1 INDICATIONS AND USAGE Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules, a CNS stimulant, is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients 6 years and older.

( 1 ) Limitations of Use The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules are 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) 1.1 Attention Deficit Hyperactivity Disorder Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients 6 years and older.

Limitations of Use The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules are 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 ) ].

6 ADVERSE REACTIONS 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 )] 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 )] Seizures [see Warnings and Precautions ( 5.6 )] Peripheral Vasculopathy, including Raynaud’s Phenomenon [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 ( 5.9 )] Pediatric patients ages 6 to 12: Most common adverse reactions (≥5% and with a higher incidence than on placebo) were loss of appetite, insomnia, abdominal pain, emotional lability, vomiting, nervousness, nausea, and fever.

( 6.1 ) Pediatric patients ages 13 to 17: Most common adverse reactions (≥5% and with a higher incidence than on placebo) were loss of appetite, insomnia, abdominal pain, weight loss, and nervousness.

( 6.1 ) Adults: Most common adverse reactions ≥5% and with a higher incidence than on placebo were dry mouth, loss of appetite, insomnia, headache, weight loss, nausea, anxiety, agitation, dizziness, tachycardia, diarrhea, asthenia, and urinary tract infections.

( 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 practice.

The premarketing development program for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release included exposures in a total of 1,315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects).

Of these, 635 patients (ages 6 to 12) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N=40).

Safety data on all patients are included in the discussion that follows.

Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing.

Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized event categories.

In the tables and listings that follow, COSTART terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed.

Adverse Reactions Leading to Discontinuation of Treatment In two placebo-controlled studies of up to 5 weeks duration among children with ADHD, 2.4% (10/425) of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-treated patients discontinued due to adverse reactions (including three patients with loss of appetite, one of whom also reported insomnia) compared to 2.7% (7/259) receiving placebo.

The most frequent adverse reactions leading to discontinuation of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release in controlled and uncontrolled, multiple-dose clinical trials of children (N=595) were anorexia (loss of appetite) (2.9%), insomnia (1.5%), weight loss (1.2%), emotional lability (1%), and depression (0.7%).

Over half of these patients were exposed to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release for 12 months or more.

In a separate placebo-controlled 4-week study in adolescents with ADHD, five patients (2.1%) discontinued treatment due to adverse events among dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-treated patients (N=233) compared to none who received placebo (N=54).

The most frequent adverse event leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-treated patients and at a rate at least twice that of placebo) was insomnia (1.3%, n=3).

In one placebo-controlled 4-week study among adults with ADHD with doses 20 mg to 60 mg, 23 patients (12.0%) discontinued treatment due to adverse events among dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-treated patients (N=191) compared to one patient (1.6%) who received placebo (N=64).

The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-treated patients and at a rate at least twice that of placebo) were insomnia (5.2%, n=10), anxiety (2.1%, n=4), nervousness (1.6%, n=3), dry mouth (1.6%, n=3), anorexia (1.6%, n=3), tachycardia (1.6%, n=3), headache (1.6%, n=3), and asthenia (1.0%, n=2).

Adverse Reactions Occurring in Controlled Trials Adverse reactions reported in a 3-week clinical trial of children and a 4-week clinical trial in adolescents and adults, respectively, treated with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release or placebo are presented in the tables below.

Table 1: Adverse Reactions Reported by 2% or More of Children (6 to 12 Years Old) Receiving Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release with Higher Incidence than on Placebo in a 584 Patient Clinical Study Body System Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release Placebo Preferred Term (n=374) (n=210) General Abdominal Pain (stomachache) 14% 10% Fever 5% 2% Infection 4% 2% Accidental Injury 3% 2% Asthenia (fatigue) 2% 0% Digestive System Loss of Appetite 22% 2% Vomiting 7% 4% Nausea 5% 3% Dyspepsia 2% 1% Nervous System Insomnia 17% 2% Emotional Lability 9% 2% Nervousness 6% 2% Dizziness 2% 0% Metabolic/Nutritional Weight Loss 4% 0% Table 2: Adverse Reactions Reported by 5% or More of Adolescents (13 to 17 Years Old) Weighing ≤75 kg/165 lbs Receiving Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release with Higher Incidence than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study* Body System Preferred Term Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release Placebo (n=233) (n=54) Note: The following reactions did not meet the criterion for inclusion in Table 2 but were reported by 2 to 4% of adolescent patients receiving dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting.

* Included doses up to 40 mg.

a Appears the same due to rounding.

b Dose-related adverse reactions.

General Abdominal Pain (stomachache) 11% 2% Digestive System Loss of Appetite b 36% 2% Nervous System Insomnia b 12% 4% Nervousness 6% 6% a Metabolic/Nutritional Weight Loss b 9% 0% Table 3: Adverse Reactions Reported by 5% or More of Adults Receiving Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release with Higher Incidence than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study* Body System Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release Placebo Preferred Term (n=191) (n=64) Note: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2 to 4% of adult patients receiving dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g., teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence.

* Included doses up to 60 mg.

a Appears the same due to rounding.

General Headache 26% 13% Asthenia 6% 5% Digestive System Dry Mouth 35% 5% Loss of Appetite 33% 3% Nausea 8% 3% Diarrhea 6% 0% Nervous System Insomnia 27% 13% Agitation 8% 5% Anxiety 8% 5% Dizziness 7% 0% Nervousness 13% 13% a Cardiovascular System Tachycardia 6% 3% Metabolic/Nutritional Weight Loss 10% 0% Urogenital System Urinary Tract Infection 5% 0% Hypertension In a controlled 4-week outpatient clinical study of adolescents with ADHD, isolated systolic blood pressure elevations ≥15 mmHg were observed in 7/64 (11%) placebo-treated patients and 7/100 (7%) patients receiving dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release 10 or 20 mg.

Isolated elevations in diastolic blood pressure ≥8 mmHg were observed in 16/64 (25%) placebo-treated patients and 22/100 (22%) dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-treated patients.

Similar results were observed at higher doses [see Warnings and Precautions ( 5.2 )] .

In a single-dose pharmacokinetic study in 23 adolescents with ADHD, isolated increases in systolic blood pressure (above the upper 95% CI for age, gender, and stature) were observed in 2/17 (12%) and 8/23 (35%), subjects administered 10 mg and 20 mg dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release, respectively.

Higher single doses were associated with a greater increase in systolic blood pressure.

All increases were transient, appeared maximal at 2 to 4 hours postdose and, not associated with symptoms.

6.2 Adverse Reactions Associated with the Use of Amphetamine, Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release, or Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Immediate-Release The following adverse reactions have been identified during postapproval use of amphetamine, dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release, or dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate immediate-release.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always 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.

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, motor and verbal tics, aggression, anger, logorrhea, dermatillomania, paresthesia (including formication), and bruxism.

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 and Connective Tissue Disorders: Rhabdomyolysis.

Skin: Alopecia.

Vascular Disorders: Raynaud’s phenomenon.