Lisdexamfetamine Dimesylate Oral

INDICATIONS AND USAGE ARYNTA is indicated for the treatment of: Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older [see Clinical Studies ( 14.1 )] Moderate to severe binge eating disorder (BED) in adults [see Clinical Studies ( 14.2 )] . Limitations of Use: The use of ARYNTA is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 )] . ARYNTA 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 ARYNTA for the treatment of obesity have not been established [see Warnings and Precautions ( 5.2 )] . ARYNTA is a central nervous system (CNS) stimulant indicated for the treatment of ( 1 ): Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older. Moderate to severe binge eating disorder (BED) in adults Limitations of Use : The use of ARYNTA is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.5 , 8.4 ) ARYNTA is not indicated for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of ARYNTA for the treatment of obesity have not been established ( 5.2 )

DOSAGE AND ADMINISTRATION Indicated Population Initial Dose Titration Schedule Recommended Dose Maximum Dose ADHD (Adults and pediatric patients 6 years and older) ( 2.2 ) 30 mg every morning 10 mg or 20 mg weekly 30 mg to 70 mg per day 70 mg per day BED (Adults) ( 2.3 ) 30 mg every morning 20 mg weekly 50 mg to 70 mg per day 70 mg per day • Prior to treatment, assess for presence of cardiac disease ( 2.4 ) • Severe renal impairment: Maximum dose is 50 mg/day ( 2.5 ) • End stage renal disease (ESRD): Maximum dose is 30 mg/day ( 2.5 ) 2.1 Pretreatment Screening Prior to treating patients with ARYNTA, assess: • for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5.2 )] . • the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating ARYNTA [see Warnings and Precautions ( 5.8 )] . 2.2 General Administration Information Take ARYNTA orally in the morning with or without food; avoid afternoon doses because of the potential for insomnia. Instruct caregivers/patients to read the ‘Instructions for Use’ for complete administration instructions. • Use the oral dosing syringe and bottle adapter provided with ARYNTA. • Ensure that the bottle adapter is firmly inserted into the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. • Throw away (discard) any remaining ARYNTA 30 days after first opening the bottle. 2.3 Dosage for Treatment of ADHD The recommended starting dosage in adults and pediatric patients 6 years and older is 30 mg once daily in the morning. Dosage may be adjusted in increments of 10 mg or 20 mg at approximately weekly intervals up to maximum recommended dosage of 70 mg once daily [see Clinical Studies ( 14.1 )] . 2.4 Dosage for Treatment of Moderate to Severe BED in Adults The recommended starting dosage in adults is 30 mg once daily to be titrated in increments of 20 mg at approximately weekly intervals to achieve the recommended target dose of 50 mg to 70 mg once daily. The maximum recommended dosage is 70 mg once daily [see Clinical Studies ( 14.2 )]. Discontinue ARYNTA if binge eating does not improve. 2.5 Dosage in Patients with Renal Impairment In patients with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m 2 ), the maximum dosage should not exceed 50 mg once daily. In patients with end stage renal disease (ESRD, GFR < 15 mL/min/1.73 m 2 ), the maximum recommended dosage is 30 mg once daily [see Use in Specific Populations ( 8.6 )] . 2.6 Dosage Modifications due to Drug Interactions 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 ARYNTA dosage accordingly [see Drug Interactions ( 7.1 )] .

WARNINGS AND PRECAUTIONS • Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease ( 5.2 ) • Increased Blood Pressure and Heart Rate : Monitor blood pressure and pulse. ( 5.3 ) • Psychiatric Adverse Reactions : Prior to initiating ARYNTA, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing ARYNTA. ( 5.4 ) • Long-Term Suppression of Growth in Pediatric Patients : Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.5 ) • Peripheral Vasculopathy, including Raynaud's phenomenon : Careful observation for digital changes is necessary during ARYNTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.6 ) • Serotonin Syndrome : Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue ARYNTA and initiate supportive treatment. ( 4 , 5.7 , 10 ) • Motor and Verbal Tics, and Worsening of Tourette's Syndrome : Before initiating ARYNTA, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. ( 5.8 ) 5.1 Abuse, Misuse, and Addiction ARYNTA has a high potential for abuse and misuse. The use of ARYNTA exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. ARYNTA can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence ( 9.2 )] . Misuse and abuse of CNS stimulants, including ARYNTA, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing ARYNTA, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store ARYNTA in a safe place, preferably locked, and instruct patients to not give ARYNTA to anyone else. Throughout ARYNTA treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid ARYNTA use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases. Monitor all ARYNTA -treated patients for potential tachycardia and hypertension. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed episode. Prior to initiating ARYNTA 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 the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing ARYNTA. 5.5 Long-Term Suppression of Growth in Pediatric Patients ARY NTA is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations ( 8.4 )] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. In a 4-week, placebo-controlled trial of ARYNTA in pediatric patients ages 6 to 12 years old with ADHD, there was a dose-related decrease in weight in the ARYNTA 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 )] . Closely monitor growth (weight and height) in ARYNTA-treated pediatric patients. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon CNS stimulants, including ARYNTA, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during ARYNTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for ARYNTA-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Serotonin Syndrome 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 )] . The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to the active metabolite of ARYNTA (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 ARYNTA with MAOI drugs is contraindicated [see Contraindications ( 4 )] . Discontinue treatment with ARYNTA and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. If concomitant use of ARYNTA with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate ARYNTA with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin

CONTRAINDICATIONS ARYNTA is contraindicated in patients with: • Known hypersensitivity to amphetamine products or other ingredients of ARYNTA. Anaphylactic reactions, Stevens-Johnson Syndrome, angioedema, and urticaria have been observed in postmarketing reports [see Adverse Reactions ( 6.2 )]. • Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions ( 5.7 ) and Drug Interactions ( 7.1 )]. • Known hypersensitivity to amphetamine products or other ingredients in ARYNTA ( 4 ) • Use with monoamine oxidase (MAO) inhibitor, or within 14 days of the last MAO inhibitor dose ( 4 , 7.1 )

DRUG INTERACTIONS Acidifying and Alkalinizing Agents : Agents that alter urinary pH can alter blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels. Adjust ARYNTA dosage accordingly. ( 2.6 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Amphetamines Table 5 Drugs Having Clinically Important Interactions with Amphetamines MAO Inhibitors (MAOI) Prevention or Management Do not administer ARYNTA during or within 14 days following the administration of MAOI [see Contraindications ( 4 )] . Mechanism and Clinical Effect(s) 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. Serotonergic Drugs Prevention or Management Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ARYNTA initiation or dosage increase. If serotonin syndrome occurs, discontinue ARYNTA and the concomitant serotonergic drug(s) [see Warnings and Precautions ( 5.7 )] . Mechanism and Clinical Effect(s) The concomitant use of lisdexamfetamine dimesylate and serotonergic drugs increases the risk of serotonin syndrome. CYP2D6 Inhibitors Prevention or Management Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during ARYNTA initiation and after a dosage increase. If serotonin syndrome occurs, discontinue ARYNTA and the CYP2D6 inhibitor [see Warnings and Precautions ( 5.7 ) and Overdosage ( 10 )]. Mechanism and Clinical Effect(s) The concomitant use of lisdexamfetamine dimesylate and CYP2D6 inhibitors may increase the exposure of dextroamphetamine, the active metabolite of lisdexamfetamine dimesylate compared to the use of the drug alone and increase the risk of serotonin syndrome. Alkalinizing Agents Prevention or Management Co-administration of ARYNTA and urinary alkalinizing agents should be avoided. Mechanism and Clinical Effect(s) Urinary alkalinizing agents can increase blood levels and potentiate the action of amphetamine. Acidifying Agents Prevention or Management Increase dose based on clinical response. Mechanism and Clinical Effect(s) Urinary acidifying agents can lower blood levels and efficacy of amphetamines. Tricyclic Antidepressants Prevention or Management Monitor frequently and adjust or use alternative therapy based on clinical response. Mechanism and Clinical Effect(s) 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.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Known hypersensitivity to amphetamine products or other ingredients of ARYNTA [see Contraindications ( 4 )] • Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications ( 4 ) and Drug Interactions ( 7.1 )] • Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions ( 5.1 ), and Drug Abuse and Dependence ( 9.2 , 9.3 )] • Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions ( 5.2 )] • Increased Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] • Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.4 )] • Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.5 )] • Peripheral Vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions ( 5.6 )] • Serotonin Syndrome [see Warnings and Precautions ( 5.7 )] • Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) in pediatric patients ages 6 to 17 years, and/or adults with ADHD were anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting. ( 6.1 ) Most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) in adults with BED were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc., at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 practice. Attention Deficit Hyperactivity Disorder The safety data in this section is based on data from the 4-week controlled parallel-group clinical studies of Lisdexamfetamine Dimesylate 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 pediatric patients ages 6 to 12 years (Study 1), 8% (18/218) of ARYNTA-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 pediatric patients ages 13 to 17 years (Study 4), 3% (7/233) of ARYNTA-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 ARYNTA-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 ARYNTA Treated Patients with ADHD in Clinical Trials The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in pediatric patients ages 6 to 17 years, 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 ARYNTA Treated Patients with ADHD in Clinical Trials Adverse reactions reported in the controlled trials in pediatric patients ages, 6 to 12 years (Study 1), pediatric patients ages 13 to 17 years (Study 4), and adult patients (Study 7) treated with ARYNTA or placebo are presented in Tables 1, 2 and 3 below. Table 1 Adverse Reactions Reported by 2% or More of Pediatric Patients Ages 6 to 12 Years with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 1) Lisdexamfetamine Dimesylate (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% Table 2 Adverse Reactions Reported by 2% or More of Pediatric Patients Ages 13 to 17 Years with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 4) L isdexamfetamine Dimesylate (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% Table 3. Adverse Reactions Reported by 2% or More of Adult Patients with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 7) Lisdexamfetamine Dimesylate (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 lisdexamfetamine dimesylate and 0% on placebo; decreased libido was observed in 1.4% of subjects on lisdexamfetamine dimesylate and 0% on placebo. Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD In a controlled trial of lisdexamfetamine dimesylate in pediatric patients 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 lisdexamfetamine dimesylate, 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 pediatric patients ages 6 to 12 years who received lisdexamfetamine dimesylate over 12 months suggests that consistently medicated pediatric patients (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 lisdexamfetamine dimesylate in pediatric patients ages 13 to 17 years, mean

Mechanism of Action 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.