Lisdexamfetamine - An Up-To-Date Review

Overview

Lisdexamfetamine is a CNS (central nervous system) stimulant used to treat ADHD (attention-deficit hyperactivity disorder) in children, adults, and adolescents. It became the first medication approved by the US FDA (United States Food and Drug Administration) to treat ADHD in adults. Lisdexamfetamine was approved by the FDA for pediatric use in February 2007 and for adult use in April 2008. It widens attention span, minimizes restlessness, and is usually prescribed as an adjunct in the therapeutic management of ADHD. Lisdexamfetamine dimesylate is the active ingredient in Lisdexamfetamine. This medication is taken orally and is not affected by gastric pH. It is converted into a naturally occurring amino acid on absorption, showing reduced abuse potential.

Drug Group

Lisdexamfetamine belongs to a novel CNS stimulant class that is a prodrug to amphetamines. It is a psychostimulant drug as it causes the release of neurotransmitters such as dopamine and norepinephrine from the neuronal endings. These neurotransmitters contribute to alertness and increased concentration. Lisdexamfetamine is also a dopamine uptake inhibitor since it prevents dopamine transport back into the neuronal cells.

Dosage Forms and Available Strengths

Lisdexamfetamine is available as oral capsules and chewable tablets in various dosing strengths.

• Oral Capsule - 10 mg (milligram), 20 mg, 30 mg, 40 mg , 50 mg, 60 mg, and 70 mg.

• Oral Chewable Tablets - 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg.

For Patients

What Is ADHD?

ADHD is a spectrum of neurodevelopmental disorders characterized by social, behavioral, and emotional problems usually evident in various forms of severity (very mild to extremely severe). It is widely seen in childhood but also manifests in adolescents and adults. Some of the common clinical manifestations of ADHD are as follows:

• Inattention or decreased span of attention.

• Extremely restless.

• Overactive or hyperactive.

• Impulsive.

• Easily distracted.

• Poor relationships with peers and family.

• Unpredictable mood changes.

The therapeutic guidelines and regimens for ADHD involve a combination of behavioral, psychoeducational, and pharmacological interventions. Though amphetamines and related stimulants effectively correct ADHD symptoms, they carry a high risk of abuse. Long-acting preparations or formulations, such as Lisdexamfetamine, are found to decrease abuse potential with enhanced therapeutic outcomes.

What Is Lisdexamfetamine Used For?

Lisdexamfetamine is commonly prescribed to treat the following clinical conditions:

• Attention deficit hyperactivity disorder (ADHD) in adults, children, and adolescents.

• Binge eating disorders in adult individuals.

How Does Lisdexamfetamine Work?

Lisdexamfetamine is a prodrug, which means it exists in an inherent inactive form containing Lisdexamfetamine dimesylate (active ingredient). This active ingredient comprises dextroamphetamine (d-amphetamine) and L-lysine (essential amino acid).

The drug exhibits its pharmacological effects through the following steps:

• The two components of Lisdexamfetamine are broken down by hydrolysis induced by enzymes, releasing the active component, d-amphetamine.

• This d-amphetamine molecule exhibits therapeutic activity by blocking the reuptake of dopamine and norepinephrine back into the nerve cells.

• It also causes the release of biogenic amines like dopamine from the nerve endings into the circulation.

• These neurotransmitters help enhance alertness, increase concentration, and improve motivation in ADHD individuals.

What Is the Dosage of Lisdexamfetamine?

The dosage recommendations for Lisdexamfetamine depend on the clinical severity and the degree of response to the prescribed therapy.

• For individuals six years of age and older, the recommended initial dose is a single dose of 30 mg per day in the morning.

• Dosage is gradually increased by 10 or 20 mg at weekly intervals, depending on the clinical response, and could reach up to 70 mg per day (maximum dose).

• In Renal Impairment - If the GFR (glomerular filtration rate) ranges from 15 to 30 mL/min/1.73 m2 (milliliter per minute per 1.73-meter square), the maximum dose allowed is 50 mg per day (mg/day). The dosage must not exceed 30 mg/day in cases of end-stage renal disease where the GFR is below 15 mL/min/1.73 m2.

How to Use Lisdexamfetamine?

The doctor or physician prescribes Lisdexamfetamine according to the clinical status of the condition. The drug should be taken only on the doctor’s advice and should not be suddenly stopped, as it could result in withdrawal symptoms. Lisdexamfetamine should be taken in the following ways:

• Mode of Administration - Oral route.

• Lisdexamfetamine is generally prescribed as a daily morning dose, along with or without meals.

• Afternoon or evening doses are avoided due to the potential risk of insomnia (sleeplessness).

• The capsule should be taken as a whole (single dose) and should not be divided.

• Chewable Lisdexamfetamine tablets should be chewed completely before swallowing.

• Lisdexamfetamine capsules could be substituted with their chewable counterparts based on mg-per-mg dosage, that is, 50 mg capsule for 50 mg chewable tablet.

• If unable to swallow, the capsules (as a whole or only contents) could be dissolved in yogurt, orange juice, or water. The contents must dissolve completely, and the preparation should be consumed immediately without souring.

• The dosage should not be stopped or changed based on self-opinion. Periodic checking with the doctor is mandatory, and following the prescribed dosing recommendations is important.

What Are the Side Effects of Lisdexamfetamine?

Lisdexamfetamine is a well-tolerated drug and does not cause serious side effects. However, some adverse reactions are encountered during dose adjustments or overdosage. Medical assistance is needed if side effects persist or worsen.

The commonly reported side effects of Lisdexamfetamine therapy are as follows:

• Nausea.

• Vomiting.

• Constipation.

• Stomach pain or abdominal discomfort.

• Loss of appetite.

• Dryness of mouth.

• Sweating.

• Weight loss.

• Headaches.

• Restlessness.

• Nervousness.

• Trouble sleeping.

• Dizziness.

• Irritability.

• Increased blood pressure.

• Blurred vision.

• Fast pounding or rapid, irregular heartbeat.

• Changes in mood or behavior like agitation, depression, or aggression.

• Uncontrollable muscle movements.

• Seizures.

• Shortness of breathing.

What Are the Precautionary Measures to Follow While Taking Lisdexamfetamine?

Some precautionary measures to be followed before and during Lisdexamfetamine therapy are:

• Pre-treatment Screening - Cardiac functioning, renal efficiency, and potential abuse risk are evaluated before prescribing Lisdexamfetamine.

• A history of past medications, current medications, nutritional supplements, or use of any other products must be reported to the doctor before starting the drug.

• Dietary Considerations - Lisdexamfetamine could be taken with food or under fasting conditions. A high-fat diet could be avoided while taking Lisdexamfetamine, as it prolongs absorption.

• Missed Dose - The missed dose could be taken as soon as the patient remembers it. However, the dose can be skipped to prevent overdose if it is time for the next schedule. The regular schedule should be followed starting the next morning. The dose should be taken only in the morning. It is better to avoid taking it in the afternoon or evening, as it would lead to sleeplessness at night.

• Overdose - In the event of accidental overdose or the development of unusual symptoms, medical help or supportive care must be sought. The nearest poison control center or healthcare facility must be immediately contacted.

For Doctors

Indications

The FDA approved using Lisdexamfetamine in the following clinical conditions:

• As a component of the ADHD management regime, which involves both pharmacological and socio-physiological therapeutic approaches.

• To improve behavior patterns such as paying attention, staying focused, and reducing fidgeting in ADHD individuals.

• Lisdexamfetamine is also indicated for treating binge eating.

Pharmacodynamics

Lisdexamfetamine is broadly categorized as a CNS stimulant and is the prodrug of dextroamphetamine. These are sympathomimetic amines with non-catecholamine activity. These chemicals increase alertness and behavioral changes by causing CNS stimulation.

The pharmacodynamic effects of Lisdexamfetamine are as follows:

• Lisdexamfetamine dimesylate is the active form of the drug, where dextroamphetamine is covalently linked to L-lysine.

• Gastric pH does not affect this covalent bond, thus contributing to long-lasting action duration and reduced abuse potential.

• After absorption, when this Lisdexamfetamine molecule comes in contact with red blood cells (RBCs), the covalent bond is broken due to hydrolysis by RBC enzymes, releasing dextroamphetamine and L-lysine into the circulation.

• The released active molecule, d-amphetamine, is responsible for the therapeutic effects of Lisdexamfetamine.

What Is the Mechanism of Action of Lisdexamfetamine?

The therapeutic action mechanism of Lisdexamfetamine in attention deficit hyperactivity disorder (ADHD) is as follows:

• Dextroamphetamine, the active molecule, increases monoamines’ (norepinephrine, dopamine) release from the presynaptic storage vesicles in the nerve endings, thereby increasing their levels in the extraneuronal compartments.

• Also, the reuptake of these neurotransmitters is blocked by the active molecule of Lisdexamfetamine (the parent molecule does not block reuptake) by binding to the receptor sites at the nerve terminals.

• Both of these mechanisms increase dopamine, norepinephrine, and other monoamine levels in extraneuronal space, leading to increased alertness, enhanced concentration, and improved motivation.

• Lisdexamfetamine therapeutically increases the neurotransmitter synaptic levels of the prefrontal cerebral cortex, resulting in effective changes in behavior.

Pharmacokinetics

• Absorption - Following oral administration of Lisdexamfetamine, its drug components undergo rapid absorption from the gastrointestinal tract. The tmax (time taken to attain peak plasma concentration) for the capsule ranges from one hour to 3.5 hours, and for chewable tablets, it is found to be one hour to 4.4 hours post-administration on fasting conditions. The presence of food (high-fat diet) tends to increase tmax by one hour.

• Distribution - Dextroamphetamine does not accumulate and shows a steady-state volume of distribution in healthy individuals.

• Metabolism - Lisdexamfetamine gets metabolized by the enzymatic activity of the red blood cells. It undergoes hydrolysis to release its active components. Liver enzymes such as cytochrome P450 have no role in Lisdexamfetamine metabolism.

• Half-Life - D-amphetamine's half-life of d-amphetamine is approximately 12 hours following oral intake of Lisdexamfetamine.

• Elimination - Nearly 96 percent of Lisdexamfetamine radioactivity is eliminated through urine, and around 0.3 percent is eliminated through feces.

• Clearance - The clearance rate in younger adults (18 to 45 years) is 1 L/hr/kg (liter per hour per kilogram), and in individuals between 55 and 74 years, it is found to be 0.7 L/hr/kg. The clearance rate decreases as age increases, reaching 0.55 L/hr/kg in individuals over 75 years.

What Are the Contraindications of Lisdexamfetamine?

Lisdexamfetamine is contraindicated (totally avoided) in the following medical conditions:

• Allergy or hypersensitivity to Lisdexamfetamine, its components, and also amphetamines.

• It should not be recommended to manage weight loss in individuals.

• In individuals taking MAO (Monoamine oxidase) inhibitors (Linezolid) or within 14 days after MAO therapy.

Toxicity

Lisdexamfetamine causes adverse toxic reactions due to overdosage or increased levels of amphetamines in the blood circulation.

Some of the reported toxicities are as follows:

• Tremors.

• Hyperreflexia.

• Rapid respiration.

• Confusion.

• Assaultiveness.

• Hallucinations and panic states.

• Hyperpyrexia

• Rhabdomyolysis.

• Depression and fatigue.

• Arrhythmias.

• Hypertension.

• Hypotension resulting in circulatory collapse.

• Gastrointestinal disturbances like abdominal cramps.

• Lethal poisoning along with convulsions or coma.

What Are the Warnings and Precautions Associated with Lisdexamfetamine?

Lisdexamfetamine is a CNS stimulant and should be used cautiously in certain clinical conditions.

The warnings and precautions associated with Lisdexamfetamine use are given below:

• Abuse Potential and Drug Dependence - Lisdexamfetamine is classified as a Schedule II controlled substance. Being a CNS stimulant, it carries a high abuse potential, which includes overuse or impaired control of drug use, craving and compulsive drug-using symptoms, and continuous craving. To prevent abuse of Lisdexamfetamine, abuse risk screening is conducted before starting the therapy. During the therapy, prescription records are regularly monitored, counseling sessions for family and friends are held, symptoms of abuse are evaluated, and the dosage of Lisdexamfetamine is periodically assessed.

• Cardiovascular Risk Potential - Cardiac abnormalities such as chest pain, syncope, myocardial infarction, stroke, and sudden death are reported. Lisdexamfetamine should be avoided in individuals with cardiac ailments like arrhythmia, coronary artery disease, or cardiomyopathy.

• Elevated Blood Pressure - Lisdexamfetamine tends to enhance blood pressure and heartbeats. During therapy, individuals must be monitored for any potential risk of tachycardia or hypertension.

• Psychiatric Adverse Conditions - Lisdexamfetamine carries the potential risk of inducing thought or behavior disturbances in individuals with pre-existing psychosis. It could also trigger maniac changes in bipolar disorder.

• Hypersensitivity - Some individuals experience reactions like rashes, anaphylactic shock, or urticaria.

• Renal impairment - Dose adjustments are required in individuals with renal dysfunction since most drugs are eliminated through the kidneys.

• Growth Suppression - Lisdexamfetamine is reported to slow growth rates and cause weight gain in pediatric individuals. Regular monitoring of height and weight is essential while administering the drug to pediatric populations.

• Raynaud’s Phenomenon - Peripheral vasculopathy causing numbness in the fingers occurs during Lisdexamfetamine treatment.

• Serotonin Syndrome - The risk of developing this life-threatening clinical condition, characterized by increased heartbeats, hallucinations, restlessness, and twitching of muscles, is seen when Lisdexamfetamine is co-administered with serotonergic agents like monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or selective serotonin reuptake inhibitors (SSRIs).

What Are the Drug Interactions of Lisdexamfetamine?

Some common drug interactions reported with Lisdexamfetamine are:

• MAO Inhibitors (MAOI) - MAOIs are antidepressants that reduce amphetamine effects. Concomitant use of Lisdexamfetamine with MAOIs leads to toxic neurological side effects or malignant hyperpyrexia.

• Serotonergic Agents - Serotonin-norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), triptans, Fentanyl, Tramadol, and Buspirone could cause serotonin syndrome when used with Lisdexamfetamine.

• Acidifying Agents - Urinary acidifying medications like Ammonium chloride enhance the excretion of Lisdexamfetamine through urine, thereby reducing its efficacy.

• Alkalinizing Agents - Urinary alkalinizing drugs such as Acetazolamide elevate the blood levels of Lisdexamfetamine, leading to toxic side effects.

Use in Specific Population

• Pregnancy - Only limited clinical data is available for Lisdexamfetamine-associated risks causing birth defects or miscarriage. Adverse outcomes during pregnancy, such as premature delivery or low birth weight babies, are reported in mothers using amphetamines. Clinical monitoring of withdrawal symptoms is mandatory during pregnancy.

• Lactation and Breastfeeding - There is a potential risk of developing adverse side effects in breastfed babies if their lactating mothers are on Lisdexamfetamine. Hence, it is not recommended during breastfeeding.

• Pediatric Use - Though Lisdexamfetamine is approved for children (above age six), their growth parameters, such as weight and height, should be periodically monitored. It is not used for children under six years of age.

• Geriatric Use - Dose adjustments according to clinical parameters related to cardiac and renal functioning are mandatory in elderly individuals.