Dexmethylphenidate

1 INDICATIONS AND USAGE AZSTARYS is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and older. Limitations of Use The use of AZSTARYS 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 ( 5.7 ), Use in Specific Populations ( 8.4 )]. AZSTARYS is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and older. ( 1 ) Limitations of Use The use of AZSTARYS 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 (5.7, 8.4).

12.1 Mechanism of Action Serdexmethylphenidate is a prodrug of dexmethylphenidate. Dexmethylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known.

2 DOSAGE AND ADMINISTRATION Pediatric Patients 6 to 12 years : Recommended starting dosage is 39.2 mg/7.8 mg orally once daily in the morning. Dosage may be increased to 52.3 mg/10.4 mg daily or decreased to 26.1 mg/5.2 mg daily after one week. Maximum recommended dosage is 52.3 mg/10.4 mg once daily. ( 2.2 ) Adults and Pediatric Patients 13 to 17 years: Recommended starting dosage is 39.2 mg/7.8 mg orally once daily in the morning. Increase the dosage after one week to 52.3 mg/10.4 mg once daily depending on response and tolerability. ( 2.2 ) Administer with or without food. ( 2.3 ) Swallow capsules whole or open and sprinkle onto applesauce or add to water. ( 2.3 ) To avoid substitution errors and overdosage, do not substitute for other methylphenidate products on a milligram-per-milligram basis. ( 2.4 ) 2.1 Pretreatment Screening Prior to treating patients with AZSTARYS, 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 AZSTARYS [see Warnings and Precautions ( 5.10 )]. 2.2 Recommended Dosage Pediatric Patients 6 to 12 years of age The recommended starting dosage of AZSTARYS is 39.2 mg serdexmethylphenidate/7.8 mg dexmethylphenidate once daily in the morning. The dosage may be increased after one week to a dosage of 52.3 mg serdexmethylphenidate/10.4 mg dexmethylphenidate per day, or decreased after one week to a dosage of 26.1 mg serdexmethylphenidate/5.2 mg dexmethylphenidate per day, depending on response and tolerability. Maximum recommended dosage is 52.3 mg serdexmethylphendiate/10.4 mg dexmethyphenidate once daily. Adults and Pediatric Patients 13 to 17 years of age The recommended starting dosage of AZSTARYS is 39.2 mg serdexmethylphenidate/7.8 mg dexmethylphenidate once daily in the morning. Increase the dosage after one week to a dosage of 52.3 mg serdexmethylphenidate/10.4 mg dexmethylphenidate per day, depending on response and tolerability. Maximum recommended dosage is 52.3 mg serdexmethylphenidate/10.4 mg dexmethylphenidate once daily. 2.3 Administration Instructions Administer AZSTARYS orally once daily in the morning with or without food [see Clinical Pharmacology ( 12.3 )] . AZSTARYS capsules may be taken whole, or opened and the entire contents sprinkled into 50 mL of water or over 2 tablespoons of applesauce. Consume all the drug/food mixture immediately or within 10 minutes of mixing; do not store for future use [see Clinical Pharmacology ( 12.3 )] . 2.4 Switching from Other Methylphenidate Products If switching from other methylphenidate products, discontinue that treatment, and titrate with AZSTARYS using the titration schedule described above. Do not substitute AZSTARYS for other methylphenidate products on a milligram-per-milligram basis because these products have different pharmacokinetic profiles from AZSTARYS and may have different methylphenidate base composition [see Description ( 11 ), Clinical Pharmacology ( 12.3 )] . 2.5 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue AZSTARYS. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue AZSTARYS.

6 ADVERSE REACTIONS The following are discussed in more 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) ] Known hypersensitivity to methylphenidate or other ingredients of AZSTARYS [see Contraindications (4) ] Hypertensive Crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4) ] 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) ] Priapism [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.6) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7) ] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9) ] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.10) ] Based on accumulated data from other methylphenidate products, the most common (>5% and twice the rate of placebo) adverse reactions are appetite decreased, insomnia, nausea, vomiting, dyspepsia, abdominal pain, weight decreased, anxiety, dizziness, irritability, affect lability, tachycardia, and blood pressure increased. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Corium, LLC at 1-855-253-2407 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. Adverse Reactions in Studies with Other Methylphenidate Products in Pediatric Patients and Adults with ADHD Commonly reported (≥ 5% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: decreased appetite, decreased weight, nausea, abdominal pain, dyspepsia, vomiting, insomnia, anxiety, affect lability, irritability, dizziness, increased blood pressure, and tachycardia. Adverse Reactions in Studies with AZSTARYS in Pediatric Patients (6 to 12 years) with ADHD Short-Term Study A short-term study conducted in pediatric patients 6 to 12 years of age with ADHD was comprised of a 3-week, open-label, dose optimization phase in which all patients received AZSTARYS (n=155), followed by a 1-week, double-blind, controlled phase in which patients were randomized to continue AZSTARYS (n=74) or switch to placebo (n=76). Because of the study design, the reported adverse reaction rates cannot be used to predict the rates that may be expected in clinical practice. Long-Term Study A long-term, open-label safety study was conducted in pediatric patients 6 to 12 years of age with ADHD who either completed the short-term study or were de novo patients. This study was comprised of a 3-week dose optimization phase for patients not recently treated with AZSTARYS followed by a 12-month treatment phase for all patients during which 238 patients received open- label AZSTARYS and had evaluable safety data. A total of 154 patients were treated for 12 months. Because of the open-label, uncontrolled design of this study, the reported adverse reaction rates cannot be assessed in terms of a causal relationship to AZSTARYS treatment. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]); z- scores normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change less than 0.5 SD is considered not clinically significant. In this study, the mean increase in weight from baseline t

5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, 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 AZSTARYS, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing AZSTARYS. (5.4) Priapism : If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. (5.5) Peripheral Vasculopathy, including Raynaud's Phenomenon : Careful observation for digital changes is necessary during AZSTARYS treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. (5.6) Long-Term Suppression of Growth in Pediatric Patients : Monitor height and weight at appropriate intervals in pediatric patients. (5.7) Acute Angle Closure Glaucoma : AZSTARYS-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. (5.8) Increased Intraocular Pressure (IOP) and Glaucoma : Prescribe AZSTARYS to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. (5.9) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating AZSTARYS, 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. (5.10) 5.1 Abuse, Misuse, and Addiction AZSTARYS has a high potential for abuse and misuse. The use of AZSTARYS exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. AZSTARYS 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 AZSTARYS, 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 AZSTARYS, 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 AZSTARYS in a safe place, preferably locked, and instruct patients to not give AZSTARYS to anyone else. Throughout AZSTARYS 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 AZSTARYS 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 approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Some patients may have larger increases. Monitor all AZSTARYS-treated patients for hypertension and tachycardia. 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

4 CONTRAINDICATIONS AZSTARYS is contraindicated in patients: with known hypersensitivity to serdexmethylphenidate, methylphenidate, or other components of AZSTARYS. Bronchospasm, rash, and pruritus have been reported in patients who received AZSTARYS. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products [see Adverse Reactions ( 6.2 )] . receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crisis [see Drug Interactions ( 7.1 )] . Known hypersensitivity to serdexmethylphenidate, methylphenidate, or product components. ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. ( 4 )

10 OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of AZSTARYS should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.