DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE MONOHYDRATE, DEXTROAMPHETAMINE SULFATE, AND AMPHETAMINE SULFATE

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules contain mixed salts of a single-entity amphetamine, a CNS stimulant. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules contain equal amounts (by weight) of four salts: dextroamphetamine sulfate and amphetamine sulfate, dextroamphetamine saccharate and amphetamine aspartate monohydrate. This results in a 3:1 mixture of dextro- to levo- amphetamine base equivalent. The 12.5 mg, 25 mg, 37.5 mg and 50 mg strength capsules are for oral administration. They are designed to contain two types of drug extended release pellets. One type of extended release pellets contains an outer coating of drug to immediately release drug upon administration. CAPSULE STRENGTHS EACH CAPSULE CONTAINS: 12.5 mg 25 mg 37.5 mg 50 mg Dextroamphetamine Saccharate 3.125 mg 6.250 mg 9.375 mg 12.500 mg Amphetamine Aspartate Monohydrate 3.125 mg 6.250 mg 9.375 mg 12.500 mg Dextroamphetamine Sulfate 3.125 mg 6.250 mg 9.375 mg 12.500 mg Amphetamine Sulfate 3.125 mg 6.250 mg 9.375 mg 12.500 mg Total mixed amphetamine salts 12.500 mg 25 mg 37.5 mg 50 mg Total amphetamine base equivalence 7.8 mg 15.6 mg 23.5 mg 31.3 mg Inactive Ingredients : ethylcellulose, hypromellose 2910, iron oxide red, iron oxide yellow, methacrylic acid copolymer dispersion; methyl acrylate, methyl methacrylate, and methacrylic acid copolymer; polyethylene glycol 400, polysorbate 80, sugar spheres (which contains corn starch and sucrose), talc, titanium dioxide, and triethyl citrate. The capsule shells contain gelatin, sodium lauryl sulfate, titanium dioxide. In addition, the 12.5 mg capsule shell contains carboxymethylcellulose, iron oxide red, and iron oxide yellow; the 25 mg capsule shell contains carboxymethylcellulose, FD&C Blue #1, iron oxide red, and iron oxide yellow; the 37.5 mg capsule shell contains carboxymethylcellulose, FD&C Blue #1 and FD&C Red #40, and iron oxide red; 50 mg capsule shell contains FD&C Blue #1 and FD&C Red #40. The printing ink for 12.5 mg, 25 mg, and 37.5 mg capsule contains ammonium hydroxide, iron oxide black, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. The printing ink for the 50 mg capsule contains ammonium hydroxide, povidone, propylene glycol, simethicone (which contains dimethicone and silicon dioxide), shellac, sodium hydroxide, and titanium dioxide.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 13 years and older [see Clinical Studies ( 14 )]. Limitations of Use : Pediatric patients 12 years and younger experienced higher plasma exposure than patients 13 years and older at the same dose, and experienced higher rates of adverse reactions, mainly insomnia and decreased appetite [see Use in Specific Populations ( 8.4 )]. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 13 years and older. ( 1 ) Limitations of Use : Pediatric patients 12 years and younger experienced higher plasma exposure than patients 13 years and older at the same dose and experienced higher rates of adverse reactions, mainly insomnia and decreased appetite. ( 8.4)

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules should be administered once daily upon awakening. Recommended Starting Dose Titration Schedule Maximum Daily Dose Adults 12.5 mg 12.5 mg weekly 50 mg Pediatrics (13 to 17) 12.5 mg 12.5 mg weekly 25 mg In adult patients with severe renal impairment the maximum dose should not exceed 25 mg daily. Use in adult patients with ESRD is not recommended. ( 2.6 , 8.6 ) The maximum dose in pediatric patients with severe renal impairment is 12.5 mg daily. Use in pediatric patients with ESRD is not recommended. ( 2.6 , 8.6 ) Patients are advised to take consistently either with or without food. ( 2.2 ) Administer upon awakening because the effects may last up to 16 hours and there is the potential for insomnia. ( 2.2 ) Prior to treatment, assess for presence of cardiac disease. ( 2.1 ) To avoid substitution errors and overdosage, do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles. ( 2.7 ) 2.1 Pretreatment Screening Prior to treating patients with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules [see Warnings and Precautions ( 5.10 )] 2.2 General Administration Information Because the effects of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules may last up to 16 hours and there is potential for insomnia, administer once daily in the morning upon awakening. In the event of a missed dose, do not administer later in the day. Do not administer additional medication to make up for the missed dose [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14 )]. 2.3 Administration Instructions Administer dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules orally with or without food. Advise patients to take dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules consistently either with food or without food [see Clinical Pharmacology ( 12.3 )]. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules may be administered in one of the following ways: Swallow dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules whole, or Open capsule and sprinkle the entire contents over a spoonful of applesauce. The sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the sprinkled applesauce in its entirety without chewing. The dose of a single capsule should not be divided. 2.4 Recommended Dosage Adults (18 to 55 years) The recommended starting dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules is 12.5 mg once daily in the morning upon awakening. Initial doses of 25 mg once daily may be considered for some patients. Dosage may be adjusted in increments of 12.5 mg no sooner than weekly, up to a maximum dose of 50 mg once daily, based on the therapeutic needs and response of the patient. Doses above 50 mg daily have shown no additional clinically meaningful benefit. Pediatric Patients (13 to 17 years) The recommended starting dose is 12.5 mg once daily in the morning upon awakening. Dosage may be adjusted in increments of 12.5 mg no sooner than weekly, up to a recommended maximum dose of 25 mg once daily. The dose should be individualized according to the needs and response of the patient. Doses higher than 25 mg have not been evaluated in clinical trials in pediatric patients. 2.5 Dosage Modifications Due to Drug Interactions Agents that alter gastrointestinal and 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsule dosage accordingly [see Drug Interactions ( 7.1 )]. 2.6 Dosage in Patients with Renal Impairment In adult patients with severe renal impairment (GFR between 15 to <30 mL/min/1.73 m 2 ), the recommended starting dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules is 12.5 mg daily with a maximum recommended dose of 25 mg daily. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are not recommended for use in patients with end stage renal disease (ESRD <15 mL/min/1.73 m 2 ). In pediatric patients (13 to 17 years) with severe renal impairment, the maximum dose is 12.5 mg, if tolerated [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )]. 2.7 Switching From Other Amphetamine Products For patients switching from another medication or any other amphetamine products, discontinue that treatment, and titrate with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules using the titration schedule [see Dosage and Administration (2.4) ] . Do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles [see Warnings and Precautions ( 5.9 ), Description ( 11 ), Clinical Pharmacology ( 12.3 )].

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are contraindicated in patients with: Known hypersensitivity to amphetamine, or other components of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see Adverse Reactions ( 6.2 )] . Concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor, because of an increased risk of hypertensive crisis [see Drug Interactions ( 7.1 )] . Known hypersensitivity to amphetamine products or other ingredients in dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. (4 ) Use with monoamine oxidase (MAO) inhibitors, or within 14 days of the last MAO inhibitor 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 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] Hypersensitivity to amphetamine products or other ingredients of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules [see Contraindications ( 4 )] Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications ( 4 ), 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 )] Seizures [see Warnings and Precautions ( 5.7 )] Serotonin Syndrome [see Warnings and Precautions ( 5.8 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.10 )] Most common adverse reactions in patients with ADHD (incidence ≥5% and at a rate at least twice placebo) are: Pediatrics (13 years and older): insomnia, decreased appetite, decreased weight, irritability, and nausea. ( 6.1 ) Adults: insomnia, decreased appetite, decreased weight, dry mouth, increased heart rate, and anxiety. (6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules were studied in adults (18 to 55 years) and pediatric patients (13 to 17 years) who met Diagnostic and Statistical Manual of Mental Disorders, 4 th or 5 th editions (DSM-IV-TR ® or DSM-5) criteria for ADHD. The safety data for adults were pooled from three randomized, double-blind, placebo-controlled studies in doses of 12.5 mg to 75 mg per day (1.5 times the maximum recommended dosage). Doses higher than 50 mg per day did not demonstrate additional clinical benefit and are not recommended. The safety data for pediatric patients (13 to 17 years) is from 1 randomized, double-blind, placebo-controlled study of doses of 12.5 mg to 25 mg. The total exposure in patients treated with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules totalled 704; this included pediatric patients, 78 adolescent patients and 626 adult patients from multiple well-controlled trials. The duration of use ranged from 4 to 7 weeks [see Clinical Studies ( 14 )] . Adverse Reactions Leading to Discontinuation of Treatment In pooled controlled trials of adult patients, 9% (54/626) of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsule-treated patients discontinued due to adverse reactions compared to 2% (7/328) of placebo-treated patients. The most frequent adverse reactions leading to discontinuation (i.e., leading to discontinuation in at least 1% of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsule-treated patients and at a rate at least twice that of placebo) were insomnia (2%, n=15), blood pressure increased (2%, n=10), decreased appetite (1%, n=5), and headache (1%, n=4). In a controlled trial including adolescent patients (13 to 17 years), 5% (4/78) of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsule-treated patients discontinued due to adverse reactions compared to 0% (0/79) of placebo-treated patients. The most frequent adverse reaction leading to discontinuation (i.e., leading to discontinuation in at least 1% of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsule-treated patients and at a rate at least twice that of placebo) were dizziness (1%, n=1), depression (1%, n=1), abdominal pain upper (1%, n=1), and viral infection (1%, n=1). Adverse Reactions Occurring at an Incidence of ≥2% and at Least Twice Placebo Among Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Extended-Release Capsule-Treated Adults in Clinical Trials The most common adverse reactions reported in adults were insomnia, decreased appetite, dry mouth, decreased weight, heart rate increased, and anxiety. Table 1 lists the adverse reactions that occurred ≥2% compared to placebo. The most common adverse reaction (insomnia) generally occurred early during treatment with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. Table 1: Adverse Reactions Reported by 2% or More of Adults Taking Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Extended-Release Capsules and at Least Twice the Incidence in Patients Taking Placebo in 3 Clinical Trials (4, 6, and 7 Weeks) Body System Adverse Reaction Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Extended-Release Capsules* (N = 626) Placebo (N = 328) Nervous System Anxiety 7% 3% Feeling Jittery 2% 1% Agitation 2% 0% Bruxism 2% 0% Psychiatric Disorders Insomnia 31% 8% Depression 3% 0% Metabolism and Nutritional Disorders Decreased Appetite 30% 4% Weight Decreased 9% 0% Gastrointestinal System Dry Mouth 23% 4% Diarrhea 3% 1% Cardiovascular System Heart Rate Increased 9% 0% Palpitations 4% 2% Genitourinary System Dysmenorrhea a 4% 2% Erectile Dysfunction b 2% 1% * Includes doses up to 75 mg (1.5 times the maximum recommended dosage). a Dysmenorrhea was observed in 11 females. b Erectile dysfunction was observed in 6 males. Adverse Reactions Occurring at an Incidence of 2% or More and at Least Twice Placebo Among Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Extended-Release Capsule-Treated Adolescents (13 to 17 years) in a 4 Week Clinical Trial The most common adverse reactions reported in adolescents were decreased appetite, nausea, insomnia, abdominal pain upper, irritability, and weight decreased. Table 2 lists the adverse reactions that occurred ≥2% compared to placebo. Table 2: Adverse Reactions Reported by ≥2% or More of Adolescents Taking Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Extended-Release Capsules and at Least Twice the Incidence in Patients Taking Placebo in a 4 Week Clinical Trial Body System Adverse Reaction Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Extended-Release Capsules (N = 78) Placebo (N = 79) Nervous System Dizziness 4% 0% Metabolism and Nutrition Disorders Decreased appetite 22% 6% Weight decreased 5% 1% Psychiatric Disorders Irritability 6% 3% Insomnia* 8% 3% Gastrointestinal Disorders Nausea 8% 4% Abdominal pain upper 4% 1% * Insomnia includes terms: initial insomnia, middle insomnia, terminal insomnia and insomnia. 6.2 Adverse Reactions Associated with the Use of Amphetamines The following adverse reactions have been associated with the use of amphetamines. The following adverse reactions have been identified during postapproval use of amphetamines. 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: Dyspnea, sudden death. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, euphoria, dyskinesia, dysphoria, headache, tics, fatigue, aggression, anger, logorrhea, dermatillomania, and paresthesia (including formication), motor and verbal tics. Endocrine: Impotence, changes in libido, frequent or prolonged erections. Eye Disorders: Mydriasis. Gastrointestinal: Unpleasant taste, constipation, intestinal ischemia. Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis. Skin: Alopecia. Vascular Disorders: Raynaud’s phenomenon.

Acidifying and Alkalinizing Agents: Agents that alter GI and urinary pH can alter blood levels of amphetamine. Acidifying agents (GI and urinary) decrease amphetamine blood levels, while alkalinizing agents (GI and urinary) increase amphetamine blood levels. Adjust dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsule dosage accordingly. ( 2.5 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Amphetamines Table 3: Drugs Having Clinically Important Interactions with Amphetamines Monoamine Oxidase Inhibitors (MAOIs) 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules during or within 14 days following the administration of MAOI [see Contraindications ( 4 )]. Serotonergic Drugs Clinical Impact The concomitant use of amphetamines 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and concomitant serotonergic drug(s) [see Warnings and Precautions ( 5.7 )]. Alkalinizing Agents Clinical Impact May increase exposure to amphetamine and exacerbate the action of amphetamine. Intervention Caution should be taken when coadministering dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and gastrointestinal and urinary alkalinizing agents. Acidifying Agents Clinical Impact Lower blood levels and efficacy of amphetamines. Intervention Increase dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules based on clinical response. Tricyclic Antidepressants Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing sustained increases in the concentration of d -amphetamine in the brain; cardiovascular effects can be potentiated. Intervention Monitor frequently and adjust dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules dose or use alternative therapy based on clinical response. CYP2D6 Inhibitors Clinical Impact May increase the exposure of amphetamine. Intervention Start with lower doses and monitor frequently and adjust dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules dose or use alternative therapy based on clinical response. Gastric pH Modulators Clinical Impact Potential change in shape of PK profile and exposure may occur. Intervention Monitor patients for changes in clinical effect and 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.