METADATE CD

WARNING: ABUSE, MISUSE, AND ADDICTION METADATE CD 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 METADATE CD, 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 METADATE CD, 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 METADATE CD treatment, reassess e ach 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. METADATE CD 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 METADATE CD, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing METADATE CD, 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 METADATE CD, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing METADATE CD. ( 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 METADATE CD 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 : METADATE CD-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 METADATE CD 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 METADATE CD, 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 METADATE CD has a high potential for abuse and misuse. The use of METADATE CD exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. METADATE CD 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 METADATE CD, 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 METADATE CD, 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 METADATE CD in a safe place, preferably locked, and instruct patients to not give METADATE CD to anyone else. Throughout METADATE CD 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 dosage. Avoid METADATE CD use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac problems. 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 METADATE CD 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 METADATE CD 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 dosages, 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 CNC stimulant-treated patients, compared to 0% of placebo-treated patients If such symptoms occur, consider discontinuing METADATE CD. 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 methylphenidate withdrawal (drug holidays or during discontinuation). METADATE CD-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 METADATE CD, 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 in or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during METADATE CD treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for METADATE CD-treated patients who develop signs of symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients METADATE CD is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Population ( 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 children ages 7 to 10 years who were randomized to either methylphenidate or non- medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non- medication treated children over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate treatment 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 METADATE CD-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, METADATE CD-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 METADATE CD to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor METADATE CD-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 METADATE CD, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor METADATE CD-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: Abuse, Misuse, and Addiction [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] Hypersensitivity to Methylphenidate and Other Component of METADATE CD [see Contraindications ( 4 )] Hypertensive Crisis when Used Concomitantly with MAOIs [see Contraindications ( 4 ) and Drug Interactions ( 7 )] 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 )] The most common adverse reactions (≥ 5% and twice the rate of placebo) were anorexia and insomnia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aytu BioPharma at 1-855-298-8246 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 practice. Clinical trials experience with METADATE CD included 188 pediatric patients 6 to 15 years old with ADHD exposed to METADATE CD. Patients received METADATE CD 20 mg, 40 mg, and/or 60 mg per day. The 188 patients were evaluated in the following studies: Study 1, a 3-week placebo-controlled clinical study consisting of a total of 314 pediatric patients (ages 6 to 15 years; METADATE CD n=155); Study 2, a placebo-controlled, crossover clinical study consisting of 25 pediatric patients (ages 7 to 12 years); and Study 3, an uncontrolled clinical study consisting of 8 pediatric patients (ages 6 to 10 years). Adverse Reactions Leading to Discontinuation of Treatment In the 3-week placebo-controlled, parallel-group trial, two METADATE CD-treated patients (1%) and no placebo-treated patients discontinued due to an adverse reaction (rash and pruritus; and headache, abdominal pain, and dizziness, respectively). Most Common Adverse Reactions The most common adverse reactions that occurred in 5% or more of patients treated with METADATE CD in a pool of Studies 1, 2 and 3 (ages 6 to 15 years) where the incidence in patients treated with METADATE CD was at least twice the incidence in placebo-treated patients were anorexia and insomnia. Adverse reactions that occurred in ≥5% of patients treated with METADATE CD and greater than placebo in pooled Studies, 1, 2, and 3 are presented in Table 2: Table 2: Adverse Reactions ( ≥5% and Greater than Placebo) in Pediatric Patients Ages 6 to 15 Years Receiving METADATE CD in Pooled Three to Four Week Trials Body System Preferred Term METADATE CD (n=188) % Placebo (n=190) % General Headache 12 8 Abdominal Pain (stomachache) 7 4 Digestive System Anorexia 9 2 Nervous System Insomnia 5 2 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of METADATE CD and other methylphenidate HCl 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. Adverse Reactions with METADATE CD Blood and the lymphatic system disorders: thrombocytopenia Cardiac disorders: cardiac arrest, sudden death Immune system disorders: angioedema Musculoskeletal and connective tissue disorders: rhabdomyolysis Psychiatric disorders: abnormal behavior, aggression, anxiety, irritability, obsessive-compulsive disorder, suicidal behavior (including completed suicide), libido changes, serotonin syndrome in combination with serotonergic drugs Nervous System Disorder : migraine, reversible ischemic neurological deficit, bruxism Skin and subcutaneous tissue disorders: fixed drug eruption Vascular disorders: peripheral coldness, Raynaud’s phenomenon Adverse Reactions with Other Methylphenidate HCl Products Blood and the lymphatic system disorders: leukopenia, anemia, pancytopenia Cardiac disorders: palpitations; increased blood pressure, tachycardia, angina pectoris, cardiac arrhythmia, myocardial infarction, bradycardia, extrasystole Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, increased intraocular pressure, mydriasis Gastrointestinal disorders : nausea, abdominal pain, dry mouth, vomiting, dyspepsia, diarrhea, constipation General Disorders: fatigue, hyperpyrexia Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Immune system disorders : hypersensitivity, including anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas Infections and infestations: nasopharyngitis Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, myalgia, muscle twitching Nervous System Disorder : nervousness, dizziness, headache, dyskinesia, including choreoatheetoid movements, drowsiness, tremor, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs, motor and verbal tics Psychiatric disorders: depressed mood, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), affect liability, mania, disorientation Renal and urinary disorders: hematuria Reproductive system and breast disorders: gynecomastia Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, dyspnea, cough Skin and subcutaneous tissue disorders: scalp hair loss, hyperhidrosis, angioneurotic edema, erythema, exfoliative dermatitis, thrombocytopenic purpura, urticaria, erythema multiforme rash Urogenital disorders: priapism Vascular disorders: isolated cases of cerebral arteritis and/or occlusion

<table width="601.6px"><caption>Table 2: Adverse Reactions ( &#x2265;5% and Greater than Placebo) in Pediatric Patients Ages 6 to 15 Years Receiving METADATE CD in Pooled Three to Four Week Trials</caption><col/><col/><col/><col/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold"><content styleCode="underline">Body System</content></content></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold"><content styleCode="underline">Preferred Term</content></content></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">METADATE CD <content styleCode="underline">(n=188)</content></content></paragraph><content styleCode="bold">%</content></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo <content styleCode="underline">(n=190)</content></content></paragraph><content styleCode="bold">%</content></td></tr><tr><td rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">General</content></td><td styleCode=" Botrule Toprule Lrule Rrule"> Headache</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 12</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 8</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> Abdominal Pain (stomachache)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 7</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 4</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Digestive System</content></td><td styleCode=" Botrule Toprule Lrule Rrule"> Anorexia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> 9</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Nervous System</content></td><td styleCode=" Botrule Toprule Lrule Rrule"> Insomnia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">5</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2</td></tr></tbody></table>