Quillivant XR

WARNING: ABUSE, MISUSE, AND ADDICTION QUILLIVANT XR 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 QUILLIVANT XR, 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 QUILLIVANT XR, 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 QUILLIVANT XR 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) , Drug Abuse and Dependence (9.2) ]. WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. QUILLIVANT XR 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 QUILLIVANT XR, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing QUILLIVANT XR, 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 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 QUILLIVANT XR, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing QUILLIVANT XR. ( 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 QUILLIVANT XR 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 ) Acute Angle Closure Glaucoma : QUILLIVANT XR -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 QUILLIVANT XR 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 QUILLIVANT XR, 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 QUILLIVANT XR has a high potential for abuse and misuse. The use of QUILLIVANT XR exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. QUILLIVANT XR 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 QUILLIVANT XR, 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 QUILLIVANT XR, 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 QUILLIVANT XR in a safe place, preferably locked, and instruct patients to not give QUILLIVANT XR to anyone else. Throughout QUILLIVANT XR 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 QUILLIVANT XR 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 mm Hg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all QUILLIVANT XR-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 QUILLIVANT XR 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 QUILLIVANT XR. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adults 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 methylphenidate withdrawal (drug holidays or during discontinuation). QUILLIVANT XR-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 QUILLIVANT XR, 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 of digital changes is necessary during QUILLIVANT XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for QUILLIVANT XR-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients QUILLIVANT XR is not approved and is not recommended for use 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 QUILLIVANT XR-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 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, QUILLIVANT XR -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 and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2) ] . Prescribe QUILLIVANT XR to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor QUILLIVANT XR -treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.10 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 QUILLIVANT XR, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor QUILLIVANT XR -treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Known hypersensitivity to methylphenidate products or other ingredients of QUILLIVANT XR [see Contraindications (4) ] Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) , 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) ] 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. ( 6.1 ) 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 QUILLIVANT XR in Children and Adolescents with ADHD There is limited experience with QUILLIVANT XR in controlled trials. Based on this limited experience, the adverse reaction profile of QUILLIVANT XR appears similar to other methylphenidate extended-release products. The most common (≥2% in the QUILLIVANT XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 45 ADHD patients (ages 6 to 12 years) were affect lability, excoriation, initial insomnia, tic, decreased appetite, vomiting, motion sickness, eye pain, and rash. Table 2: Common Adverse Reactions occurring in ≥2% of subjects on QUILLIVANT XR and greater than placebo during the controlled cross-over phase Adverse reaction QUILLIVANT XR N= 45 Placebo N= 45 Affect lability 9% 2% Excoriation 4% 0 Initial Insomnia 2% 0 Tic 2% 0 Decreased appetite 2% 0 Vomiting 2% 0 Motion sickness 2% 0 Eye pain 2% 0 Rash 2% 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

<table><caption>Table 2: Common Adverse Reactions occurring in &#x2265;2% of subjects on QUILLIVANT XR and greater than placebo during the controlled cross-over phase</caption><col width="123"/><col width="207"/><col width="222"/><tbody><tr><td align="center" styleCode=" Toprule Lrule Rrule"><content styleCode="bold">Adverse reaction</content></td><td align="center" styleCode=" Toprule Lrule Rrule"><content styleCode="bold">QUILLIVANT XR</content> N= 45</td><td align="center" styleCode=" Toprule Lrule Rrule"><content styleCode="bold">Placebo</content> N= 45</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Affect lability</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">9%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">2%</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Excoriation</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">4%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">0</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Initial Insomnia</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">2%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">0</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Tic </td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">2%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">0</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Decreased appetite </td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">2%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">0</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Vomiting</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">2%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">0</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Motion sickness</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">2%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">0</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Eye pain</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">2%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">0</td></tr><tr><td valign="bottom" styleCode=" Toprule Lrule Rrule">Rash</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">2%</td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule">0</td></tr></tbody></table>