QUILLICHEW ER

QuilliChew ER (methylphenidate hydrochloride extended-release chewable tablets) is available in three dosage strengths - 20 mg, 30 mg and 40 mg. The dosage strengths are expressed in terms of methylphenidate hydrochloride equivalents; however only 15% of methylphenidate is present as methylphenidate hydrochloride salt. The remaining 85% is present as methylphenidate ionically-bound to the sulfonate groups of sodium polystyrene sulfonate particles. QuilliChew ER contains approximately 30% immediate-release and 70% extended-release methylphenidate. The QuilliChew ER extended-release chewable tablets are cherry flavored. Methylphenidate HCl is a central nervous system (CNS) stimulant. The chemical name is methyl α- phenyl-2-piperidineacetate hydrochloride, and its structural formula is shown in Figure 1. Figure 1: Methylphenidate HCl Structure Methylphenidate HCl is a white, odorless crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. QuilliChew ER also contains the following inactive ingredients: aspartame [see Warnings and Precautions ( 5.8 ) ] , cherry flavor, citric acid, crospovidone, D&C red #30 (for 30 mg strength), D&C red #7 (for 40 mg strength), guar gum, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl acetate, polyvinyl alcohol, povidone, silicon dioxide, sodium polystyrene sulfonate, talc, triacetin, xanthan gum. structure

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 ).

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.

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 ) ].

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

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.

16.2 Storage and Handling Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF). [See USP Controlled Room Temperature.]