July 30, 2015
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Vyvanse

"March 4, 2013 -- Nearly 30% of children with ADHD continue to struggle with the condition as adults, and some may develop other mental health issues, commit suicide, or end up in jail, a new study shows.

"We suffer from the misconceptio"...

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 4.2 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.

Drug Interaction Studies

Figure 1: Effect of Other Drugs on VYVANSE

Effect of Other Drugs on VYVANSE - Illustration

Figure 2: Effect of VYVANSE on Other Drugs

Effect of VYVANSE on Other Drugs - Illustration

Studies in Specific Populations

Renal Impairment

In a pharmacokinetic study of lisdexamfetamine in subjects with normal and impaired renal function mean d-amphetamine clearance was reduced from 0.7 L/hr/kg in normal subjects to 0.4 L/hr/kg in subjects with severe renal impairment (GFR 15 to < 30mL/min/1.73m²) and 0.3 L/hr/kg in ESRD patients. Dialysis did not significantly affect the clearance of d-amphetamine; the mean clearance of d-amphetamine was 0.3 L/hr/kg for both pre- and post- dialysis [see Use in Specific Populations].

Figure 3: Specific Populations*

Studies in Specific Populations - Illustration

*Figure 3 shows the geometric mean ratios and the 90% confidence limits for Cmax and AUC of d-amphetamine. Comparison for gender uses males as the reference. Comparison for age uses 55-64 years as the reference.

Animal Toxicology And/Or Pharmacology

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

Clinical Studies

Efficacy of VYVANSE in the treatment of ADHD has been established in the following trials:

  • Three short-term trials in children (6 to 12 years, Studies 1, 2, 3)
  • One short-term trial in adolescents (13 to 17 years, Study 4)
  • One short-term trial in children and adolescents (6 to 17 years, Study 5)
  • Two short-term trials in adults (18 to 55 years, Studies 7, 8)
  • Two randomized withdrawal trials in children and adolescents (6 to 17 years, Study 6), and adults (18 to 55 years, Study 9)

Efficacy of VYVANSE in the treatment of BED has been established in two 12-week trials in adults (18 to 55 years) with moderate to severe BED (Study 10 and 11).

Attention Deficit Hyperactivity Disorder (ADHD)

Patients Ages 6 To 12 Years Old With ADHD

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 7). 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 openlabel 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 7). 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 7, Figure 4).

Patients Ages 13 to 17 Years Old with ADHD

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 7).

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

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 7).

Patients Ages 6 to 17 Years Old: Maintenance Treatment in ADHD

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 postrandomization 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 doubleblind 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 in ADHD

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 7).

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 openlabel, 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 7, Figure 6).

Adults: Maintenance Treatment in ADHD

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 7: Summary of Primary Efficacy Results from Short-term Studies of VYVANSE in Children, Adolescents, and Adults with ADHD

Study Number (Age range) Primary Endpoint Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI)
Study 1 (6 - 12 years) ADHD-RS- IV VYVANSE (30 mg/day)* 43.2 (6.7) -21.8 (1.6) -15.6 (-19.9, -11.2)
VYVANSE (50 mg/day)* 43.3 (6.7) -23.4 (1.6) -17.2 (-21.5, -12.9)
VYVANSE (70 mg/day)* 45.1(6.8) -26.7 (1.5) -20.5 (-24.8, -16.2)
Placebo 42.4 (7.1) -6.2 (1.6) --
Study 2 (6 - 12 years) Average SKAMP-DS VYVANSE (30, 50 or 70 mg/day)* -- b 0.8 (0.1)d -0.9 (-1.1, -0.7)
Placebo -- b 1.7 (0.1)d --
Study 3 (6 - 12 years) Average SKAMP-DS VYVANSE (30, 50 or 70 mg/day)* 0.9 (1.0)c 0.7 (0.1)d -0.7 (-0.9, -0.6)
Placebo 0.7 (0.9)c 1.4 (0.1)d --
Study 4 (13 - 17 years) ADHD-RS- IV VYVANSE (30 mg/day)* 38.3 (6.7) -18.3 (1.2) -5.5 (-9.0, -2.0)
VYVANSE (50 mg/day)* 37.3 (6.3) -21.1 (1.3) -8.3 (-11.8, -4.8)
VYVANSE (70 mg/day)* 37.0 (7.3) -20.7 (1.3) -7.9 (-11.4, -4.5)
Placebo 38.5 (7.1) -12.8 (1.2) --
Study 5 (6 - 17 years) ADHD-RS- IV VYVANSE (30, 50 or 70 mg/day)* 40.7 (7.3) -24.3 (1.2) -18.6 (-21.5, -15.7)
Placebo 41.0 (7.1) -5.7 (1.1) --
Study 7 (18 - 55 years) ADHD-RS- IV VYVANSE (30 mg/day)* 40.5 (6.2) -16.2 (1.1) -8.0 (-11.5, -4.6)
VYVANSE (50 mg/day)* 40.8 (7.3) -17.4 (1.0) -9.2 (-12.6, -5.7)
VYVANSE (70 mg/day)* 41.0 (6.0) -18.6 (1.0) -10.4 (-13.9, -6.9)
Placebo 39.4 (6.4) -8.2 (1.4) --
Study 8 (18 - 55 years) Average PERMP VYVANSE (30, 50 or 70 mg/day)* 260.1 (86.2)c 312.9 (8.6)d 23.4 (15.6, 31.2)
Placebo 261.4 (75.0)c 289.5 (8.6)d --
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline.
b Pre-dose SKAMP-DS was not collected.
c Pre-dose SKAMP-DS (Study 3) or PERMP (Study 8) total score, averaged over both periods.
d LS Mean for SKAMP-DS (Study 2 and 3) or PERMP (Study 8) is post-dose average score over all sessions of the treatment day, rather than change from baseline.
* Doses statistically significantly superior to placebo.

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 - Illustration

Higher score on the SKAMP-Deportment scale indicates more severe symptoms

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

Higher score on the PERMP scale indicates less severe symptoms.

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

Binge Eating Disorder (BED)

A phase 2 study evaluated the efficacy of VYVANSE 30, 50 and 70 mg/day compared to placebo in reducing the number of binge days/week in adults with at least moderate to severe BED. This randomized, double-blind, parallel-group, placebo-controlled, forced-dose titration study consisted of an 11-week double-blind treatment period (3 weeks of forced-dose titration followed by 8 weeks of dose maintenance). VYVANSE 30 mg/day was not statistically different from placebo on the primary endpoint. The 50 and 70 mg/day doses were statistically superior to placebo on the primary endpoint.

The efficacy of VYVANSE in the treatment of BED was demonstrated in two 12-week randomized, double-blind, multi-center, parallel-group, placebo-controlled, dose-optimization studies in adults aged 18-55 years (Study 10: N=374, Study 11: N=350) with moderate to severe BED. A diagnosis of BED was confirmed using DSM-IV criteria for BED. Severity of BED was determined based on having at least 3 binge days per week for 2 weeks prior to the baseline visit and on having a Clinical Global Impression Severity (CGI-S) score of ≥4 at the baseline visit. For both studies, a binge day was defined as a day with at least 1 binge episode, as determined from the subject's daily binge diary.

Both 12-week studies consisted of a 4-week dose-optimization period and an 8-week dosemaintenance period. During dose-optimization, subjects assigned to VYVANSE began treatment at the titration dose of 30 mg/day and, after 1 week of treatment, were subsequently titrated to 50mg/day. Additional increases to 70 mg/day were made as tolerated and clinically indicated. Following the dose-optimization period, subjects continued on their optimized dose for the duration of the dose-maintenance period.

The primary efficacy outcome for the two studies was defined as the change from baseline at Week 12 in the number of binge days per week. Baseline is defined as the weekly average of the number of binge days per week for the 14 days prior to the baseline visit. Subjects from both studies on VYVANSE had a statistically significantly greater reduction from baseline in mean number of binge days per week at Week 12. In addition, subjects on VYVANSE showed greater improvement as compared to placebo across key secondary outcomes with higher proportion of subjects rated improved on the CGI-I rating scale, higher proportion of subjects with 4-week binge cessation, and greater reduction in the Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) total score.

Table 8: Summary of Primary Efficacy Results in BED

Study Number Treatment Group Primary Efficacy Measure: Binge Days per Week at Week 12
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI)
Study 10 VYVANSE (50 or 70 mg/day)* 4.79 (1.27) -3.87 (0.12) -1.35 (-1.70, -1.01)
Placebo 4.60 (1.21) -2.51 (0.13) --
Study 11 VYVANSE (50 or 70 mg/day)* 4.66 (1.27) -3.92 (0.14) -1.66 (-2.04, -1.28)
Placebo 4.82 (1.42) -2.26 (0.14) --
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline.
* Doses statistically significantly superior to placebo.

Examination of population subgroups based on age (there were no patients over 65), gender, and race did not reveal any clear evidence of differential responsiveness in the treatment of BED.

Last reviewed on RxList: 2/5/2015
This monograph has been modified to include the generic and brand name in many instances.

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