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Clinical Studies Experience

The premarketing development program for Vyvanse included exposures in a total of 995 participants in clinical trials (348 pediatric patients aged 6 to 12 years, 233 adolescent patients aged 13 to 17 years, 358 adult patients and 56 healthy adult subjects). Of these, 348 pediatric (aged 6 to 12) patients were evaluated in two controlled clinical studies (one parallel-group and one crossover), one open-label extension study, and one single-dose clinical pharmacology study, 233 adolescent (aged 13 to 17) patients were evaluated in one controlled clinical study, and 358 adult patients were evaluated in one controlled clinical study and one open-label extension study. The information included in this section is based on data from the 4-week parallel-group controlled clinical studies in pediatric and adult patients with ADHD. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reactions categories. In the tables and listings that follow, MedDRA terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced a treatment-emergent adverse reaction of the type listed at least once.

Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials

In the controlled pediatric (aged 6 to 12) trial, 9% (20/218) of Vyvanse-treated patients discontinued due to adverse reactions compared to 1% (1/72) who received placebo. The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of Vyvansetreated patients and at a rate at least twice that of placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, insomnia, and rash (2/218 each; 1%).

In the controlled adolescent (aged 13 to 17) trial, 4% (10/233) of Vyvanse-treated patients discontinued due to adverse events compared to 1% (1/77) who received placebo. The most frequent adverse reactions leading to discontinuation and considered to be drug-related were irritability (3/233; 1%), decreased appetite (2/233; 1%), and insomnia (2/233; 1%).

In the controlled adult trial, 6% (21/358) of Vyvanse-treated patients discontinued due to adverse events compared to 2% (1/62) who received placebo. The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of Vyvanse-treated patients and at a rate at least twice that of placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%), hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%).

Adverse Reactions Occurring at an Incidence of 2% or More Among Vyvanse Treated Patients in Clinical Trials

Adverse reactions reported in the controlled trials in pediatric (aged 6 to 17 years) and adult patients treated with Vyvanse or placebo are presented in Tables 1, 2, and 3 below. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse reaction incidence rate in the population studied.

Pediatric

Table 1 : Adverse Reactions Reported by 2% or More of Children (Aged 6 to 12 Years) Taking Vyvanse in a 4-Week Clinical Trial

Table 2 : Adverse Reactions Reported by 2% or More of Adolescent (Aged 13 to 17 Years) Patients Taking Vyvanse in a 4-Week Clinical Trial

Adult

Table 3 : Adverse Reactions Reported by 2% or More of Adult Patients Taking Vyvanse in a 4-Week Clinical Trial

In addition, adverse reactions observed at a rate of less than 2% included decreased libido and erectile dysfunction.

Vital Signs

Weight Loss – In the controlled adult trial, mean weight loss after 4 weeks of therapy was 2.8 lbs, 3.1 lbs, and 4.3 lbs, for patients receiving final doses of 30 mg, 50 mg, and 70 mg of Vyvanse, respectively, compared to a mean weight gain of 0.5 lbs for patients receiving placebo.

Postmarketing Reports

The following adverse reactions have been identified during post approval use of Vyvanse. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders - Palpitation

Eye Disorders - Vision blurred, mydriasis, diplopia

General Disorders and Administration Site Conditions - Fatigue

Hepatobiliary Disorders - Eosinophilic Hepatitis

Immune System Disorders – Anaphylactic reaction, hypersensitivity

Nervous System Disorders – Somnolence, seizure, dyskinesia

Psychiatric Disorder - Psychotic episodes, mania, hallucination, depression, aggression, dysphoria, euphoria, logorrhoea, dermatillomania

Skin and Subcutaneous Tissue Disorder - Stevens-Johnson Syndrome, angioedema, urticaria

Adverse Reactions Associated with the Use of Amphetamine

Cardiovascular

Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.

Central Nervous System

Psychotic episodes at recommended doses, overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, depression, tremor, headache, exacerbation of motor and phonic tics and Tourette's syndrome, seizures, stroke.

Gastrointestinal

Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances.

Allergic

Urticaria, rashes, and hypersensitivity reactions, including angioedema and anaphylaxis. Serious skin reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported.

Endocrine

Impotence, changes in libido.

Agents Whose Blood Levels May be Impacted by Vyvanse

Extended release guanfacine: In a drug interaction study (N=40), administration of an extended release guanfacine (4 mg) in combination with Vyvanse (50mg) increased guanfacine maximum plasma concentration by 19%, whereas, exposure (area under the curve; AUC) was increased by 7%. These small changes are not expected to be clinically meaningful. In this study, no effect on d-amphetamine exposure was observed following co-administration of extended release guanfacine and Vyvanse.

Agents that Lower Blood Levels of Amphetamines

Urinary Acidifying Agents

These agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion.

Methenamine Therapy

Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.

Agents that Increase Blood Levels of Amphetamines

Urinary Alkalinizing Agents

These agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion.

Monoamine Oxidase Inhibitors

MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results.

Agents Whose Effects May be Reduced by Amphetamines

Adrenergic Blockers

Adrenergic blockers are inhibited by amphetamines.

Antihistamines

Amphetamines may counteract the sedative effect of antihistamines.

Antihypertensives

Amphetamines may antagonize the hypotensive effects of antihypertensives.

Veratrum Alkaloids

Amphetamines inhibit the hypotensive effect of veratrum alkaloids.

Ethosuximide

Amphetamines may delay intestinal absorption of ethosuximide.

Agents Whose Effects May be Potentiated by Amphetamines

Antidepressants, Tricyclic

Amphetamines may enhance the activity of tricyclic antidepressants or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.

Meperidine

Amphetamines potentiate the analgesic effect of meperidine.

Phenobarbital

Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action.

Phenytoin

Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action.

Agents that May Reduce the Effects of Amphetamines

Chlorpromazine

Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.

Haloperidol

Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines.

Lithium Carbonate

The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate.

Agents that May Potentiate the Effects of Amphetamines

Norepinephrine

Amphetamines enhance the adrenergic effect of norepinephrine.

Propoxyphene Overdosage

In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.

Drug/Laboratory Test Interactions

Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamine may interfere with urinary steroid determinations.

Drug Abuse And Dependence

Controlled Substance

Vyvanse is classified as a Schedule II controlled substance.

Abuse and Dependence

Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high-dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines may include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.

Human Studies

In a human abuse liability study, when equivalent oral doses of 100 mg lisdexamfetamine dimesylate and 40 mg immediate-release d-amphetamine sulfate were administered to individuals with a history of drug abuse, lisdexamfetamine dimesylate 100 mg produced subjective responses on a scale of “Drug Liking Effects” (primary endpoint) that were significantly less than d-amphetamine immediate-release 40 mg. However, oral administration of 150 mg lisdexamfetamine dimesylate produced increases in positive subjective responses on this scale that were statistically indistinguishable from the positive subjective responses produced by 40 mg of oral immediate-release d-amphetamine and 200 mg of diethylpropion (C-IV).¹

Intravenous administration of 50 mg lisdexamfetamine dimesylate to individuals with a history of drug abuse produced positive subjective responses on scales measuring “Drug Liking”, “Euphoria”, “Amphetamine Effects”, and “Benzedrine Effects” that were greater than placebo but less than those produced by an equivalent dose (20 mg) of intravenous d-amphetamine.

Animal Studies

In animal studies, lisdexamfetamine dimesylate produced behavioral effects qualitatively similar to those of the CNS stimulant d-amphetamine. In monkeys trained to self-administer cocaine, intravenous lisdexamfetamine dimesylate maintained self-administration at a rate that was statistically less than that for cocaine, but greater than that of placebo.

REFERENCES

1 Jasinski DR, Krishnan S. Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse. Journal of Psychopharmacology. 2009; 23(4);419-27.

Last reviewed on RxList: 9/27/2011
This monograph has been modified to include the generic and brand name in many instances.