COTEMPLA XR-ODT

COTEMPLA XR-ODT contains methylphenidate, a central nervous system (CNS) stimulant. COTEMPLA XR-ODT is an extended-release orally disintegrating tablet intended for once daily administration. COTEMPLA XR-ODT contains approximately 25% immediate-release and 75% extended-release methylphenidate. Methylphenidate is ionically-bound to the sulfonate of polystyrene sulfonate particles. COTEMPLA XR-ODT contains 8.6 mg, 17.3 mg or 25.9 mg of methylphenidate which is the same as the amount of methylphenidate (base equivalent) found, respectively, in 10 mg, 20 mg and 30 mg strength methylphenidate hydrochloride products. The chemical name of methylphenidate is methyl α-phenyl-2-piperidineacetate, and its structural formula is shown in Figure 1. Figure 1: Methylphenidate Structure C 14 H 19 NO 2 Mol. Wt. 233.31 COTEMPLA XR-ODT also contains the following inactive ingredients: Mannitol, Fructose, Microcrystalline Cellulose, Crospovidone, Methacrylic Acid, Polystyrene Sulfonate, Citric Acid, Colloidal Silicon Dioxide, Grape Flavor, Natural Masking Type Powder, Triethyl Citrate, Magnesium Stearate, Ethylcellulose, Sucralose, Lake Blend Purple, and Polyethylene Glycol 3350. Figure 1

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)

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.

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 )

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

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.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store COTEMPLA XR-ODT blister packages in the reusable travel case after removal from the carton.