FDA label c035ee75-b190-461b-bc9f-c5173b1b3b45

WARNING: MISUSE, ABUSE, ADDICTION, AND DIVERSION VYVANSE (lisdexamfetamine dimesylate) is a Schedule II controlled substance. Stimulants, such as amphetamines and methylphenidates, are subject to misuse, abuse, addiction, and criminal diversion [ see Drug Abuse and Dependence (9) ] . Misuse of amphetamines may cause sudden death and serious cardiovascular adverse events [ see Overdosage (10) ] . WARNING: MISUSE, ABUSE, ADDICTION, AND DIVERSION See full prescribing information for complete boxed warning. VYVANSE (lisdexamfetamine dimesylate) is a Schedule II controlled substance. Stimulants, such as amphetamines and methylphenidates, are subject to misuse, abuse, addiction, and criminal diversion ( 9 ) Misuse of amphetamines may cause sudden death and serious cardiovascular adverse events ( 10 )

5 WARNINGS AND PRECAUTIONS Serious Cardiovascular Reactions: Sudden death in children and adolescents with structural cardiac abnormalities or other serious heart problems, as well as sudden death, stroke, and myocardial infarction in adults has been reported in CNS stimulant treatment at usual doses. Stimulant products generally should not be used in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, or other serious heart problems ( 5.1 ) Increase in Blood Pressure: Monitor blood pressure and pulse in patients taking Vyvanse. Use with caution in patients for whom blood pressure increases may be problematic ( 5.2 ) Psychiatric Adverse Reactions: Use of stimulants may cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychosis. Clinical evaluation for bipolar disorder is recommended prior to stimulant use. Monitor for aggressive behavior ( 5. 3 ) Long-Term Suppression of Growth: Monitor height and weight in pediatric patients during treatment ( 5.4 ) Seizures: May lower the convulsive threshold. Discontinue if seizures develop ( 5.5 ) 5.1 Serious Cardiovascular Reactions Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g. electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. 5.2 Increased Blood Pressure Stimulant medications cause a modest increase in average blood pressure (about 2-4 mm Hg) and average heart rate (about 3-6 bpm) and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g. those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. 5.3 Psychiatric Adverse Reactions Pre-existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment-emergent psychotic or manic symptoms, e.g. hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania, can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment of ADHD should be monitored for the appearance of, or worsening of, aggressive behavior or hostility. 5.4 Long-Term Suppression of Growth In pediatric patients, growth (weight and height) 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 Adverse Reactions (6.1) ] . 5.5 Seizures Stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, Vyvanse should be discontinued. 5.6 Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. 5.7 Tics Amphetamines have been reported to exacerbate motor and phonic tics and Tourette's syndrome. Therefore, clinical evaluation for tics and Tourette's syndrome should precede use of Vyvanse.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling Serious Cardiovascular Reactions [ see Warnings and Precautions (5.1) ] Increased Blood Pressure [ see Warnings and Precautions (5.2) ] Psychiatric Adverse Reactions [ see Warnings and Precautions (5.3) ] Long-Term Suppression of Growth in Pediatric Patients [ see Warnings and Precautions (5.4) ] Seizures [ see Warnings and Precautions (5.5) ] Visual Disturbance [ see Warnings and Precautions (5.6) ] Tics [ see Warnings and Precautions (5.7) ] Most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) 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 ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience 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 clinical practice. The premarketing development program for Vyvanse included exposures in a total of 995 participants in clinical trials (348 pediatric patients aged 6 to 12 years, 233 adolescent patients aged 13 to 17 years, 358 adult patients and 56 healthy adult subjects). Of these, 348 pediatric (aged 6 to 12) patients were evaluated in two controlled clinical studies (one parallel-group and one crossover), one open-label extension study, and one single-dose clinical pharmacology study, 233 adolescent (aged 13 to 17) patients were evaluated in one controlled clinical study, and 358 adult patients were evaluated in one controlled clinical study and one open-label extension study. The information included in this section is based on data from the 4-week parallel-group controlled clinical studies in pediatric and adult patients with ADHD [ see Clinical Studies (14) ] . Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reactions categories. The stated frequencies of adverse reactions represent the proportion of individuals who experienced an adverse reaction of the type listed at least once. Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials In the controlled pediatric (ages 6 to 12 years) trial, 9% (20/218) of Vyvanse-treated patients discontinued due to adverse reactions compared to 1% (1/72) who received placebo. The most frequent adverse reactions leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of Vyvanse-treated patients and at a rate at least twice that of placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, insomnia, and rash (2/218 each; 1%). In the controlled adolescent (ages 13 to 17 years) trial, 4% (10/233) of Vyvanse-treated patients discontinued due to adverse reactions compared to 1% (1/77) who received placebo. The most frequent adverse reactions leading to discontinuation and considered to be drug-related were irritability (3/233; 1%), decreased appetite (2/233; 1%), and insomnia (2/233; 1%). In the controlled adult trial, 6% (21/358) of Vyvanse-treated patients discontinued due to adverse reactions compared to 2% (1/62) who received placebo. The most frequent adverse reactions leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of Vyvanse-treated patients and at a rate at least twice that 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%). Adverse Reactions Occurring at an Incidence of 2% or More Among Vyvanse Treated Patients in Clinical Trials Adverse reactions reported in the controlled trials in pediatric patients ages 6 to 12 years, adolescent patients ages 13 to 17 years, and adult patients treated with Vyvanse or placebo are presented in Tables 1, 2, and 3 below. Pediatric Table 1 Adverse Reactions Reported by 2% or More of Children (Ages 6 to 12 Years) Taking Vyvanse in a 4-Week Clinical Trial Body System Preferred Term Vyvanse (n=218) Placebo (n=72) Gastrointestinal Disorders Abdominal Pain Upper 12% 6% Vomiting 9% 4% Nausea 6% 3% Dry Mouth 5% 0% General Disorder and Administration Site Conditions Pyrexia 2% 1% Investigations Weight Decreased 9% 1% Metabolism and Nutrition Decreased Appetite 39% 4% Nervous System Disorders Dizziness 5% 0% Somnolence 2% 1% Psychiatric Disorders Insomnia a 23% 3% Irritability 10% 0% Affect lability 3% 0% Tic 2% 0% Skin and Subcutaneous Tissue Disorders Rash 3% 0% a Insomnia includes the following preferred terms reported in the study: Initial Insomnia, Insomnia. Note: This table includes those reactions for which the incidence in patients taking Vyvanse is at least twice the incidence in patients taking placebo. Table 2 Adverse Reactions Reported by 2% or More of Adolescent (Ages 13 to 17 Years) Patients Taking Vyvanse in a 4-Week Clinical Trial Body System Preferred Term Vyvanse (n=233) Placebo (n=77) Gastrointestinal Disorders Dry Mouth 4% 1% Investigations Weight Decreased 9% 0% Metabolism and Nutrition Decreased Appetite 34% 3% Psychiatric Disorders Insomnia b 13% 4% b Insomnia includes the following preferred terms reported in the study: Initial Insomnia, Insomnia. Note: This table includes those reactions for which the incidence in patients taking Vyvanse is at least twice the incidence in patients taking placebo Adult Table 3 Adverse Reactions Reported by 2% or More of Adult Patients Taking Vyvanse in a 4-Week Clinical Trial Body System Preferred Term Vyvanse (n=358) Placebo (n=62) Gastrointestinal Disorders Dry Mouth 26% 3% Diarrhea 7% 0% Nausea 7% 0% General Disorder and Administration Site Conditions Feeling Jittery 4% 0% Investigations Blood Pressure Increased 3% 0% Heart Rate Increased 2% 0% Metabolism and Nutrition Disorders Decreased Appetite 27% 3% Anorexia 5% 0% Nervous System Disorders Tremor 2% 0% Psychiatric Disorders Insomnia c 27% 8% Anxiety 6% 0% Agitation 3% 0% Restlessness 3% 0% Respiratory ,Thoracic, and Mediastinal Disorders Dyspnea 2% 0% Skin and Subcutaneous Tissue Disorders Hyperhidrosis 3% 0% c Insomnia includes the following preferred terms reported in the study: Initial Insomnia, Insomnia, Middle Insomnia. Note: This table includes those reactions for which the incidence in patients taking Vyvanse is at least twice the incidence in patients taking placebo. In addition, adverse reactions observed at a rate of less than 2% in adults included decreased libido and erectile dysfunction. Weight Loss and Slowing Growth Rate in Pediatric Patients In a controlled trial of Vyvanse in children ages 6 to 12 years, 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 60.6 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. Weight Loss in Adults In the controlled adult trial, 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. 6.2 Postmarketing Experience 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. Cardiac Disorders - Palpitations, cardiomyopathy Eye Disorders - Mydriasis, diplopia Hepatobiliary Disorders - Eosinophilic hepatitis Immune System Disorders - Anaphylactic reaction, hypersensitivity Nervous System Disorders - Dyskinesia Psychiatric Disorder - Depression, dysphoria, euphoria, logorrhoea, dermatillomania Skin and Subcutaneous Tissue Disorder - Stevens-Johnson Syndrome, angioedema, urticaria

<table> <col/> <col/> <col/> <col/> <tbody> <tr> <td styleCode=" Toprule "> <paragraph>Body System</paragraph> </td> <td valign="top" styleCode=" Toprule ">Preferred Term</td> <td valign="top" styleCode=" Toprule "> Vyvanse (n=218)</td> <td valign="top" styleCode=" Toprule "> Placebo (n=72)</td> </tr> <tr> <td styleCode=" Toprule "> Gastrointestinal Disorders</td> <td styleCode=" Toprule "> Abdominal Pain Upper</td> <td styleCode=" Toprule "> 12%</td> <td styleCode=" Toprule "> 6%</td> </tr> <tr> <td> </td> <td> Vomiting</td> <td> 9%</td> <td> 4%</td> </tr> <tr> <td> </td> <td> Nausea</td> <td> 6%</td> <td> 3%</td> </tr> <tr> <td> </td> <td> Dry Mouth</td> <td> 5%</td> <td> 0%</td> </tr> <tr> <td styleCode=" Toprule "> General Disorder and Administration Site Conditions</td> <td styleCode=" Toprule "> Pyrexia</td> <td styleCode=" Toprule "> 2%</td> <td styleCode=" Toprule "> 1%</td> </tr> <tr> <td styleCode=" Toprule "> Investigations</td> <td styleCode=" Toprule "> Weight Decreased</td> <td styleCode=" Toprule "> 9%</td> <td styleCode=" Toprule "> 1%</td> </tr> <tr> <td styleCode=" Toprule "> Metabolism and Nutrition</td> <td styleCode=" Toprule "> Decreased Appetite</td> <td styleCode=" Toprule "> 39%</td> <td styleCode=" Toprule "> 4%</td> </tr> <tr> <td styleCode=" Toprule "> Nervous System Disorders</td> <td styleCode=" Toprule "> Dizziness</td> <td styleCode=" Toprule "> 5%</td> <td styleCode=" Toprule "> 0%</td> </tr> <tr> <td> </td> <td> Somnolence</td> <td> 2%</td> <td> 1%</td> </tr> <tr> <td styleCode=" Toprule "> Psychiatric Disorders</td> <td styleCode=" Toprule "> Insomnia^a </td> <td styleCode=" Toprule "> 23%</td> <td styleCode=" Toprule "> 3%</td> </tr> <tr> <td> </td> <td> Irritability</td> <td> 10%</td> <td> 0%</td> </tr> <tr> <td> </td> <td> Affect lability</td> <td> 3%</td> <td> 0%</td> </tr> <tr> <td> </td> <td> Tic</td> <td> 2%</td> <td> 0%</td> </tr> <tr> <td styleCode=" Botrule Toprule "> Skin and Subcutaneous Tissue Disorders</td> <td styleCode=" Botrule Toprule "> Rash</td> <td styleCode=" Botrule Toprule "> 3%</td> <td styleCode=" Botrule Toprule "> 0%</td> </tr> </tbody> </table>

<table> <col/> <col/> <col/> <col/> <tbody> <tr> <td valign="top" styleCode=" Toprule ">Body System </td> <td valign="top" styleCode=" Toprule ">Preferred Term </td> <td valign="top" styleCode=" Toprule ">Vyvanse (n=233) </td> <td valign="top" styleCode=" Toprule ">Placebo (n=77) </td> </tr> <tr> <td styleCode=" Toprule "> Gastrointestinal Disorders</td> <td styleCode=" Toprule "> Dry Mouth</td> <td styleCode=" Toprule "> 4%</td> <td styleCode=" Toprule "> 1%</td> </tr> <tr> <td styleCode=" Toprule "> Investigations</td> <td styleCode=" Toprule "> Weight Decreased</td> <td styleCode=" Toprule "> 9%</td> <td styleCode=" Toprule "> 0%</td> </tr> <tr> <td styleCode=" Toprule "> Metabolism and Nutrition</td> <td styleCode=" Toprule "> Decreased Appetite</td> <td styleCode=" Toprule "> 34%</td> <td styleCode=" Toprule "> 3%</td> </tr> <tr> <td styleCode=" Botrule Toprule "> Psychiatric Disorders</td> <td styleCode=" Botrule Toprule "> Insomnia^b </td> <td styleCode=" Botrule Toprule "> 13%</td> <td styleCode=" Botrule Toprule ">4% </td> </tr> </tbody> </table>

<table> <col/> <col/> <col/> <col/> <tbody> <tr> <td styleCode=" Toprule ">Body System </td> <td styleCode=" Toprule ">Preferred Term </td> <td styleCode=" Toprule ">Vyvanse (n=358) </td> <td styleCode=" Toprule ">Placebo (n=62) </td> </tr> <tr> <td styleCode=" Toprule "> Gastrointestinal Disorders</td> <td styleCode=" Toprule "> Dry Mouth</td> <td styleCode=" Toprule "> 26%</td> <td styleCode=" Toprule ">3% </td> </tr> <tr> <td> </td> <td> Diarrhea</td> <td> 7%</td> <td> 0%</td> </tr> <tr> <td> </td> <td> Nausea</td> <td> 7%</td> <td> 0%</td> </tr> <tr> <td styleCode=" Toprule "> General Disorder and Administration Site Conditions</td> <td styleCode=" Toprule "> Feeling Jittery</td> <td styleCode=" Toprule "> 4%</td> <td styleCode=" Toprule ">0% </td> </tr> <tr> <td styleCode=" Toprule "> Investigations</td> <td styleCode=" Toprule "> Blood Pressure Increased</td> <td styleCode=" Toprule "> 3%</td> <td styleCode=" Toprule ">0%</td> </tr> <tr> <td> </td> <td> Heart Rate Increased</td> <td> 2%</td> <td>0% </td> </tr> <tr> <td styleCode=" Toprule "> Metabolism and Nutrition Disorders</td> <td styleCode=" Toprule "> Decreased Appetite</td> <td styleCode=" Toprule "> 27%</td> <td styleCode=" Toprule "> 3%</td> </tr> <tr> <td> </td> <td> Anorexia</td> <td> 5%</td> <td>0% </td> </tr> <tr> <td styleCode=" Toprule "> Nervous System Disorders</td> <td styleCode=" Toprule "> Tremor</td> <td styleCode=" Toprule "> 2%</td> <td styleCode=" Toprule ">0% </td> </tr> <tr> <td styleCode=" Toprule "> Psychiatric Disorders</td> <td styleCode=" Toprule "> Insomnia^c </td> <td styleCode=" Toprule "> 27%</td> <td styleCode=" Toprule "> 8%</td> </tr> <tr> <td> </td> <td> Anxiety</td> <td> 6%</td> <td>0% </td> </tr> <tr> <td> </td> <td> Agitation</td> <td> 3%</td> <td>0%</td> </tr> <tr> <td> </td> <td> Restlessness</td> <td> 3%</td> <td>0% </td> </tr> <tr> <td styleCode=" Toprule "> Respiratory ,Thoracic, and Mediastinal Disorders</td> <td styleCode=" Toprule "> Dyspnea</td> <td styleCode=" Toprule "> 2%</td> <td styleCode=" Toprule ">0% </td> </tr> <tr> <td styleCode=" Botrule Toprule "> Skin and Subcutaneous Tissue Disorders</td> <td styleCode=" Botrule Toprule "> Hyperhidrosis</td> <td styleCode=" Botrule Toprule "> 3%</td> <td styleCode=" Botrule Toprule ">0%</td> </tr> </tbody> </table>