ARYNTA lisdexamfetamine dimesylate oral 10 mg/mL Solution — NDC 24338-019-01 (Billing 24338-0019-01)

5 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 )

5.1Abuse, 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.

5.2Risks 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.

5.3Increased 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.

5.4Psychiatric 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).

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6 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.

6.1Clinical 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%), headach… [Excerpted — this section continues on DailyMed.]

7 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 )

7.1Drugs 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.

9 DRUG ABUSE AND DEPENDENCE

9.1Controlled Substance ARYNTA contains lisdexamfetamine, a prodrug of amphetamine, a Schedule II controlled substance.

9.2Abuse ARYNTA has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] . ARYNTA can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect.

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of lisdexamfetamine, a prodrug of amphetamine, may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. 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.

Studies of ARYNTA 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 lisdexamfetamine dimesylate, 40 mg of immediate-release d-amphetamine sulphate (a controlled II substance), and 200 mg of diethylpropion hydrochloride (a controlled IV substance). lisdexamfetamine dimesylate 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 lisdexamfetamine dimesylate 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.

9.3Dependence Physical Dependence ARYNTA may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including ARYNTA include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance ARYNTA may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

9.1Controlled Substance ARYNTA contains lisdexamfetamine, a prodrug of amphetamine, a Schedule II controlled substance.