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Vyvanse

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Vyvanse

CLINICAL PHARMACOLOGY

Mechanism Of Action

Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. Amphetamines 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 have been conducted in patients ages 6 to 12 years with ADHD and in healthy adult volunteers.

In 18 patients ages 6 to 12 years 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 ages 6 to 12 years and over a range of 50 mg to 250 mg in adults. Dextroamphetamine pharmacokinetic parameters following administration of lisdexamfetamine dimesylate in adults exhibited low inter-subject ( < 25%) and intra-subject ( < 8%) variability. Safety and efficacy have not been studied above the maximum recommended dose of 70mg.

There is no accumulation of dextroamphetamine AUC at steady state in healthy adults and no accumulation of lisdexamfetamine after once-daily dosing for 7 consecutive days.

Neither food (a high fat meal or yogurt) nor orange juice affect the observed AUC and Cmax of dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of Vyvanse capsules. Food prolongs Tmax by approximately 1 hour (from 3.8 hrs at fasted state to 4.7 hrs after a high fat meal or to 4.8 hrs with yogurt). 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 pediatric patients ages 6 to 12 years 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 red blood cells. In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamfetamine; 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.

Animal Toxicology And/Or Pharmacology

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.

Clinical Studies

The short-term efficacy of Vyvanse in the treatment of ADHD was established on the basis of three controlled trials in children ages 6 to 12 years (Studies 1, 2, and 3), one controlled trial in adolescents ages 13 to 17 years (Study 4), one controlled trial in children and adolescents ages 617 years (Study 5), and two controlled trials in adults (Study 7 and 8) who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition – text revision (DSM-IV-TR) criteria for ADHD. Maintenance of efficacy after long-term use (at least 6 months) of Vyvanse in the treatment of ADHD was demonstrated in two randomized withdrawal trials in children and adolescents (Study 6), and adults (Study 9).

A double-blind, randomized, placebo-controlled, parallel-group study (Study 1) was conducted in children ages 6 to 12 years (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 patients receiving Vyvanse were initiated on 30 mg for the first week of treatment. Patients 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), an 18-item questionnaire with a score range of 0-54 points that measures the core symptoms of ADHD which includes both hyperactive/impulsive and inattentive subscales. 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 similar; however, the highest dose (70 mg/day) was numerically superior to both lower doses (Study 1 in Table 4). 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 (Study 2) was conducted in children ages 6 to 12 years (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 optimization with Adderall XR®, patients were randomly assigned to continue their optimized 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. Efficacy assessments were conducted at 1, 2, 3, 4.5, 6, 8, 10, and 12 hours post-dose using the Swanson, Kotkin, Agler, M.Flynn, and Pelham Deportment scores (SKAMP-DS), a 4-item subscale of the SKAMP with scores ranging from 0 to 24 points that measures deportment problems leading to classroom disruptions. A significant difference in patient behavior, based upon the average of investigator ratings on the SKAMP-DS across the 8 assessments were observed between patients when they received Vyvanse compared to patients when they received placebo (Study 2 in Table 4). The drug effect reached statistical significance from hours 2 to 12 post-dose, but was not significant at 1 hour.

A second double-blind, placebo-controlled, randomized, crossover design, analog classroom study (Study 3) was conducted in children ages 6 to 12 years (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 optimization with Vyvanse (30 mg, 50 mg, 70 mg), patients were randomly assigned to continue their optimized dose of 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 when they received Vyvanse compared to patients when they received placebo (Study 3 in Table 4, Figure 4).

Patients Ages 13 to 17 Years Old

A double-blind, randomized, placebo-controlled, parallel-group study (Study 4) was conducted in adolescents ages 13 to 17 years (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 patients receiving Vyvanse were initiated on 30 mg for the first week of treatment. Patients 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). 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 (Study 4 in Table 4).

Patients Ages 6 to 17 Years Old: Short-Term Treatment

A double-blind, randomized, placebo- and active-controlled parallel-group, dose-optimization study (Study 5) was conducted in children and adolescents ages 6 to 17 years (n=336) who met DSM-IV criteria for ADHD. In this eight-week study, patients were randomized to a daily morning dose of Vyvanse (30, 50 or 70mg/day), an active control, or placebo (1:1:1). The study consisted of a Screening and Washout Period (up to 42 days), a 7-week Double-blind Evaluation Period (consisting of a 4-week Dose-Optimization Period followed by a 3-week Dose-Maintenance Period), and a 1-week Washout and Follow-up Period. During the Dose Optimization Period, subjects were titrated until an optimal dose, based on tolerability and investigator's judgment, was reached. Vyvanse showed significantly greater efficacy than placebo. The placebo-adjusted mean reduction from baseline in the ADHD-RS-IV total score was 18.6. Subjects on Vyvanse also showed greater improvement on the Clinical Global Impression-Improvement (CGI-I) rating scale compared to subjects on placebo (Study 5 in Table 4).

Patients Ages 6 to 17 Years Old: Maintenance Treatment

Maintenance of Efficacy Study (Study 6) - A double-blind, placebo-controlled, randomized withdrawal study was conducted in children and adolescents ages 6 to 17 (N=276) who met the diagnosis of ADHD (DSM-IV criteria). A total of 276 patients were enrolled into the study, 236 patients participated in Study 5 and 40 subjects directly enrolled. Subjects were treated with open-label Vyvanse for at least 26 weeks prior to being assessed for entry into the randomized withdrawal period. Eligible patients had to demonstrate treatment response as defined by CGI-S < 3 and Total Score on the ADHD-RS ≤ 22. Patients that maintained treatment response for 2 weeks at the end of the open label treatment period were eligible to be randomized to ongoing treatment with the same dose of Vyvanse (N=78) or switched to placebo (N=79) during the double-blind phase. Patients were observed for relapse (treatment failure) during the 6 week double blind phase. A significantly lower proportion of treatment failures occurred among Vyvanse subjects (15.8%) compared to placebo (67.5%) at endpoint of the randomized withdrawal period. The endpoint measurement was defined as the last post-randomization treatment week at which a valid ADHD-RS Total Score and CGI-S were observed. Treatment failure was defined as a ≥ 50% increase (worsening) in the ADHD-RS Total Score and a ≥ 2-point increase in the CGI-S score compared to scores at entry into the double-blind randomized withdrawal phase. Subjects who withdrew from the randomized withdrawal period and who did not provide efficacy data at their last on-treatment visit were classified as treatment failures (Study 6, Figure 5).

Adults: Short-Term Treatment

A double-blind, randomized, placebo-controlled, parallel-group study (Study 7) was conducted in adults ages 18 to 55 (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 patients receiving Vyvanse were initiated on 30 mg for the first week of treatment. Patients 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). 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 (Study 7 in Table 4).

The second study was a multi-center, randomized, double-blind, placebo-controlled, cross-over, modified analog classroom study (Study 8) of Vyvanse to simulate a workplace environment in 142 adults ages 18 to 55 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). Patients 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), a skill-adjusted math test that measures attention in ADHD. PERMP total score results from the sum of the number of math problems attempted plus the number of math problems answered correctly. 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 (Study 8 in Table 4, Figure 6).

Adults: Maintenance Treatment

A double-blind, placebo-controlled, randomized withdrawal design study (Study 9) was conducted in adults ages 18 to 55 (N=123) who had a documented diagnosis of ADHD or met DSM-IV criteria for ADHD. At study entry, patients must have had documentation of treatment with Vyvanse for a minimum of 6 months and had to demonstrate treatment response as defined by Clinical Global Impression Severity (CGI-S) ≤ 3 and Total Score on the ADHD-RS < 22. ADHD-RS Total Score is a measure of core symptoms of ADHD. The CGI-S score assesses the clinician's impression of the patient's current illness state and ranges from 1 (not at all ill) to 7 (extremely ill). Patients that maintained treatment response at week 3 of the open label treatment phase (N=116) were eligible to be randomized to ongoing treatment with the same dose of Vyvanse (N=56) or switched to placebo (N=60) during the double-blind phase. Patients were observed for relapse (treatment failure) during the 6-week double-blind phase. The efficacy endpoint was the proportion of patients with treatment failure during the double-blind phase. Treatment failure was defined as a ≥ 50% increase (worsening) in the ADHD-RS Total Score and ≥ 2-point increase in the CGI-S score compared to scores at entry into the double-blind phase. Maintenance of efficacy for patients treated with Vyvanse was demonstrated by the significantly lower proportion of patients with treatment failure (9%) compared to patients receiving placebo (75%) at endpoint during the double-blind phase (Study 9, Figure 7).

Table 4: Summary of Primary Efficacy Results from 1-7 Week Studies of Vyvanse in Children, Adolescents, and Adults with ADHD

Study No.
(Age range)
Primary Endpoint Measure Placebo Vyvanse 30 mg/day Vyvanse 50 mg/day Vyvanse 70 mg/day Vyvanse 30, 50, or 70 mg/day
1 (6 -12 years) ADHD-RS- IV Mean Baseline Score 42.4 43.2 43.3 45.1 -
LS Mean difference from Placebo
(95% CI)a
- -15.6
(-20.8, -10.4)
-17.2
(-22.3, -12.1)
-20.5
(-25.6, -15.4)
-
2 (6 -12 years) Average SKAMP-DS Mean Pre-dose Score b - - - - -
LS Mean difference from Placebo
(95% CI)a
- - - - -0.9
(-1.1, -0.7)
3 (6 -12 years) Average SKAMP-DS Mean Pre-dose Score 0.7 - - - 0.9
LS Mean difference from Placebo
(95% CI)a
- - - - -0.7
(-0.9, -0.6)
4 (13 -17 years) ADHD-RS- IV Mean Baseline Score 38.5 38.3 37.3 37.0 -
LS Mean difference from Placebo
(95% CI)a
- -5.5
(-9.7, -1.3)
-8.3
(-12.5, -4.1)
-7.9
(-12.1, -3.8)
-
5 (6-17 years) ADHD-RS- IV Mean Baseline Score 41.0 - - - 40.7
LS Mean difference from Placebo
(95% CI)a
- - - - -18.6
(-21.5, -15.7)
7 (18 -55 years) ADHD-RS- IV Mean Baseline Score 39.4 40.5 40.8 41.0 -
LS Mean difference from Placebo
(95% CI)a
- -8.0
(-12.1,-3.9)
-9.2
(-13.2, -5.1)
-10.4
(-14.5,-6.3)
-
8 (18 -55 years) Average PERMP Mean Pre-dose Score 261.4 - - - 260.1
LS Mean difference from Placebo
(95% CI)a
- - - - 23.4
(15.6, 31.2)
aDifference (drug – placebo) in Least Squares Mean for the primary efficacy outcome along with 95% confidence intervals. If there are multiple Vyvanse dose arms, adjusted CIs are reported. For ADHD-RS-IV and SKAMP-DS scales, a higher score indicates more severe symptoms, so a negative LS mean difference indicates improvement from placebo
(studies 1-5, and 7). For the PERMP scale, a higher score indicates less severe symptoms, so a positive LS mean difference indicates improvement from placebo.
bPre-dose SKAMP-DS was not collected
CI: Confidence interval

Figure 4 : LS Mean SKAMP Deportment Subscale Score by Treatment and Time-point for Children Ages 6 to 12 with ADHD after 1 Week of Double Blind Treatment (Study 3)

LS Mean SKAMP Deportment Subscale Score by Treatment and Time-point for Children Ages 6 to 12 with ADHD after 1 Week of Double Blind Treatment - Illustration

Figure 5 : Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children and Adolescent Ages 6-17 (Study 6)

Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children and Adolescent Ages 6-17 - Illustration

Figure 6 : LS Mean (SE) PERMP Total Score by Treatment and Time-point for Adults Ages 18 to 55 with ADHD after 1 Week of Double Blind Treatment (Study 8)

LS Mean (SE) PERMP Total Score by Treatment and Time-point for Adults Ages 18 to 55 with ADHD after 1 Week of Double Blind Treatment - Illustration

Figure 7 : Kaplan-Meier Estimation of Time to Treatment Failure in Adults with ADHD (Study 9)

Kaplan-Meier Estimation of Time to Treatment Failure in Adults with ADHD - Illustration

Last reviewed on RxList: 8/11/2014
This monograph has been modified to include the generic and brand name in many instances.

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