QuilliChew ER

1 INDICATIONS AND USAGE QuilliChew ER is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies ( 14 ) ]. Limitations of Use The use of QuilliChew ER 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 ) ]. QuilliChew ER is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). ( 1 ) Limitations of Use The use of QuilliChew ER 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 ).

2 DOSAGE AND ADMINISTRATION QuilliChew ER may be taken with or without food. ( 2.1 ) For patients 6 years and above, recommended starting dose is 20 mg given orally once daily in the morning. Dosage may be titrated weekly in increments of 10 mg, 15 mg or 20 mg per day. Daily dosage above 60 mg is not recommended. ( 2.1 ) 2.1 Pretreatment Screening Prior to treating patients with QuilliChew ER, 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 QuilliChew ER [see Warnings and Precautions (5.10) ]. 2.2 Recommended Dosage The recommended starting dosage of QuilliChew ER for patients 6 years and above is 20 mg once daily orally in the morning. The dose may be titrated up or down weekly in increments of 10 mg, 15 mg or 20 mg. The 10 mg and 15 mg doses can each be achieved by breaking in half the functionally scored 20 mg and 30 mg tablets, respectively. Daily doses above 60 mg have not been studied and are not recommended. As with any CNS stimulant, during titration of QuilliChew ER, the prescribed dose should be adjusted, if necessary, until a well-tolerated, therapeutic dose is achieved. 2.3 Administration Instructions QuilliChew ER should be orally administered once daily in the morning with or without food [see Clinical Pharmacology ( 12.3 ) ]. 2.4 Switching from other Methylphenidate Products If switching from other methylphenidate products, discontinue that treatment, and titrate with QuilliChew ER using the above titration schedule. Do not substitute for other methylphenidate products on a milligram-per-milligram basis, because of different methylphenidate base compositions and differing pharmacokinetic profiles [see Description ( 11 ) , Clinical Pharmacology ( 12.3 ) ]. 2.5 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reaction occur, reduce dosage, or, if necessary, discontinue QuilliChew ER. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue QuilliChew ER.

4 CONTRAINDICATIONS Known hypersensitivity to methylphenidate or product components. ( 4.1 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. ( 4.2 , 7.1 ) 4.1 Hypersensitivity to Methylphenidate or other Components of QuilliChew ER QuilliChew ER is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of QuilliChew ER. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products [see Adverse Reactions ( 6.2 ) ] . 4.2 Monoamine Oxidase Inhibitors QuilliChew ER is contraindicated during concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (MAOI), because of the risk of hypertensive crisis [see Drug Interactions ( 7.1 ) ].

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 QuilliChew ER, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing QuilliChew ER. ( 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 QuilliChew ER treatment. 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: 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. ( 5.7 ) Risks in Phenylketonurics: QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame. ( 5.8 ) Acute Angle Closure Glaucoma: QuilliChew ER -treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.9 ) Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe QuilliChew ER 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. ( 5.10 ) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating QuilliChew ER, 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. ( 5.11 ) 5.1 Abuse, Misuse, and Addiction QuilliChew ER has a high potential for abuse and misuse. The use of QuilliChew ER exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. QuilliChew ER 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 QuilliChew ER, 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 QuilliChew ER, 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 QuilliChew ER in a safe place, preferably locked, and instruct patients to not give QuilliChew ER to anyone else. Throughout QuilliChew ER 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 occurred in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid QuilliChew ER use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, 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 bpm). Some patients may have larger increases. Monitor all QuilliChew ER-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 Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating QuilliChew ER 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, or 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 QuilliChew ER. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during a period of methylphenidate withdrawal (drug holidays or during discontinuation). QuilliChew ER treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including QuilliChew ER, 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 of digital changes is necessary during QuilliChew ER treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for QuilliChew ER-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients QuilliChew ER 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. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had 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 development period. Closely monitor growth (weight and height) in QuilliChew ER-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame. Each 20 mg, 30 mg, and 40 mg extended-release chewable tablet contains 3 mg, 4.5 mg, and 6 mg phenylalanine, respectively. Before prescribing QuilliChew ER in patients with PKU, consider the combined daily amount of phenylalanine from all sources, including QuilliChew ER. 5.9 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, QuilliChew ER -treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.10 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2) ]. Prescribe QuilliChew ER to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor QuilliChew ER -treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.11 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, 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 QuilliChew ER, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor QuilliChew ER-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7 ) 7.1 Clinically Important Drug Interactions MAOI Inhibitors Do not administer QuilliChew ER concomitantly with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment. Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Antihypertensive Drugs QuilliChew ER may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the hypertensive drug as needed [see Warnings and Precautions (5.3) ]. Halogenated Anesthetics Concomitant use of halogenated anesthetics and QuilliChew ER may increase the risk of sudden blood pressure and heart rate increase during surgery. Avoid use of QuilliChew ER in patients being treated with anesthetics on the day of surgery. Risperidone Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.

6 A DVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Known hypersensitivity to methylphenidate products or other ingredients of QuilliChew ER [see Contraindications (4.1) ] • Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4.2) , Drug Interactions (7.1) ] • Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions (5.1) , 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) ] • 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) ] • Risks in Phenylketonuria [see Warnings and Precautions (5.8) ] • Acute Angle Closure Glaucoma [see Warnings and Precautions (5.9) ] • Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.10) ] • Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.11) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc. at (732) 940-0358 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 Children, Adolescents, and Adults with ADHD Commonly reported (≥2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: appetite decreased, weight decreased, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, blood pressure increased, heart rate increased, tachycardia, palpitations, hyperhidrosis, and pyrexia. Adverse Reactions in Studies with QuilliChew ER in Children with ADHD There is limited experience with QuilliChew ER in controlled trials. The safety data in this section is based on data from a laboratory classroom study conducted in 90 pediatric subjects (ages 6 to 12 years) with ADHD. The study consisted of a 6-week dose optimization period, followed by a randomized, double-blind, parallel group treatment period with the individually optimized dose of QuilliChew ER or placebo. The most common (≥2% in the QuilliChew ER group and greater than placebo) adverse reactions reported in the double-blind, randomized, placebo-controlled phase in patients optimized to doses of QuilliChew ER 20 to 60 mg/day are described in Table 1. Table 1: Common Adverse Reactions Occurring in ≥2% of Subjects on QuilliChew ER and Greater than Placebo During the Double-Blind Period of the ADHD Laboratory Classroom Study Adverse reaction QuilliChew ER N= 4 2 n (%) Placebo N= 4 4 n (%) Decreased appetite 1 (2.4) 0 (0) Aggression 1 (2.4) 0 (0) Emotional poverty 1 (2.4) 0 (0) Nausea 1 (2.4) 0 (0) Headache 1 (2.4) 0 (0) Weight decreased 1 (2.4) 0 (0) 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of methylphenidate products. 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. These adverse reactions are as follows: Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment General Disorders: Chest pain, Chest discomfort, Hyperpyrexia Hepatobiliary Disorders: Severe hepatocellular injury Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Libido changes, Mania Urogenital System: Priapism Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema Vascular Disorders: Raynaud’s phenomenon

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/ . Risk Summary There are limited published studies and small case series that report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. There are clinical considerations [see Clinical Considerations ] . No teratogenic effects were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses 2 and 11 times, respectively, the maximum recommended human dose (MRHD). However, spina bifida was observed in rabbits at a dose 40 times the MRHD [see Data ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions CNS stimulant medications, such as QuilliChew ER, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m 2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m 2 basis).