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Vyvanse (Lisdexamfetamine Dimesylate) - Description and Clinical Pharmacology

 
 



Vyvanse (lisdexamfetamine dimesylate) C-II Rx Only

DESCRIPTION

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 -[(1 S)-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 30 mg, 50 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 and FD&C Red #40.

CLINICAL PHARMACOLOGY

Mechanism of Action and Pharmacology

Vyvanse is a prodrug of dextroamphetamine. After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract and converted 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.

Pharmacokinetics

Pharmacokinetic studies of dextroamphetamine after oral administration of lisdexamfetamine dimesylate have been conducted in healthy adult and pediatric (6-12 yrs) patients with ADHD.

In 18 pediatric patients (6-12 yrs) 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 dimesylate 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 accumulation of dextroamphetamine AUC at steady state in healthy adults and no accumulation of lisdexamfetamine dimesylate 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 AUC 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 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 dimesylate is rapidly absorbed from the gastrointestinal tract. Lisdexamfetamine dimesylate is converted to dextoamphetamine and L-lysine, which is believed to occur by first-pass intestinal and/or hepatic metabolism. 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% intact lisdexamfetamine. Plasma concentrations of unconverted lisdexamfetamine dimesylate 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.

Special Populations

The pharmacokinetics of dextroamphetamine is similar in pediatric (6-12 years) and adolescent (13-17 years) ADHD patients, and healthy adult volunteers. Any differences in kinetics seen after oral administration are a result of differences in mg/kg dosing.

Gender

Systemic exposure to dextroamphetamine is similar for men and women given the same mg/kg dose.

Clinical Trials

A double-blind, randomized, placebo-controlled, parallel-group study was conducted in children aged 6-12 (N=290) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Patients were randomized to fixed dose treatment groups receiving final doses of 30, 50, or 70 mg of Vyvanse or placebo once daily in the morning for four weeks. Significant improvements in patient behavior, based upon investigator ratings on the ADHD Rating Scale (ADHD-RS), were observed at endpoint for all Vyvanse doses compared to patients who received placebo. Mean effects at all doses were fairly similar, although the highest dose (70 mg/day) was numerically superior to both lower doses (30 and 50 mg/day). The effects were maintained throughout the day based on parent ratings (Connor's Parent Rating Scale) in the morning (approximately 10 am), afternoon (approximately 2 pm), and early evening (approximately 6 pm).

A double-blind, placebo-controlled, randomized, crossover design, analog classroom study was conducted in children aged 6-12 (N=52) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Following a 3-week open-label dose titration with ADDERALL XR, patients were randomly assigned to continue the same dose of ADDERALL XR (10, 20, or 30 mg), Vyvanse (30, 50, and 70 mg), or placebo once daily in the morning for 1 week each treatment. A significant difference in patient behavior, based upon the average of investigator ratings on the Swanson, Kotkin, Agler, M.Flynn and Pelham (SKAMP)-Deportment scores across the 8 sessions of a 12 hour treatment day, was observed between patients who received Vyvanse compared to patients who received placebo. The drug effect was similar for all 8 sessions.

ANIMAL TOXICOLOGY

Acute administration of high doses of amphetamine (d- or d,l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

Manufactured for: New River Pharmaceuticals Inc., Blacksburg, VA 24060. Made in USA.

Distributed by: Shire US Inc., Wayne, PA 19087

For more information call 1-800-828-2088, or visit www.Vyvanse.com

Vyvanse is a trademark of Shire LLC.

Copyright 2007 New River Pharmaceuticals Inc.

Rev 02/07 104A 04

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