Vyvanse, a prodrug of the CNS stimulant dextroamphetamine, is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Vyvanse is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome.
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, logorrhea
Skin and Subcutaneous Tissue Disorder — Stevens-Johnson Syndrome, angioedema, urticaria
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.
Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances.
Urticaria, rashes, and hypersensitivity reactions, including angioedema and anaphylaxis. Serious skin reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported.
Impotence, changes in libido.
Extended release guanfacine: In a drug interaction study (N=40), administration of an extended release guanfacine (4 mg) in combination with Vyvanse (50 mg) 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.
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.
Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.
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.
Adrenergic blockers are inhibited by amphetamines.
Amphetamines may counteract the sedative effect of antihistamines.
Amphetamines may antagonize the hypotensive effects of antihypertensives.
Amphetamines inhibit the hypotensive effect of veratrum alkaloids.
Amphetamines may delay intestinal absorption of ethosuximide.
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.
Amphetamines potentiate the analgesic effect of meperidine.
Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action.
Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action.
Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.
Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines.
The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate.
Amphetamines enhance the adrenergic effect of norepinephrine.
In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.
Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamine may interfere with urinary steroid determinations.
Animal reproduction studies of lisdexamfetamine dimesylate have not been performed. Studies have been performed with the active metabolite of lisdexamfetamine, d-amphetamine, either alone or in combination with l-amphetamine, as noted below.
Pregnancy Category C
Amphetamine (d- to l-enantiomer ratio of 3:1) had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity.
A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d,l-) at doses similar to those used clinically can result in longterm neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.
There are no adequate and well-controlled studies in pregnant women. There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (vater association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude.
The effects of Vyvanse on labor and delivery in humans is unknown.
Amphetamines are excreted into human milk. Mothers taking amphetamines should be advised to refrain from nursing.
Vyvanse is indicated for use in pediatric patients with ADHD aged 6 to 17 years. Vyvanse has not been studied in children under 6 years of age. Long-term effects of amphetamines in children have not been well established.
A study was conducted in which juvenile rats received oral doses of 4, 10, or 40 mg/kg/day of lisdexamfetamine dimesylate from day 7 to day 63 of age. These doses are approximately 0.3, 0.7, and 3 times the maximum recommended human daily dose of 70 mg on a mg/m2 basis. Dose-related decreases in food consumption, bodyweight gain, and crown-rump length were seen; after a four-week drug-free recovery period, bodyweights and crown-rump lengths had significantly recovered in females but were still substantially reduced in males. Time to vaginal opening was delayed in females at the highest dose, but there were no drug effects on fertility when the animals were mated beginning on day 85 of age.
In a study in which juvenile dogs received lisdexamfetamine dimesylate for 6 months beginning at 10 weeks of age, decreased bodyweight gain was seen at all doses tested (2, 5, and 12 mg/kg/day, which are approximately 0.5, 1, and 3 times the maximum recommended human daily dose on a mg/m2 basis). This effect partially or fully reversed during a four-week drug-free recovery period.
Vyvanse has not been studied in the geriatric population.
Vyvanse is classified as a Schedule II controlled substance.
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.
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.
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.
Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.
Symptoms: Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.
Treatment: Consult with a Certified Poison Control Center for up-to-date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic, and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication.
The prolonged release of Vyvanse in the body should be considered when treating patients with overdose.
Vyvanse (lisdexamfetamine dimesylate) is designed as a capsule for once-a-day oral administration. The chemical designation for lisdexamfetamine dimesylate is (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate. The molecular formula is C15H25N3O•(CH4O3S)2, which corresponds to a molecular weight of 455.60. The chemical structure is:
Lisdexamfetamine dimesylate is a white to off-white powder that is soluble in water (792 mg/mL). Vyvanse capsules contain 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of lisdexamfetamine dimesylate and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, and one or more of the following: D&C Red #28, D&C Yellow #10, FD&C Blue #1, FD&C Green #3, and FD&C Red #40.
Lisdexamfetamine is a prodrug of dextroamphetamine. After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and converted primarily in blood due to the hydrolytic activity of red blood cells to dextroamphetamine, which is responsible for the drug’s activity. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines are thought to 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.
Pharmacokinetic studies of dextroamphetamine after oral administration of lisdexamfetamine have been conducted in healthy adult and pediatric (aged 6 to 12) patients with ADHD.
In 18 pediatric patients (aged 6 to 12) with ADHD, the Tmax of dextroamphetamine was approximately 3.5 hours following single-dose oral administration of lisdexamfetamine dimesylate either 30 mg, 50 mg, or 70 mg after an 8-hour overnight fast. The Tmax of lisdexamfetamine was approximately 1 hour. Linear pharmacokinetics of dextroamphetamine after single-dose oral administration of lisdexamfetamine dimesylate was established over the dose range of 30 mg to 70 mg in children aged 6 to 12 years.
There is no unexpected accumulation of dextroamphetamine AUC at steady state in healthy adults and no accumulation of lisdexamfetamine after once-daily dosing for 7 consecutive days.
Food does not affect the observed AUC and Cmax of dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of Vyvanse capsules but prolongs Tmax by approximately 1 hour (from 3.8 hrs at fasted state to 4.7 hrs after a high fat meal). After an 8-hour fast, the AUCs for dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.
Weight/Dose normalized AUC and Cmax were 22% and 12% lower, respectively, in adult females than in males on day 7 following a 70 mg/day dose of lisdexamfetamine dimesylate for 7 days. Weight/Dose normalized AUC and Cmax values were the same in girls and boys following single doses of 30-70 mg.
Metabolism and Excretion
After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract. Lisdexamfetamine is converted to dextroamphetamine and l-lysine, primarily in blood due to the hydrolytic activity of blood cells. In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamphetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes. 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. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in studies of lisdexamfetamine dimesylate in volunteers.
Dextroamphetamine is known to inhibit monoamine oxidase. The ability of dextroamphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites, but there are no in vivo studies of p450 enzyme inhibition.
The pharmacokinetics of dextroamphetamine is similar in pediatric (aged 6 to 12) and adolescent (aged 13 to 17) ADHD patients, and healthy adult volunteers. Any differences in kinetics seen after oral administration are a result of differences in mg/kg dosing.
Systemic exposure to dextroamphetamine is similar for men and women given the same mg/kg dose.
Formal pharmacokinetic studies for race have not been conducted.