Cotempla XR-ODT

1 INDICATIONS AND USAGE COTEMPLA XR-ODT is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age [see Clinical Studies (14) ]. Limitations of Use The use of COTEMPLA XR-ODT 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)] . COTEMPLA XR-ODT is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age. ( 1 ) Limitations of Use The use of COTEMPLA XR-ODT 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 Recommended starting dose for pediatric patients 6 to 17 years of age is 17.3 mg given orally once daily in the morning. Dosage may be increased weekly in increments of 8.6 mg to 17.3 mg per day. Daily dosage above 51.8 mg is not recommended. ( 2.2 ) Patients are advised to take COTEMPLA XR-ODT consistently either with food or without food. ( 2.2 ) 2.1 Pretreatment Screening Prior to treating patients with COTEMPLA XR-ODT, 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 sydrome before initiating COTEMPLA XR-ODT [see Warnings and Precautions (5.10) ]. 2.2 General Dosing Information COTEMPLA XR-ODT is given orally once daily in the morning. Advise patients to take COTEMPLA XR-ODT consistently either with food or without food [see Clinical Pharmacology (12.3) ] . The recommended starting dose of COTEMPLA XR-ODT for patients 6 to 17 years of age is 17.3 mg once daily in the morning. The dose may be titrated weekly in increments of 8.6 mg to 17.3 mg. Daily doses above 51.8 mg have not been studied and are not recommended. The dose should be individualized according to the needs and responses of the patient. 2.3 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage, or, if necessary, discontinue COTEMPLA XR-ODT. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue COTEMPLA XR-ODT. 2.4 COTEMPLA XR-ODT Administration Instruct the patient or caregiver on the following administration instructions: Do not remove the tablet from the blister pack until just prior to dosing. Take the tablet immediately after opening the blister pack. Do not store the tablet for future use. Use dry hands when opening the blister pack. Remove the tablet by peeling back the foil on the blister pack. Do not push the tablet through the foil. As soon as the blister is opened, remove the tablet and place on the patient's tongue. Place the whole tablet on the tongue and allow it to disintegrate without chewing or crushing. The tablet will disintegrate in saliva so that it can be swallowed. No liquid is needed to take the tablet.

4 CONTRAINDICATIONS COTEMPLA XR-ODT is contraindicated in patients with: Known hypersensitivity to methylphenidate or other components of COTEMPLA XR-ODT. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate products [see Adverse Reactions (6.2) ] . Concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor because of the risk of hypertensive crisis [see Drug Interactions (7.1) ] . Known hypersensitivity to methylphenidate or product components. ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. ( 4 )

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. Consider the benefits and risks in patients for whom an increase in blood pressure or heart rate would be problematic. ( 5.3 ) Psychiatric Adverse Reactions : Prior to initiating COTEMPLA XR-ODT, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing COTEMPLA XR-ODT. ( 5.4 ) Priapism : If abnormally sustained or frequent and painful erection occur, patients should seek immediate medical attention. ( 5.5 ) Peripheral Vasculopathy, including Raynaud's Phenomenon : Careful observation for digital changes is necessary during COTEMPLA XR-ODT treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of perifphral vasculophathy. ( 5.6 ) Long-term Suppression of Growth in Pediactric 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 : COTEMPLA XR-ODT-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 COTEMPLA XR-ODT 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 COTEMPLA XR-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. (5.10) 5.1 Abuse, Misuse, and Addiction COTEMPLA XR-ODT has a high potential for abuse and misuse. The use of COTEMPLA XR-ODT exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. COTEMPLA XR-ODT can be diverted for nonmedical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)] . Misuse and abuse of CNS stimulants, including COTEMPLA XR-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 COTEMPLA XR-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 COTEMPLA XR-ODT in a safe place, preferably locked, and instruct patients to not give COTEMPLA XR-ODT to anyone else. Throughout COTEMPLA XR-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 occurred in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosages. Avoid COTEMPLA XR-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 approximately 2 to 4 mm Hg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all COTEMPLA XR-ODT-treated patients for hypertension and tachycardia. 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). COTEMPLA XR-ODT-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 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 COTEMPLA XR-ODT 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 COTEMPLA XR-ODT. 5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon CNS stimulants, including COTEMPLA XR-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 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 for digital changes is necessary during COTEMPLA XR-ODT treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for COTEMPLA XRODT-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients COTEMPLA[A1] XR-ODT 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 COTEMPLA XR-ODT-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, COTEMPLA XR-ODT-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 COTEMPLA XR-ODT to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor COTEMPLA XR-ODT-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 COTEMPLA XR-ODT, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regulary monitor COTEMPLA XR-ODT-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontine treatment if clinically appropriate.

7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7 ) 7.1 Clinically Important Interactions with COTEMPLA XR-ODT Table 1: Drugs Having Clinically Important Interactions with Methylphenidate Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: 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 [see Contraindications (4) ] . Intervention: Do not administer COTEMPLA-XR ODT concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. Gastric pH Modulators Clinical Impact: May change the release profile and alter the pharmacodynamics of COTEMPLA-XR ODT. Intervention: Concomitant use of Cotempla XR-ODT with a gastric pH modulator (i.e., a H2-blocker or a proton pump inhibitor) is not recommended. Antihypertensive Drugs Clinical Impact: Cotempla XR-ODT may decrease the effectiveness of drug used to treat hypertension [see Warnings and Precautions (5.3) ]. Intervention: Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact: Concomitant use of halogenated anesthetics and COTEMPLA XR-ODT may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention: Avoid use of COTEMPLA XR-ODT in patients being treated with anesthetics on the day of surgery. Risperidone Clinical Impact: 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). Intervention: Monitor for signs of EPS.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Known hypersensitivity to methylphenidate or other ingredients of Cotempla XR-ODT [see Contraindications (4) ] Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications (4) and Drug Interactions (7.1) ] Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions (5.1) , and 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Neos Therapeutics, Inc. at 1-888-319-1789 or http://www.COTEMPLAXRODT.com 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 COTEMPLA XR-ODT in Children with ADHD There is limited experience with COTEMPLA XR-ODT in controlled trials. Based on this limited experience, the adverse reaction profile of COTEMPLA XR-ODT appears similar to other methylphenidate extended release-products. 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 intraocolar pressure, Mydriasis, Visual impairment General Disorders : Chest pain, Chest discomfort, Hyperpyrexia Immune System Disorders : Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritis 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 COTEMPLA XR-ODT during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes [see Data ] . There are risks to the fetus associated with the use of central nervous system (CNS) stimulants during pregnancy [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 4 and 18 times, respectively, the maximum recommended human dose (MRHD) of 51.8 mg (as base). However, spina bifida was observed in rabbits at a dose 60 times the MRHD [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions CNS stimulants, such as COTEMPLA XR-ODT, 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 Human Data A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing methylphenidate use during pregnancy. Due to the small number of methylphenidate-exposed pregnancies with known outcomes, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size, concomitant use of other medications, lack of detail regarding dose and duration of exposure to methylphenidate and non-generalizability of the enrolled populations. 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 60 times the maximum recommended human dose (MRHD) of 51.8 mg (as base) for adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (18 times the MRHD for adolescent 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 (11 times the MRHD on a mg/m 2 basis for adolescent), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the MRHD on a mg/m 2 basis for adolescent).