activity. Clinical guidelines advise caution in the use of stimulants for depression and advise them only as second- or third-line adjunctive agents.
In February 2014, Shire announced that two late-stage clinical trials had found that Vyvanse was not an effective treatment for depression, and development for this indication was discontinued. A 2018 meta-analysis of randomized controlled trials of lisdexamfetamine for antidepressant augmentation in people with major depressive disorder—the first to be conducted—found that lisdexamfetamine was not significantly better than placebo in improving Montgomery–Åsberg Depression Rating Scale scores, response rates, or remission rates. However, there was indication of a small effect in improving depressive symptoms that approached trend-level significance. Lisdexamfetamine was well-tolerated in the meta-analysis. The quantity of evidence was limited, with only four trials included. In a subsequent 2022 network meta-analysis, lisdexamfetamine was significantly effective as an antidepressant augmentation for treatment-resistant depression.
Although lisdexamfetamine has shown limited effectiveness in the treatment of depression in clinical trials, a phase II clinical study found that the addition of lisdexamfetamine to an antidepressant improved executive dysfunction in people with mild major depressive disorder but persisting executive dysfunction.