The following Structured Product Label (SPL) was submitted to the FDA by Takeda Pharmaceuticals America, Inc. for the product Vyvanse (NDC 59417-106). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding warning: abuse and dependence, 1 indications and usage, other, 2.1 pre-treatment screening, 2.2 general instructions for use, 2.3 dosage for treatment of adhd, 2.4 dosage for treatment of moderate to severe bed in adults, 2.5 dosage in patients with renal impairment, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
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 Warnings and Precautions (5.1, 5.2), and Drug Abuse and Dependence (9.2, 9.3)].
VYVANSE® is indicated for the treatment of:
Limitation of Use:
VYVANSE is not indicated or recommended for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of VYVANSE for the treatment of obesity have not been established [see Warnings and Precautions (5.2)].
Information for VYVANSE capsules:
Information for VYVANSE chewable tablets:
VYVANSE capsules can be substituted with VYVANSE chewable tablets on a unit per unit/ mg per mg basis (for example, 30 mg capsules for 30 mg chewable tablet) [see Clinical Pharmacology (12.3)].
Do not take anything less than one capsule or chewable tablet per day. A single dose should not be divided.
Information for VYVANSE capsules:
Information for VYVANSE chewable tablets:
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.
Attention Deficit Hyperactivity Disorder
The safety data in this section is based on data from the 4-week parallel-group controlled clinical studies of VYVANSE in pediatric and adult patients with ADHD [see Clinical Studies (14.1)].
Adverse Reactions Associated with Discontinuation of Treatment in ADHD Clinical Trials
In the controlled trial in patients ages 6 to 12 years (Study 1), 8% (18/218) of VYVANSE-treated patients discontinued due to adverse reactions compared to 0% (0/72) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, insomnia, decreased appetite and rash [2 instances for each adverse reaction, i.e., 2/218 (1%)]. Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included abdominal pain upper, dry mouth, weight decreased, dizziness, somnolence, logorrhea, chest pain, anger and hypertension.
In the controlled trial in patients ages 13 to 17 years (Study 4), 3% (7/233) of VYVANSE-treated patients discontinued due to adverse reactions compared to 1% (1/77) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were decreased appetite (2/233; 1%) and insomnia (2/233; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included irritability, dermatillomania, mood swings, and dyspnea.
In the controlled adult trial (Study 7), 6% (21/358) of VYVANSE-treated patients discontinued due to adverse reactions compared to 2% (1/62) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%), hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included palpitations, diarrhea, nausea, decreased appetite, dizziness, agitation, depression, paranoia and restlessness.
Adverse Reactions Occurring at an Incidence of ≥5% or More Among VYVANSE Treated Patients with ADHD in Clinical Trials
The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in children, adolescents, and/or adults were anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting.
Adverse Reactions Occurring at an Incidence of 2% or More Among VYVANSE Treated Patients with ADHD in Clinical Trials
Adverse reactions reported in the controlled trials in pediatric patients ages 6 to 12 years (Study 1), adolescent patients ages 13 to 17 years (Study 4), and adult patients (Study 7) treated with VYVANSE or placebo are presented in Tables 1, 2, and 3 below.
| VYVANSE (n=218) | Placebo (n=72) | |
|---|---|---|
| Decreased Appetite | 39% | 4% |
| Insomnia | 22% | 3% |
| Abdominal Pain Upper | 12% | 6% |
| Irritability | 10% | 0% |
| Vomiting | 9% | 4% |
| Weight Decreased | 9% | 1% |
| Nausea | 6% | 3% |
| Dry Mouth | 5% | 0% |
| Dizziness | 5% | 0% |
| Affect lability | 3% | 0% |
| Rash | 3% | 0% |
| Pyrexia | 2% | 1% |
| Somnolence | 2% | 1% |
| Tic | 2% | 0% |
| Anorexia | 2% | 0% |
| VYVANSE (n=233) | Placebo (n=77) | |
|---|---|---|
| Decreased Appetite | 34% | 3% |
| Insomnia | 13% | 4% |
| Weight Decreased | 9% | 0% |
| Dry Mouth | 4% | 1% |
| Palpitations | 2% | 1% |
| Anorexia | 2% | 0% |
| Tremor | 2% | 0% |
| VYVANSE (n=358) | Placebo (n=62) | |
|---|---|---|
| Decreased Appetite | 27% | 2% |
| Insomnia | 27% | 8% |
| Dry Mouth | 26% | 3% |
| Diarrhea | 7% | 0% |
| Nausea | 7% | 0% |
| Anxiety | 6% | 0% |
| Anorexia | 5% | 0% |
| Feeling Jittery | 4% | 0% |
| Agitation | 3% | 0% |
| Increased Blood Pressure | 3% | 0% |
| Hyperhidrosis | 3% | 0% |
| Restlessness | 3% | 0% |
| Decreased Weight | 3% | 0% |
| Dyspnea | 2% | 0% |
| Increased Heart Rate | 2% | 0% |
| Tremor | 2% | 0% |
| Palpitations | 2% | 0% |
In addition, in the adult population erectile dysfunction was observed in 2.6% of males on VYVANSE and 0% on placebo; decreased libido was observed in 1.4% of subjects on VYVANSE and 0% on placebo.
Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD
In a controlled trial of VYVANSE in children ages 6 to 12 years (Study 1), mean weight loss from baseline after 4 weeks of therapy was -0.9, -1.9, and -2.5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 1 pound weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with 4 weeks of treatment. Careful follow-up for weight in children ages 6 to 12 years who received VYVANSE over 12 months suggests that consistently medicated children (i.e. treatment for 7 days per week throughout the year) have a slowing in growth rate, measured by body weight as demonstrated by an age- and sex-normalized mean change from baseline in percentile, of -13.4 over 1 year (average percentiles at baseline and 12 months were 60.9 and 47.2, respectively). In a 4-week controlled trial of VYVANSE in adolescents ages 13 to 17 years, mean weight loss from baseline to endpoint was -2.7, -4.3, and -4.8 lbs., respectively, for patients receiving 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 2.0 pound weight gain for patients receiving placebo.
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e. treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In a controlled trial of amphetamine (d- to l-enantiomer ratio of 3:1) in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was -1.1 pounds and -2.8 pounds, respectively, for patients receiving 10 mg and 20 mg of amphetamine. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment [see Warnings and Precautions (5.5)].
Weight Loss in Adults with ADHD
In the controlled adult trial (Study 7), mean weight loss after 4 weeks of therapy was 2.8 pounds, 3.1 pounds, and 4.3 pounds, for patients receiving final doses of 30 mg, 50 mg, and 70 mg of VYVANSE, respectively, compared to a mean weight gain of 0.5 pounds for patients receiving placebo.
Binge Eating Disorder
The safety data in this section is based on data from two 12 week parallel group, flexible-dose, placebo-controlled studies in adults with BED [see Clinical Studies 14.2]. Patients with cardiovascular risk factors other than obesity and smoking were excluded.
Adverse Reactions Associated with Discontinuation of Treatment in BED Clinical Trials
In controlled trials of patients ages 18 to 55 years, 5.1% (19/373) of VYVANSE-treated patients discontinued due to adverse reactions compared to 2.4% (9/372) of placebo-treated patients. No single adverse reaction led to discontinuation in 1% or more of VYVANSE-treated patients. Less commonly reported adverse reactions (less than 1% or less than twice rate of placebo) included increased heart rate, headache, abdominal pain upper, dyspnea, rash, insomnia, irritability, feeling jittery and anxiety.
Adverse Reactions Occurring at an Incidence of ≥5% or More Among VYVANSE Treated Patients with BED in Clinical Trials
The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in adults were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety.
Adverse Reactions Occurring at an Incidence of 2% or More Among VYVANSE Treated Patients with BED in Clinical Trials
Adverse reactions reported in the pooled controlled trials in adult patients (Study 11 and 12) treated with VYVANSE or placebo are presented in Table 4 below.
| VYVANSE (N=373) | Placebo (N=372) | |
|---|---|---|
| Dry Mouth | 36% | 7% |
| Insomnia Includes all preferred terms containing the word "insomnia." | 20% | 8% |
| Decreased Appetite | 8% | 2% |
| Increased Heart Rate Includes the preferred terms "heart rate increased" and "tachycardia." | 7% | 1% |
| Feeling Jittery | 6% | 1% |
| Constipation | 6% | 1% |
| Anxiety | 5% | 1% |
| Diarrhea | 4% | 2% |
| Decreased Weight | 4% | 0% |
| Hyperhidrosis | 4% | 0% |
| Vomiting | 2% | 1% |
| Gastroenteritis | 2% | 1% |
| Paresthesia | 2% | 1% |
| Pruritus | 2% | 1% |
| Upper Abdominal Pain | 2% | 0% |
| Energy Increased | 2% | 0% |
| Urinary Tract Infection | 2% | 0% |
| Nightmare | 2% | 0% |
| Restlessness | 2% | 0% |
| Oropharyngeal Pain | 2% | 0% |
Risk Summary
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.
Clinical Considerations
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.
Data
Animal Data
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 long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.
Risk Summary
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.
ADHD
Safety and effectiveness have been established in pediatric patients with ADHD ages 6 to 17 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Safety and efficacy in pediatric patients below the age of 6 years have not been established.
BED
Safety and effectiveness in patients less than 18 years of age have not been established.
Growth Suppression
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 (5.5), Adverse Reactions (6.1)].
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.
Studies of VYVANSE in Drug Abusers
A randomized, double-blind, placebo-control, cross-over, abuse liability study in 38 patients with a history of drug abuse was conducted with single-doses of 50, 100, or 150 mg of VYVANSE, 40 mg of immediate-release d-amphetamine sulphate (a controlled II substance), and 200 mg of diethylpropion hydrochloride (a controlled IV substance). VYVANSE 100 mg produced significantly less "Drug Liking Effects" as measured by the Drug Rating Questionnaire-Subject score, compared to d-amphetamine 40 mg; and 150 mg of VYVANSE demonstrated similar "Drug-Liking Effects" compared to 40 mg of d-amphetamine and 200 mg of diethylpropion.
Intravenous administration of 50 mg lisdexamfetamine dimesylate to individuals with a history of drug abuse produced positive subjective responses on scales measuring "Drug Liking", "Euphoria", "Amphetamine Effects", and "Benzedrine Effects" that were greater than placebo but less than those produced by an equivalent dose (20 mg) of intravenous d-amphetamine.
Tolerance
Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug's desired and/or undesired effects over time) may occur during the chronic therapy of CNS stimulants including VYVANSE.
Dependence
Physical dependence (a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including VYVANSE. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include extreme fatigue and depression.
Information for VYVANSE capsules:
VYVANSE capsules contain 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of lisdexamfetamine dimesylate (equivalent to 5.8 mg, 11.6 mg, 17.3 mg, 23.1 mg, 28.9 mg, 34.7 mg, and 40.5 mg of lisdexamfetamine).
Inactive ingredients: microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, and one or more of the following: FD&C Red #3, FD&C Yellow #6, FD&C Blue #1, Black Iron Oxide, and Yellow Iron Oxide.
Information for VYVANSE chewable tablets:
VYVANSE chewable tablets contain 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg of lisdexamfetamine dimesylate (equivalent to 5.8 mg, 11.6 mg, 17.3 mg, 23.1 mg, 28.9 mg, and 34.7 mg of lisdexamfetamine).
Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, guar gum, magnesium stearate, mannitol, microcrystalline cellulose, sucralose, artificial strawberry flavor.
Absorption
Capsule formulation
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).
Elimination
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.
Metabolism
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.
Excretion
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.
Specific Populations
Exposures of dextroamphetamine in specific populations are summarized in Figure 1.
| Figure 1: Specific Populations Figure 1 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. : |
 Figure 1 (Vyvanse 02) |
Drug Interaction Studies
Effects of other drugs on the exposures of dextroamphetamine are summarized in Figure 2.
| Figure 2: Effect of Other Drugs on VYVANSE: |
 Figure 2 (Vyvanse 03) |
The effects of VYVANSE on the exposures of other drugs are summarized in Figure 3.
| Figure 3: Effect of VYVANSE on Other Drugs: |
 Figure 3 (Vyvanse 04) |
Carcinogenesis
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.
Mutagenesis
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.
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).
| Study Number (Age range) | Primary Endpoint | Treatment Group | Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI) |
|---|---|---|---|---|---|
| SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. | |||||
| Study 1 (6 - 12 years) | ADHD-RS-IV | VYVANSE (30 mg/day) Doses statistically significantly superior to placebo. | 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) | -- Pre-dose SKAMP-DS was not collected. | 0.8 (0.1) 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. | -0.9 (-1.1, -0.7) |
| Placebo | -- | 1.7 (0.1) | -- | ||
| Study 3 (6 - 12 years) | Average SKAMP-DS | VYVANSE (30, 50 or 70 mg/day) | 0.9 (1.0) Pre-dose SKAMP-DS (Study 3) or PERMP (Study 8) total score, averaged over both periods. | 0.7 (0.1) | -0.7 (-0.9, -0.6) |
| Placebo | 0.7 (0.9) | 1.4 (0.1) | -- | ||
| 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) | 312.9 (8.6) | 23.4 (15.6, 31.2) |
| Placebo | 261.4 (75.0) | 289.5 (8.6) | -- | ||
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)
Figure 4 (Vyvanse 05)
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 5 (Vyvanse 06)
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)
Figure 6 (Vyvanse 07)
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)
Figure 7 (Vyvanse 08)
Information for VYVANSE capsules:
Information for VYVANSE chewable tablets:
Disposal
Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired VYVANSE by a medicine take-back program.
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 Drug Abuse and Dependence (9.1, 9.2, and 9.3)]. 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 (5.2)].
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.
Psychiatric Risks
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 (5.4)].
Suppression of Growth
Advise patients that VYVANSE may cause slowing of growth including weight loss [see Warnings and Precautions (5.5)].
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 Adverse Reactions (6.1, 6.2)].
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 (5.6)].
Serotonin Syndrome
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 Contraindications (4), Warnings and Precautions (5.7) and Drug Interactions (7.1)]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.
Concomitant Medications
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 Drug Interactions (7.1)].
Manufactured for: Shire US Inc., 300 Shire Way, Lexington, MA 02421
Made in USA
For more information call 1-800-828-2088
VYVANSE® is a registered trademark of Shire LLC
©2018 Shire US Inc.
US Pat No. 7,105,486, 7,223,735, 7,655,630, 7,659,253, 7,659,254, 7,662,787, 7,662,788, 7,671,030, 7,671,031, 7,674,774, 7,678,770, 7,678,771, 7,687,466, 7,687,467, 7,713,936, 7,718,619, 7,723,305
Prior to treating children, adolescents, and adults with CNS stimulants, including VYVANSE, assess for the presence of cardiac disease (e.g., a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
To reduce the abuse of CNS stimulants including VYVANSE, assess the risk of abuse, prior to prescribing. After prescribing, keep careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and re-evaluate the need for VYVANSE use [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].
Take VYVANSE by mouth in the morning with or without food; avoid afternoon doses because of the potential for insomnia. VYVANSE may be administered in one of the following ways:
The recommended starting dose is 30 mg once daily in the morning in patients ages 6 and above. Dosage may be adjusted in increments of 10 mg or 20 mg at approximately weekly intervals up to maximum dose of 70 mg/day [see Clinical Studies (14.1)].
The recommended starting dose is 30 mg/day to be titrated in increments of 20 mg at approximately weekly intervals to achieve the recommended target dose of 50 to 70 mg/day. The maximum dose is 70 mg/day [see Clinical Studies (14.2)]. Discontinue VYVANSE if binge eating does not improve.
In patients with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m2), the maximum dose should not exceed 50 mg/day. In patients with end stage renal disease (ESRD, GFR < 15 mL/min/1.73 m2), the maximum recommended dose is 30 mg/day [see Use in Specific Populations (8.6)].
Agents that alter urinary pH can impact urinary excretion and alter blood levels of amphetamine. Acidifying agents (e.g., ascorbic acid) decrease blood levels, while alkalinizing agents (e.g., sodium bicarbonate) increase blood levels. Adjust VYVANSE dosage accordingly [see Drug Interactions (7.1)].
VYVANSE is contraindicated in patients with:
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 Drug Abuse and Dependence (9.2, 9.3)].
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.
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.
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 Adverse Reactions (6.1)].
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 Drug Interactions (7.1)]. 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 Clinical Pharmacology 12.3]. 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 Drug Interactions (7.1)]. 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 Contraindications (4)].
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.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The following adverse reactions have been identified during post approval use of VYVANSE. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events are as follows: cardiomyopathy, mydriasis, diplopia, difficulties with visual accommodation, blurred vision, eosinophilic hepatitis, anaphylactic reaction, hypersensitivity, dyskinesia, dysgeusia, tics, bruxism, depression, dermatillomania, alopecia, aggression, Stevens-Johnson Syndrome, chest pain, angioedema, urticaria, seizures, libido changes, frequent or prolonged erections, constipation, and rhabdomyolysis.
| MAO Inhibitors (MAOI) | |
| Clinical Impact | MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. |
| Intervention | Do not administer VYVANSE during or within 14 days following the administration of MAOI [see Contraindications (4)]. |
| Examples | selegiline, isocarboxazid, phenelzine, tranylcypromine |
| Serotonergic Drugs | |
| Clinical Impact | The concomitant use of VYVANSE and serotonergic drugs increases the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during VYVANSE initiation or dosage increase. If serotonin syndrome occurs, discontinue VYVANSE and the concomitant serotonergic drug(s) [see Warnings and Precautions (5.7)]. |
| Examples | selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort |
| CYP2D6 Inhibitors | |
| Clinical Impact | The concomitant use of VYVANSE and CYP2D6 inhibitors may increase the exposure of dextroamphetamine, the active metabolite of VYVANSE compared to the use of the drug alone and increase the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during VYVANSE initiation and after a dosage increase. If serotonin syndrome occurs, discontinue VYVANSE and the CYP2D6 inhibitor [see Warnings and Precautions (5.7) and Overdosage (10)]. |
| Examples | paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir |
| Alkalinizing Agents | |
| Clinical Impact | Urinary alkalinizing agents can increase blood levels and potentiate the action of amphetamine. |
| Intervention | Co-administration of VYVANSE and urinary alkalinizing agents should be avoided. |
| Examples | Urinary alkalinizing agents (e.g. acetazolamide, some thiazides). |
| Acidifying Agents | |
| Clinical Impact | Urinary acidifying agents can lower blood levels and efficacy of amphetamines. |
| Intervention | Increase dose based on clinical response. |
| Examples | Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts). |
| Tricyclic Antidepressants | |
| Clinical Impact | May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. |
| Intervention | Monitor frequently and adjust or use alternative therapy based on clinical response. |
| Examples | desipramine, protriptyline |
From a pharmacokinetic perspective, no dose adjustment of VYVANSE is necessary when VYVANSE is co-administered with guanfacine, venlafaxine, or omeprazole. In addition, no dose adjustment of guanfacine or venlafaxine is needed when VYVANSE is co-administered [see Clinical Pharmacology (12.3)].
From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g. theophylline, duloxetine, melatonin), CYP2D6 (e.g. atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g. omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g. midazolam, pimozide, simvastatin) is necessary when VYVANSE is co-administered [see Clinical Pharmacology (12.3)].
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 Clinical Pharmacology (12.3)] 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 Clinical Pharmacology (12.3)].
Lisdexamfetamine and d-amphetamine are not dialyzable.
No dosage adjustment of VYVANSE is necessary on the basis of gender [see Clinical Pharmacology (12.3)].
VYVANSE contains lisdexamfetamine, a prodrug of amphetamine, a Schedule II controlled substance.
CNS stimulants, including VYVANSE, other amphetamines, and methylphenidate-containing products have a high potential for abuse. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving.
Signs and symptoms of CNS stimulant abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been seen. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage (10)].
To reduce the abuse of CNS stimulants, including VYVANSE, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants, monitor for signs of abuse while on therapy, and re-evaluate the need for VYVANSE use.
Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice for treatment of overdosage. Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.
Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Serotonin syndrome has been reported with amphetamine use, including VYVANSE. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.
Lisdexamfetamine and d-amphetamine are not dialyzable.
VYVANSE (lisdexamfetamine dimesylate), a CNS stimulant, is for once-a-day oral administration. The chemical designation for lisdexamfetamine dimesylate is (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate. The molecular formula is C15H25N3O∙(CH4O3S)2, which corresponds to a molecular weight of 455.60. The chemical structure is:
Chemical Structure (Vyvanse 01)
Lisdexamfetamine dimesylate is a white to off-white powder that is soluble in water (792 mg/mL).
Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The exact mode of therapeutic action in ADHD and BED is not known.
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.
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.
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:
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.
| 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 Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI) | ||
| SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. | ||||
| Study 11 | VYVANSE (50 or 70 mg/day) Doses statistically significantly superior to placebo. | 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) | -- | |
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)
Figure 8 (Vyvanse 09)
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.
Dispense in a tight, light-resistant container as defined in the USP.
Store at room temperature, 20°C to 25° C (68°F to 77° F). Excursions permitted between 15°C and 30° C (59 to 86° F) [see USP Controlled Room Temperature].
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Pregnancy
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 (8.1)].
Lactation
Advise women not to breastfeed if they are taking VYVANSE [see Use in Specific Populations (8.2)].
| MEDICATION GUIDE VYVANSE® [Vi' - vans] (lisdexamfetamine dimesylate) CII Capsules and Chewable Tablets | ||||
What is the most important information I should know about VYVANSE? VYVANSE is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep VYVANSE in a safe place to prevent misuse and abuse. Selling or giving away VYVANSE may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines or street drugs. VYVANSE is a stimulant medicine. Some people have had the following problems when taking stimulant medicines such as VYVANSE:
Tell your doctor if you have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you carefully for heart problems before starting VYVANSE. Your doctor should check your blood pressure and heart rate regularly during treatment with VYVANSE. Call your doctor right away if you have any signs of heart problems such as chest pain, shortness of breath, or fainting while taking VYVANSE. | ||||
In Children, Teenagers, and Adults:
In Children and Teenagers | ||||
Tell your doctor about any mental problems you have or if you have a family history of suicide, bipolar illness, or depression. Call your doctor right away if you have any new or worsening mental symptoms or problems while taking VYVANSE, especially: | ||||
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Tell your doctor if you have numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes. Call your doctor right away if you have any signs of unexplained wounds appearing on fingers or toes while taking VYVANSE. | ||||
What is VYVANSE? VYVANSE is a central nervous system stimulant prescription medicine used to treat: | ||||
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VYVANSE is not for weight loss. It is not known if VYVANSE is safe and effective for the treatment of obesity. It is not known if VYVANSE is safe and effective in children with ADHD under 6 years of age or in patients with BED under 18 years of age. | ||||
Do not take VYVANSE if you: | ||||
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Before you take VYVANSE, tell your doctor if you have or if there is a family history of: | ||||
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Tell your doctor if: | ||||
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Tell your doctor about all of the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VYVANSE can affect the way other medicines work, and other medicines may affect how VYVANSE works. Using VYVANSE with other medicines can cause serious side effects. Especially tell your doctor if you take anti-depression medicines including MAOIs. Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. Do not start any new medicine while taking VYVANSE without talking to your doctor first. | ||||
How should I take VYVANSE? | ||||
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If you take too much VYVANSE, call your doctor or poison control center (1-800-222-1222) right away, or get to the nearest hospital emergency room. | ||||
What should I avoid while taking VYVANSE? Do not drive, operate machinery, or do other dangerous activities until you know how VYVANSE affects you. | ||||
What are the possible side effects of VYVANSE? VYVANSE may cause serious side effects, including: | ||||
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| The most common side effects of VYVANSE in ADHD include: | ||||
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| The most common side effects of VYVANSE in BED include: | ||||
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Talk to your doctor if you have any side effects that bother you or do not go away. These are not all the possible side effects of VYVANSE. For more information ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||||
How should I store VYVANSE? | ||||
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Keep VYVANSE and all medicines out of the reach of children. | ||||
General information about the safe and effective use of VYVANSE. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VYVANSE for a condition for which it was not prescribed. Do not give VYVANSE to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. If you would like more information, talk with your doctor. You can ask your pharmacist or healthcare provider for information about VYVANSE that is written for health professionals. | ||||
What are the ingredients in VYVANSE? Active ingredient: lisdexamfetamine dimesylate Capsule Inactive ingredients: microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The capsule shells (imprinted with S489) contain gelatin, titanium dioxide, and one or more of the following: FD&C Red #3, FD&C Yellow #6, FD&C Blue #1, Black Iron Oxide, and Yellow Iron Oxide. Chewable Tablet Inactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, guar gum, magnesium stearate, mannitol, microcrystalline cellulose, sucralose, artificial strawberry flavor. Manufactured for: Shire US Inc., 300 Shire Way, Lexington, MA 02421. VYVANSE® is a registered trademark of Shire LLC. © 2017 Shire US Inc. For more information, go to www.vyvanse.com or call 1-800-828-2088. | ||||
| This Medication Guide has been approved by the U.S. Food and Drug Administration | Revised: JAN 2017 | |||
NDC 59417-101-10
Vyvanse®
(lisdexamfetamine
dimesylate) capsules
10 mg
CII
Rx only
100 CAPSULES
Shire
Principal Display Panel (10 mg Capsule Bottle Label)
NDC 59417-102-10
Vyvanse®
(lisdexamfetamine
dimesylate) capsules
20 mg
CII
Rx only
100 CAPSULES
Shire
Principal Display Panel (20 mg Capsule Bottle Label)
NDC 59417-103-10
Vyvanse®
(lisdexamfetamine
dimesylate) capsules
30 mg
CII
Rx only
100 CAPSULES
Shire
Principal Display Panel (30 mg Capsule Bottle Label)
NDC 59417-104-10
Vyvanse®
(lisdexamfetamine
dimesylate) capsules
40 mg
CII
Rx only
100 CAPSULES
Shire
Principal Display Panel (40 mg Capsule Bottle Label)
NDC 59417-105-10
Vyvanse®
(lisdexamfetamine
dimesylate) capsules
50 mg
CII
Rx only
100 CAPSULES
Shire
Principal Display Panel (50 mg Capsule Bottle Label)
NDC 59417-106-10
Vyvanse®
(lisdexamfetamine
dimesylate) capsules
60 mg
CII
Rx only
100 CAPSULES
Shire
Principal Display Panel (60 mg Capsule Bottle Label)
NDC 59417-107-10
Vyvanse®
(lisdexamfetamine
dimesylate) capsules
70 mg
CII
Rx only
100 CAPSULES
Shire
Principal Display Panel (70 mg Capsule Bottle Label)
NDC 59417-115-01
Vyvanse®
(lisdexamfetamine
dimesylate) chewable tablets
10 mg
100 CHEWABLE
TABLETS
Chew tablets completely
before swallowing. Do
not swallow tablets whole.
CII
Rx only
Shire
Principal Display Panel (10 mg Tablet Bottle Label)
NDC 59417-116-01
Vyvanse®
(lisdexamfetamine
dimesylate) chewable tablets
20 mg
100 CHEWABLE
TABLETS
Chew tablets completely
before swallowing. Do
not swallow tablets whole.
CII
Rx only
Shire
Principal Display Panel (20 mg Tablet Bottle Label)
NDC 59417-117-01
Vyvanse®
(lisdexamfetamine
dimesylate) chewable tablets
30 mg
100 CHEWABLE
TABLETS
Chew tablets completely
before swallowing. Do
not swallow tablets whole.
CII
Rx only
Shire
Principal Display Panel (30 mg Tablet Bottle Label)
NDC 59417-118-01
Vyvanse®
(lisdexamfetamine
dimesylate) chewable tablets
40 mg
100 CHEWABLE
TABLETS
Chew tablets completely
before swallowing. Do
not swallow tablets whole.
CII
Rx only
Shire
Principal Display Panel (40 mg Tablet Bottle Label)
NDC 59417-119-01
Vyvanse®
(lisdexamfetamine
dimesylate) chewable tablets
50 mg
100 CHEWABLE
TABLETS
Chew tablets completely
before swallowing. Do
not swallow tablets whole.
CII
Rx only
Shire
Principal Display Panel (50 mg Tablet Bottle Label)
NDC 59417-120-01
Vyvanse®
(lisdexamfetamine
dimesylate) chewable tablets
60 mg
100 CHEWABLE
TABLETS
Chew tablets completely
before swallowing. Do
not swallow tablets whole.
CII
Rx only
Shire
Principal Display Panel (60 mg Tablet Bottle Label)
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