FDA label 153557ae-291f-72af-e063-6294a90ab1af

WARNING: ABUSE, MISUSE, AND ADDICTION EVEKEO ODT has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including EVEKEO ODT, 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 EVEKEO ODT, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout EVEKEO ODT treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2) ]. WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. EVEKEO ODT has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including EVEKEO ODT, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing EVEKEO ODT, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient's risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

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 EVEKEO ODT, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing EVEKEO ODT. ( 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 ) Seizures : May lower the convulsive threshold. If a seizure occurs, discontinue EVEKEO ODT . ( 5.6 ) Peripheral Vasculopathy, including Raynaud's Phenomenon : Careful observation for digital changes is necessary during EVEKEO ODT treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.7 ) Serotonin Syndrome : Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue EVEKEO ODT and initiate supportive treatment. ( 5.8 ) Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating EVEKEO ODT, 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. ( 5.9 ) 5.1 Abuse, Misuse, and Addiction EVEKEO ODT has a high potential for abuse and misuse. The use of EVEKEO ODT exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. EVEKEO ODT 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 EVEKEO ODT, 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 EVEKEO ODT, 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 EVEKEO ODT in a safe place, preferably locked, and instruct patients to not give EVEKEO ODT to anyone else. Throughout EVEKEO ODT 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 EVEKEO ODT 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 EVEKEO ODT-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 Disease CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating EVEKEO ODT treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or has a 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 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 EVEKEO ODT. 5.5 Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in EVEKEO ODT-treated pediatric patients treated with CNS stimulants. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.6 Seizures There is some clinical evidence that 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, discontinue EVEKEO ODT. 5.7 Peripheral Vasculopathy, including Raynaud's Phenomenon CNS stimulants, including EVEKEO ODT, 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 dosage 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 EVEKEO ODT treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for EVEKEO ODT-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.8 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 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 EVEKEO ODT. 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 EVEKEO ODT with MAOI drugs is contraindicated [see Contraindications (4) ] . Discontinue treatment with EVEKEO ODT and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of EVEKEO ODT with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate EVEKEO ODT 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 syndrome. 5.9 Motor and Verbal Tics, and Worsening of Tourette's Syndrome CNS stimulants, including amphetamine sulfate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported [see Adverse Reactions (6.2) ] . Before initiating EVEKEO ODT, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor EVEKEO ODT-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue treatment if clinically appropriate.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions (5.1) , and Drug Abuse and Dependence (9.2 , 9.3) ] Hypersensitivity to amphetamine, or other components of EVEKEO ODT [see Contraindications (4) ] Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1) ] 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) ] Seizures [see Warnings and Precautions (5.6) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.7) ] Serotonin Syndrome [see Warnings and Precautions (5.8) ] Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence ≥4% and at a rate at least twice placebo) in pediatric patients are: decreased appetite and insomnia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Arbor Pharmaceuticals, LLC 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 clinical practice. Study 1 was conducted with EVEKEO tablets (i.e., not the ODT formulation) in children ages 6 to 12 years who met Diagnostic and Statistical Manual of Mental Disorders, 4 th edition, Text Revision (DSM-IV-TR) criteria for ADHD. This study began with an 8-week, open-label, dose-optimization phase followed by a 2-week double-blind, placebo-controlled, randomized, crossover phase. Adverse reactions reported in > 5% of patients (N=105; doses of 10 to 40 mg/day) during the open-label phase included: decreased appetite (28%), infections (22%), abdominal pain (15%), irritability (14%), headache (13%), nausea (6%), vomiting (6%), affect lability (includes mood swings; 9%), tachycardia (9%), insomnia (10%), fatigue (10%),and dry mouth (6%). During the open-label phase, six patients discontinued due to adverse reactions: irritability (n=3), affect lability (n=1), initial insomnia (n=1), and rash (n=1). Table 1 lists the adverse reactions reported during the double-blind, cross-over phase. No patient discontinued the study for an adverse reaction during the double-blind crossover phase. Because of the trial design (an initial 8-week, open-label, active treatment phase), the adverse reaction rates described in the double-blind phase are lower than expected in clinical practice. Table 1: Adverse Reactions Reported in ≥ 2%, and > Placebo, of EVEKEO-Treated Pediatric Patients (6 to 12 Years) During the Double-Blind Cross-Over Weeks. Drug exposures and placebo exposures from cross-over were combined for analysis. System Organ Class Preferred Term EVEKEO (n= 97) Placebo (n= 97) Subjects with at least one adverse event 22% 14% Metabolism and Nutrition Disorders Decreased appetite 4% 0% Gastrointestinal Disorders Abdominal pain 3% 0% Psychiatric Disorders Affect Lability Includes mood swings. 3% 0% Insomnia 4% 0% Injury, poisoning and procedural complications Injury 3% 2% 6.2 Postmarketing Experience The following adverse reactions have been associated during post approval use of amphetamines. 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. Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses, overstimulation, irritability, restlessness, dizziness, insomnia, euphoria, mood swings, aggression, anger, logorrhea, dermatillomania, dyskinesia, dysphoria, tremor, fatigue, headache, exacerbation of motor and verbal tics and Tourette's syndrome Gastrointestinal: Dry mouth, unpleasant taste, constipation, nausea, intestinal ischemia, other gastrointestinal disturbances, anorexia, and weight loss. Allergic: Urticaria, rash, hypersensitivity reactions, including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported. Endocrine: Impotence, changes in libido, and frequent or prolonged erections. Skin : Alopecia. Vascular Disorders : Raynaud's phenomenon. Musculoskeletal: Rhabdomyolysis.

<table width="80%" ID="Table1"><caption>Table 1: Adverse Reactions Reported in &#x2265; 2%, and &gt; Placebo, of EVEKEO-Treated Pediatric Patients (6 to 12 Years) During the Double-Blind Cross-Over Weeks. <footnote ID="K2186">Drug exposures and placebo exposures from cross-over were combined for analysis.</footnote></caption><col width="60%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th valign="top">System Organ Class Preferred Term </th><th valign="top">EVEKEO (n= 97)</th><th valign="top">Placebo (n= 97)</th></tr></thead><tbody><tr styleCode="Botrule"><td><content styleCode="bold">Subjects with at least one adverse event</content></td><td>22%</td><td>14%</td></tr><tr><td colspan="3"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr><td> Decreased appetite</td><td>4%</td><td>0%</td></tr><tr><td colspan="3"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td> Abdominal pain</td><td>3%</td><td>0%</td></tr><tr><td colspan="3"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr><td> Affect Lability <footnote ID="K2260">Includes mood swings. </footnote></td><td>3%</td><td>0%</td></tr><tr><td> Insomnia</td><td>4%</td><td>0%</td></tr><tr><td colspan="3"><content styleCode="bold">Injury, poisoning and procedural complications</content></td></tr><tr><td> Injury</td><td>3%</td><td>2%</td></tr></tbody></table>