DYANAVEL XR

DYANAVEL XR (amphetamine) extended-release oral suspension and DYANAVEL XR (amphetamine) extended-release tablets contain amphetamine, a CNS stimulant, in a 3.2:1 ratio of d - to l - amphetamine. There are three active ingredients: amphetamine (complexed with sodium polystyrene sulfonate), dextroamphetamine sulfate and amphetamine aspartate. The dosage strengths are expressed in terms of amphetamine base. DYANAVEL XR contains both immediate-release and extended-release components. Structural Formula: C 9 H 13 N MW 135.21 Active Ingredients: DYANAVEL XR extended-release oral suspension 2.5 mg/mL: Each 1 mL contains 2 mg of amphetamine (in a 3.2 to 1 ratio of d- to l- amphetamine complexed with sodium polystyrene sulfonate), and 0.5 mg amphetamine (present as 0.5 mg of amphetamine aspartate and 0.3 mg of dextroamphetamine sulfate). DYANAVEL XR extended-release tablets: Each 5 mg strength tablet contains 4 mg of amphetamine (in a 3.2 to 1 ratio of d- to l- amphetamine complexed with sodium polystyrene sulfonate), and 1 mg of amphetamine (present as 1 mg of amphetamine aspartate and 0.7 mg of dextroamphetamine sulfate). Each 10 mg strength tablet contains 8 mg of amphetamine (in a 3.2 to 1 ratio of d- to l- amphetamine complexed with sodium polystyrene sulfonate), and 2 mg of amphetamine (present as 2 mg amphetamine aspartate and 1.4 mg dextroamphetamine sulfate). Each 15 mg strength tablet contains 12 mg of amphetamine (in a 3.2 to 1 ratio of d- to l- amphetamine complexed with sodium polystyrene sulfonate), and 3 mg of amphetamine (present as 3 mg amphetamine aspartate and 2 mg dextroamphetamine sulfate). Each 20 mg strength tablet contains 16 mg of amphetamine (in a 3.2 to 1 ratio of d- to l- amphetamine complexed with sodium polystyrene sulfonate), and 4 mg of amphetamine (present as 4 mg amphetamine aspartate and 2.7 mg dextroamphetamine sulfate). DYANAVEL XR extended-release oral suspension and DYANAVEL XR extended-release tablets are intended for oral administration. Inactive Ingredients: DYANAVEL XR extended-release oral suspension: anhydrous citric acid, bubblegum flavor, glycerin, methylparaben, modified starch, polysorbate 80, povidone, polyvinyl acetate, propylparaben, sodium lauryl sulfate, sodium polystyrene sulfonate, sucralose, triacetin and xanthan gum. DYANAVEL XR extended-release tablets: bubblegum flavor, crospovidone, guar gum, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl acetate, povidone, silicon dioxide, sodium polystyrene sulfonate, sucralose, talc, triacetin and xanthan gum. DXR chem draw structure

DYANAVEL XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies (14) ]. Limitations of Use The use of DYANAVEL XR 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 (5.5) , Use in Specific Populations (8.4) ]. DYANAVEL XR is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older ( 1 ) Limitations of Use The use of DYANAVEL XR 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 ( 5.5 , 8.4 ).

Recommended starting dosage is 2.5 mg or 5 mg once daily in the morning ( 2.2 ) Dosage may be increased in increments of 2.5 mg to 10 mg per day every 4 to 7 days up to a maximum daily dose of 20 mg ( 2.2 ) May be taken with or without food ( 2.3 ) Extended-release oral suspension: Shake bottle before administering ( 2.3 ) Extended-release tablets: May be chewed or swallowed whole ( 2.3 ) DYANAVEL XR oral suspension can be substituted with DYANAVEL XR tablets on a milligram per milligram basis ( 2.4 ) Do not substitute for other amphetamine products on a milligram-per-milligram basis, because of different amphetamine salt compositions and differing pharmacokinetic profiles ( 2.4 ) 2.1 Pretreatment Screening Prior to treating patients with DYANAVEL XR, 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 DYANAVEL XR [see Warnings and Precautions (5.8) ]. 2.2 Recommended Dosage The recommended starting dosage is 2.5 mg or 5 mg once daily in the morning. The dosage may be increased in increments of 2.5 mg to 10 mg per day every 4 to 7 days based on clinical response. The maximum recommended dosage is 20 mg once daily. 2.3 Administration Information Administer DYANAVEL XR orally once daily in the morning with or without food. DYANAVEL XR Extended-Release Oral Suspension Instruct patients to read the “Instructions for Use” for complete administration instructions. Ensure that the bottle adapter is firmly inserted into the bottle and do not remove once inserted. Shake the bottle of DYANAVEL XR extended-release oral suspension well before every administration. Use with the oral dosing dispenser provided by the pharmacist. DYANAVEL XR Extended-Release Tablets May be chewed or swallowed whole [see Clinical Pharmacology (12.3) ]. The 5 mg extended-release tablet is functionally scored and may be divided into equal halves (2.5 mg) at the score line. 2.4 Switching from Other Amphetamine Products DYANAVEL XR extended-release oral suspension can be substituted with DYANAVEL XR extended-release tablets on a milligram-per-milligram basis [ see Clinical Pharmacology (12.3) ] . If switching from other amphetamine products, discontinue that treatment, and titrate with DYANAVEL XR using the above titration schedule. Do not substitute for other amphetamine products on a milligram-per-milligram basis, because of different amphetamine salt compositions and differing pharmacokinetic profiles [ see Description (11) , Clinical Pharmacology (12.3) ] . 2.5 Dosage Modifications due to Drug Interactions Agents that alter urinary pH can impact urinary excretion and alter blood levels of amphetamine. Acidifying agents (e.g., ascorbic acid) decrease blood levels, while alkalinizing agents (e.g., sodium bicarbonate) increase blood levels. Adjust DYANAVEL XR dosage accordingly [ see Drug Interactions (7.1) ] .

DYANAVEL XR is contraindicated: In patients known to be hypersensitive to amphetamine, or other components of DYANAVEL XR. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [ see Adverse Reactions (6) ] . Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [ see Warnings and Precautions (5.7) , Drug Interactions (7.1) ]. Known hypersensitivity to amphetamine products or other ingredients in DYANAVEL XR ( 4 ) Use of monoamine oxidase inhibitor (MAOI) or within 14 days of the last MAOI dose ( 4 , 7.1 )

The following adverse reactions are discussed in greater detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions (5.1) , and Drug Abuse and Dependence (9.2 , 9.3 ) ] Hypersensitivity to amphetamine, or other components of DYANAVEL XR [see Contraindications (4) ] Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1) ] 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) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions (5.6) ] Serotonin Syndrome [see Warnings and Precautions (5.7) ] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.8) ] Most common adverse reactions observed with amphetamine products: dry mouth, anorexia, weight loss, abdominal pain, nausea, insomnia, restlessness, emotional lability, dizziness, tachycardia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc. at 1-732-940-0358 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 Amphetamine Products in Pediatric Patients and Adults with ADHD Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea. Eye Disorders: Vision blurred, mydriasis. Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Endocrine: Impotence, changes in libido. Skin: Alopecia. Adverse Reactions in Studies with DYANAVEL XR in Pediatric Patients with ADHD There is limited experience with DYANAVEL XR in controlled trials. Based on this limited experience, the adverse reaction profile of DYANAVEL XR appears similar to other amphetamine extended-release products. The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted with DYANAVEL XR extended-release oral suspension in 108 patients with ADHD (aged 6 to 12 years) were: epistaxis, allergic rhinitis, and upper abdominal pain. Table 1. Common Adverse Reactions Occurring in ≥2% of Patients on DYANAVEL XR Extended-Release Oral Suspension and Greater than Placebo During the Double Blind Phase. Preferred Term DYANAVEL XR (N=52) Placebo (N=48) Respiratory, thoracic and mediastinal disorders Epistaxis 3.8% 0% Rhinitis allergic 3.8% 0% Gastrointestinal disorders Abdominal pain upper 3.8% 2.1% 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of other amphetamine 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. Allergic : urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported Cardiovascular : palpitations, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use Central Nervous System : restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, aggression, anger, logorrhea, and paresthesia (including formication), motor and verbal tics Endocrine : impotence, changes in libido, frequent or prolonged erections Eye Disorders : vision blurred, mydriasis Gastrointestinal : unpleasant taste, constipation, intestinal ischemia, and other gastrointestinal disturbances Musculoskeletal, Connective Tissue, and Bone Disorders : rhabdomyolysis Psychiatric Disorders : dermatillomania, bruxism Skin : alopecia Vascular Disorders : Raynaud’s phenomenon

Acidifying and Alkalinizing Agents: Agents that alter urinary pH can alter blood levels of amphetamine. Acidifying agents can decrease amphetamine blood levels, while alkalinizing agents can increase amphetamine blood levels. Adjust DYANAVEL XR dosage accordingly ( 2.5 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Amphetamines Table 2. Drugs having clinically important interactions with amphetamines. MAO Inhibitors (MAOI) Clinical Impact MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. Intervention Do not administer DYANAVEL XR concomitantly or within 14 days following administration of MAOI [ see Contraindications (4) and Warnings and Precautions (5.7) ] . Serotonergic Drugs Clinical Impact The concomitant use of DYANAVEL XR and serotonergic drugs increases the risk of serotonin syndrome. Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during DYANAVEL XR initiation or dosage increase. If serotonin syndrome occurs, discontinue DYANAVEL XR and the concomitant serotonergic drug(s) [ see Warnings and Precautions ( 5.7 ) ] . CYP2D6 Inhibitors Clinical Impact The concomitant use of DYANAVEL XR and CYP2D6 inhibitors may increase the exposure of DYANAVEL XR compared to the use of the drug alone and increase the risk of serotonin syndrome. Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during DYANAVEL XR initiation and after a dosage increase. If serotonin syndrome occurs, discontinue DYANAVEL XR and the CYP2D6 inhibitor [ see Warnings and Precautions (5.7) , Overdosage (10) ] . Alkalinizing Agents (Urinary and Gastrointestinal) Clinical Impact Increase blood levels and potentiate the action of amphetamine. Intervention Co-administration of DYANAVEL XR and gastrointestinal or urinary alkalinizing agents should be avoided. Acidifying Agents (Urinary and Gastrointestinal) Clinical Impact Lower blood levels and efficacy of amphetamines. Intervention Increase dose based on clinical response. Tricyclic Antidepressants Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d- amphetamine in the brain; cardiovascular effects can be potentiated. Intervention Monitor frequently and adjust or use alternative therapy based on clinical response. 7.2 Drug/Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.