Vyvanse (Page 5 of 7)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis/ Mutagenesis and Impairment of Fertility
Carcinogenicity studies of lisdexamfetamine dimesylate have not been performed.
No evidence of carcinogenicity was found in studies in which d-, l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats.
Lisdexamfetamine dimesylate was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli and S. typhimurium components of the Ames test and in the L5178Y/TK+- mouse lymphoma assay in vitro.
Amphetamine (d- to l-enantiomer ratio of 3:1) did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day.
13.2 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.
14 CLINICAL STUDIES
The efficacy of Vyvanse in the treatment of ADHD was established on the basis of two controlled trials in children aged 6 to 12 years, one controlled trial in adolescents aged 13 to 17 years, and two controlled trials in adults who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) criteria for ADHD [see INDICATIONS AND USAGE (1)].
Pediatric
A double-blind, randomized, placebo-controlled, parallel-group study was conducted in children aged 6 to 12 (N=290) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Patients were randomized to receive final doses of 30 mg, 50 mg, or 70 mg of Vyvanse or placebo once daily in the morning for a total of four weeks of treatment. All subjects receiving Vyvanse were initiated on 30 mg for the first week of treatment. Subjects assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS), a measure of the core symptoms of ADHD. Endpoint was defined as the last post-randomization treatment week (i.e. Weeks 1 through 4) for which a valid score was obtained. All Vyvanse dose groups were superior to placebo in the primary efficacy outcome. Mean effects at all doses were fairly similar, although the highest dose (70 mg/day) was numerically superior to both lower doses (30 mg/day and 50 mg/day). The effects were maintained throughout the day based on parent ratings (Conners’ 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 to 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 mg, 20 mg, or 30 mg), Vyvanse (30 mg, 50 mg, or 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 7 assessments conducted at 2, 3, 4.5, 6, 8, 10, and 12 hours post-dose were observed between patients who received Vyvanse compared to patients who received placebo. The drug effect was similar for all 7 sessions.
A second double-blind, placebo-controlled, randomized, crossover design, analog classroom study was conducted in children aged 6 to 12 (N=129) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Following a 4-week open-label dose titration with Vyvanse (30 mg, 50 mg, 70 mg), patients were randomly assigned to continue Vyvanse 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 SKAMP-Deportment scores across all 7 assessments conducted at 1.5, 2.5, 5.0, 7.5, 10.0, 12.0, and 13.0 hours post-dose, were observed between patients who received Vyvanse compared to patients who received placebo.
A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adolescents aged 13 to 17 (N=314) who met DSM-IV criteria for ADHD. In this study, patients were randomized in a 1:1:1:1 ratio to a daily morning dose of Vyvanse (30 mg/day, 50 mg/day or 70 mg/day) or placebo for a total of four weeks of treatment. All subjects receiving Vyvanse were initiated on 30 mg for the first week of treatment. Subjects assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS), a measure of the core symptoms of ADHD. Endpoint was defined as the last post-randomization treatment week (i.e. Weeks 1 through 4) for which a valid score was obtained. All Vyvanse dose groups were superior to placebo in the primary efficacy outcome.
Adult
A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adults (N=420) who met DSM-IV criteria for ADHD. In this study, patients were randomized to receive final doses of 30 mg, 50 mg, or 70 mg of Vyvanse or placebo for a total of four weeks of treatment. All subjects receiving Vyvanse were initiated on 30 mg for the first week of treatment. Subjects assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS), a measure of the core symptoms of ADHD. Endpoint was defined as the last post-randomization treatment week (i.e. Weeks 1 through 4) for which a valid score was obtained. All Vyvanse dose groups were superior to placebo in the primary efficacy outcome.
The second study was a multi-center, randomized, double-blind, placebo-controlled, crossover design, modified analog classroom study of Vyvanse to simulate a workplace environment in 142 adults who met DSM-IV-TR criteria for ADHD. There was a 4-week open-label, dose optimization phase with Vyvanse (30 mg/day, 50 mg/day, or 70 mg/day in the morning). Subjects were then randomized to one of two treatment sequences: 1) Vyvanse (optimized dose) followed by placebo, each for one week, or 2) placebo followed by Vyvanse, each for one week. Efficacy assessments occurred at the end of each week, using the Permanent Product Measure of Performance (PERMP). The PERMP is a skill-adjusted math test that measures attention in ADHD. Vyvanse treatment, compared to placebo, resulted in a statistically significant improvement in attention across all post-dose time points, as measured by average PERMP total scores over the course of one assessment day, as well as at each time point measured. The PERMP assessments were administered at pre-dose (-0.5 hours) and at 2, 4, 8, 10, 12, and 14 hours post-dose.
15 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
Vyvanse capsules 30 mg: white body/orange cap (imprinted with NRP104 or S489 and 30 mg),
| Bottles of 10 | NDC 54868-5916-0 |
| Bottles of 30 | NDC 54868-5916-1 |
Vyvanse capsules 40 mg: white body/blue green cap (imprinted with NRP104 or S489 and 40 mg),
| Bottles of 10 | NDC 54868-6009-0 |
| Bottles of 30 | NDC 54868-6009-1 |
Vyvanse capsules 50 mg: white body/blue cap (imprinted with NRP104 or S489 and 50 mg),
| Bottles of 10 | NDC 54868-5827-0 |
| Bottles of 30 | NDC 54868-5827-1 |
Vyvanse capsules 70 mg: blue body/orange cap (imprinted with NRP104 or S489 and 70 mg),
| Bottles of 10 | NDC 54868-3655-0 |
| Bottles of 30 | NDC 54868-3655-1 |
Dispense in a tight, light-resistant container as defined in the USP.
Store at 25° C (77° F). Excursions permitted to 15-30° C (59-86° F) [see USP Controlled Room Temperature]
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