CNS stimulants (amphetamines and methylphenidate-containing products), including VYVANSE, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see ].
Serious Cardiovascular Reactions
Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in children and adolescents with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during VYVANSE treatment.
Blood Pressure And Heart Rate Increases
CNS stimulants cause an increase in blood pressure (mean increase about 2-4 mm Hg) and heart rate (mean increase about 3-6 bpm). Monitor all patients for potential tachycardia and hypertension.
Psychiatric Adverse Reactions
Exacerbation Of Pre-Existing Psychosis
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
Induction Of A Manic Episode In Patients With Bipolar Disorder
CNS stimulants may induce a mixed/manic episode in patients with bipolar disorder. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, and depression).
New Psychotic Or Manic Symptoms
CNS stimulants, at recommended doses, may cause psychotic or manic symptoms, e.g. hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing VYVANSE. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated patients compared to 0% in placebo-treated patients.
Suppression Of Growth
CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including VYVANSE. In a 4-week, placebo-controlled trial of VYVANSE in patients ages 6 to 12 years old with ADHD, there was a dose-related decrease in weight in the VYVANSE groups compared to weight gain in the placebo group. Additionally, in studies of another stimulant, there was slowing of the increase in height [see ].
Peripheral Vasculopathy, Including Raynaud’s Phenomenon
Stimulants, including VYVANSE, are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort [see ]. Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism [see ]. The potential for a pharmacokinetic interaction exists with the co-administration of CYP2D6 inhibitors which may increase the risk with increased exposure to the active metabolite of VYVANSE (dextroamphetamine). In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see ]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Concomitant use of VYVANSE with MAOI drugs is contraindicated [see ].
Discontinue treatment with VYVANSE and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. Concomitant use of VYVANSE with other serotonergic drugs or CYP2D6 inhibitors should be used only if the potential benefit justifies the potential risk. If clinically warranted, consider initiating VYVANSE with lower doses, monitoring patients for the emergence of serotonin syndrome during drug initiation or titration, and informing patients of the increased risk for serotonin syndrome.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling ().
Controlled Substance Status/High Potential For Abuse And Dependence
Advise patients that VYVANSE is a controlled substance and it can be abused and lead to dependence and not to give VYVANSE to anyone else [see ]. Advise patients to store VYVANSE in a safe place, preferably locked, to prevent abuse. Advise patients to dispose of remaining, unused, or expired VYVANSE by a medicine take-back program.
Serious Cardiovascular Risks
Advise patients that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with VYVANSE use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see WARNINGS AND PRECAUTIONS].
Hypertension And Tachycardia
Instruct patients that VYVANSE can cause elevations of their blood pressure and pulse rate and they should be monitored for such effects.
Advise patients that VYVANSE at recommended doses may cause psychotic or manic symptoms even in patients without prior history of psychotic symptoms or mania [see WARNINGS AND PRECAUTIONS].
Suppression Of Growth
Advise patients that VYVANSE may cause slowing of growth including weight loss [see WARNINGS AND PRECAUTIONS].
Impairment In Ability To Operate Machinery Or Vehicles
Advise patients that VYVANSE may impair their ability to engage in potentially dangerous activities such as operating machinery or vehicles. Instruct patients to find out how VYVANSE will affect them before engaging in potentially dangerous activities [see ].
Circulation Problems In Fingers And Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon]
Instruct patients beginning treatment with VYVANSE about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking VYVANSE. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for certain patients [see WARNINGS AND PRECAUTIONS].
Caution patients about the risk of serotonin syndrome with concomitant use of VYVANSE and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see , WARNINGS AND PRECAUTIONS and ]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.
Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs because there is a potential for interactions [see ].
Advise patients of the potential fetal effects from the use of VYVANSE during pregnancy.
Advise patients to notify their healthcare provider if they become pregnant or intend to become
pregnant during treatment with VYVANSE [see Use In Specific Populations].
Advise women not to breastfeed if they are taking VYVANSE [see Use In Specific Populations
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.
Impairment Of Fertility
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.
Use In Specific Populations
The limited available data from published literature and postmarketing reports on use of VYVANSE in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines [see Clinical Considerations]. In animal reproduction studies, lisdexamfetamine dimesylate (a prodrug of d-amphetamine) had no effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis. Pre-and postnatal studies were not conducted with lisdexamfetamine dimesylate. However, amphetamine (d-to l-ratio of 3:1) administration to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Fetal/Neonatal Adverse Reactions
Amphetamines, such as VYVANSE, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Infants born to amphetamine-dependent mothers have an increased risk of premature delivery and low birth weight.
Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.
Lisdexamfetamine dimesylate had no apparent effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 40 and 120 mg/kg/day, respectively. These doses are approximately 4 and 27 times, respectively, the maximum recommended human dose (MRHD) of 70 mg/day given to adolescents, on a mg/m2 body surface area basis.
A study was conducted with amphetamine (d-to l-enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. These doses are approximately 0.8, 2, and 4 times the MRHD of amphetamine (d-to l-ratio of 3:1) for adolescents of 20 mg/day, on a mg/m2 basis. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg.
A number of studies from the literature 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.
Lisdexamfetamine is a pro-drug of dextroamphetamine. Based on limited case reports in published literature, amphetamine (d-or d, l-) is present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of dextroamphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, including serious cardiovascular reactions, blood pressure and heart rate increase, suppression of growth, and peripheral vasculopathy, advise patients that breastfeeding is not recommended during treatment with VYVANSE.
Safety and effectiveness have been established in pediatric patients with ADHD ages 6 to 17
years [see , and ].
Safety and efficacy in pediatric patients below the age of 6 years have not been established.
Safety and effectiveness in patients less than 18 years of age have not been established.
Growth should be monitored during treatment with stimulants, including VYVANSE, and children who are not growing or gaining weight as expected may need to have their treatment interrupted [see WARNINGS AND PRECAUTIONS , ].
Juvenile Animal Data
Studies conducted in juvenile rats and dogs at clinically relevant doses showed growth suppression that partially or fully reversed in dogs and female rats but not in male rats after a four-week drug-free recovery period.
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 for a child. 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 for a child). This effect partially or fully reversed during a four-week drug-free recovery period.
Clinical studies of VYVANSE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data [see ] have not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Due to reduced clearance in patients with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m2), the maximum dose should not exceed 50 mg/day. The maximum recommended dose in ESRD (GFR < 15 mL/min/1.73 m2) patients is 30 mg/day [see ].
Lisdexamfetamine and d-amphetamine are not dialyzable.
No dosage adjustment of VYVANSE is necessary on the basis of gender [see ].
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.
Pharmacokinetic studies after oral administration of lisdexamfetamine dimesylate have been conducted in healthy adult (capsule and chewable tablet formulations) and pediatric (6 to 12 years) patients with ADHD (capsule formulation). After single dose administration of lisdexamfetamine dimesylate, pharmacokinetics of dextroamphetamine was found to be linear between 30 mg and 70 mg in a pediatric study, and between 50 mg and 250 mg in an adult study. Dextroamphetamine pharmacokinetic parameters following administration of lisdexamfetamine dimesylate in adults exhibited low inter-subject (<25%) and intra-subject (<8%) variability. There is no accumulation of lisdexamfetamine and dextroamphetamine at steady state in healthy adults.
Safety and efficacy have not been studied above the maximum recommended dose of 70 mg.
Following single-dose oral administration of VYVANSE capsule (30 mg, 50 mg, or 70 mg) in patients ages 6 to 12 years with ADHD under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at approximately 1 hour and 3.5 hour post dose, respectively. Weight/Dose normalized AUC and Cmax values were the same in pediatric patients ages 6 to 12 years as the adults following single doses of 30 mg to 70 mg VYVANSE capsule.
Food Effect On Capsule Formulation
Neither food (a high fat meal or yogurt) nor orange juice affects 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 hour at fasted state to 4.7 hour after a high fat meal or to 4.2 hour with yogurt). After an 8-hour fast, the AUC for dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.
Chewable Tablet Formulation
After a single dose administration of 60 mg VYVANSE chewable tablet in healthy subjects under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at approximately 1 hour and 4.4 hour post dose, respectively. Compared to 60 mg VYVANSE capsule, exposure (Cmax and AUC) to lisdexamfetamine was about 15% lower. The exposure (Cmax and AUCinf) of dextroamphetamine is similar between VYVANSE chewable tablet and VYVANSE capsule.
Food Effect on Tablet Formulation
Administration of 60 mg VYVANSE chewable tablet with food (a high-fat meal) decreases the exposure (Cmax and AUCinf) of dextroamphetamine by about 5% to 7%, and prolongs mean Tmax by approximately 1 hour (from 3.9 hrs at fasted state to 4.9 hours).
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. The mean plasma elimination half-life of dextroamphetamine was about 12 hours after oral administration of lisdexamfetamine dimesylate.
Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells after oral administration of lisdexamfetamine dimesylate. 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 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.
Drug Interaction Studies
Figure 2: Effect of Other Drugs on VYVANSE:
The effects of VYVANSE on the exposures of other drugs are summarized in Figure 3.
Figure 3: Effect of VYVANSE on Other Drugs:
Animal Toxicology And/Or Pharmacology
Efficacy of VYVANSE in the treatment of ADHD has been established in the following trials:
Efficacy of VYVANSE in the treatment of moderate to severe BED in adults has been established in the following trials:
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 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 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 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 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 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 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
|Primary Endpoint||Treatment Group||Mean Baseline Score
|LS Mean Change from Baseline
(6 -12 years)
|ADHD-RSIV||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)||–|
(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||–|
(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||–|
|ADHD-RSIV||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)||–|
|ADHD-RSIV||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)||–|
|ADHD-RSIV||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)||–|
|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.
Higher score on the SKAMP-Deportment scale indicates more severe symptoms
Figure 5: Kaplan-Meier Estimated Proportion of Patients with Treatment Failure for Children and Adolescent Ages 6-17 (Study 6)
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)
Higher score on the PERMP scale indicates less severe symptoms.
Figure 7: Kaplan-Meier Estimated Proportion of Subjects with Relapse in Adults with ADHD (Study 9)
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 (Study 10) 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 (Study 11 and Study 12) in adults aged 18-55 years (Study 11: N=374, Study 12: 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 dose-maintenance 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 11||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 12||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.
A double-blind, placebo controlled, randomized withdrawal design study (Study 13) was conducted to evaluate maintenance of efficacy based on time to relapse between VYVANSE and placebo in adults aged 18 to 55 (N=267) with moderate to severe BED. In this longer-term study patients who had responded to VYVANSE in the preceding 12-week open-label treatment phase were randomized to continuation of VYVANSE or placebo for up to 26 weeks of observation for relapse. Response in the open-label phase was defined as 1 or fewer binge days each week for four consecutive weeks prior to the last visit at the end of the 12-week open-label phase and a CGI-S score of 2 or less at the same visit. Relapse during the double-blind phase was defined as having 2 or more binge days each week for two consecutive weeks (14 days) prior to any visit and having an increase in CGI-S score of 2 or more points compared to the randomized-withdrawal baseline. Maintenance of efficacy for patients who had an initial response during the open-label period and then continued on VYVANSE during the 26-week double-blind randomized-withdrawal phase was demonstrated with VYVANSE being superior over placebo as measured by time to relapse.
Figure 8: Kaplan-Meier Estimated Proportion of Subjects with Relapse in Adults with BED (Study 13)
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.
This content was originally published here.