Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate and Amphetamine Sulfate

1 INDICATIONS AND USAGE Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and 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, and amphetamine sulfate extended-release capsules 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 ) 1.1 Attention Deficit Hyperactivity Disorder 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 adults and pediatric patients 6 years and older. Limitations of Use The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules 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 )] .

2 DOSAGE AND ADMINISTRATION • Pediatric patients (ages 6 to 17): 10 mg once daily in the morning. Maximum dose for children 6 to 12 years of age is 30 mg once daily. ( 2.2 , 2.3 , 2.4 ) • Adults: 20 mg once daily in the morning. ( 2.5 ) • Pediatric patients (ages 6 to 17) with severe renal impairment: 5 mg once daily in the morning. Maximum dose for children 6 to 12 years of age with severe renal impairment is 20 mg once daily. ( 2.6 , 8.6 ) • Adults with severe renal impairment: 15 mg once daily in the morning. ( 2.6 , 8.6 ) • Patients with end stage renal disease (ESRD): Not recommended. ( 2.6 , 8.6 ) 2.1 Prereatment 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 ( 5.9 )] . 2.2 General Administration Information Individualize the dosage according to the therapeutic needs and response of the patient. Administer dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules at the lowest effective dosage. Based on bioequivalence data, patients taking divided doses of immediate-release dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (for example, twice daily), may be switched to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules at the same total daily dose taken once daily. Titrate at weekly intervals to appropriate efficacy and tolerability as indicated. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules may be taken whole, or the capsule may be opened and the entire contents sprinkled on applesauce. If the patient is using the sprinkle administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules may be taken orally with or without food. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules should be given upon awakening. Afternoon doses should be avoided because of the potential for insomnia. 2.3 Recommended Dosage in Pediatric Patients 6 to 12 Years In pediatric patients 6 to12 years of age with ADHD and are either starting treatment for the first time or switching from another medication, start with 10 mg once daily in the morning; daily dosage may be adjusted in increments of 5 mg or 10 mg at weekly intervals. When in the judgment of the clinician a lower initial dose is appropriate, patients may begin treatment with 5 mg once daily in the morning. The maximum recommended dose for children 6 to 12 years of age is 30 mg/day; doses greater than 30 mg/day have not been studied in children. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have not been studied i…

5 WARNINGS AND PRECAUTIONS • Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 ) • Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse at appropriate intervals. ( 5.3 ) • Psychiatric Adverse Reactions: Prior to initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. ( 5.4 ) • Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.5 ) • Seizures: May lower the convulsive threshold. Discontinue in the presence of seizures. ( 5.6 ) • Peripheral Vasculopathy, including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.7 ) • Serotonin Syndrome: Increased risk when coadministered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and initiate supportive treatment ( 4 , 5.8 , 10 ). • Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. ( 5.9 ) 5.1 Abuse, Misuse, and Addiction Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have a high potential for abuse and misuse. The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence ( 9.2 )] . Misuse and abuse of CNS stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroam…

4 CONTRAINDICATIONS Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsule administration is contraindicated in patients: • known to be hypersensitive 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 )]. • 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 ( 5.8 ), Drug Interactions ( 7.1 )]. • Known hypersensitivity or idiosyncrasy to amphetamine ( 4 ) • During or within 14 days following the administration of monoamine oxidase inhibitors (MAOI) ( 4 , 7.1 )

7 DRUG INTERACTIONS • Alkalinizing agents (GI antacids and urinary): These agents increase blood levels of amphetamine. ( 2.7 , 7.1 ) • Acidifying agents (GI and urinary): These agents reduce blood levels of amphetamine. ( 7.1 ) 7.1 Clinically Important Interactions with Amphetamines Table 4: Drugs Having Clinically Important Interactions with Amphetamines Monoamine Oxidase Inhibitors (MAOIs) 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. Intervention Do not administer dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules concomitantly or within 14 days after discontinuing MAOI [see Contraindications ( 4 )]. Serotonergic Drugs Clinical Impact The concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules 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 capsule initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and the concomitant serotonergic drug(s) [see Warnings and Precautions ( 5.8 )]. CYP2D6 Inhibitors Clinical Impact The concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and CYP2D6 inhibitors may increase the exposure of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsule initiation and after a dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and the CYP2D6 inhibitor [see Warnings and Precautions ( 5.8 ), Overdosage ( 10 )]. Alkalinizing Agents Clinical Impact Increase blood levels and potentiate the action of amphetamine. Intervention Co-administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and gastrointestinal or urinary alkalinizing agents should be avoided. Acidifying Agents 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. Proton Pump Inhibitors Clinical Impact Time to maximum concentration (T max ) of amphetamine is decreased compared to when administered alone. Intervention Monitor patients for changes in clinical effect and adjust therapy based on clinical response. 7.2 Drug-Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is g…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/othermedications/ . Risk Summary Available data from published epidemiologic studies and postmarketing reports on use of prescription amphetamine in pregnant women have not identified a drug-associated risk of major birth defects and miscarriage (see Data). Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers taking amphetamines during pregnancy (see Clinical Considerations) . No apparent effects on morphological development were observed in embryo-fetal development studies, with oral administration of amphetamine to rats and rabbits during organogenesis at doses 2 and 12 times, respectively, the maximum recommended human dose (MRHD) of 20 mg/day given to adolescents, on a mg/m 2 basis. However, in a pre- and postnatal development study, amphetamine ( d- to l- ratio of 3:1) administered orally to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Amphetamines, such as dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions, increasing the risk of premature delivery. Infants born to mothers taking amphetamines during pregnancy have an increased risk of premature delivery and low birth weight. Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness. Data Animal Data Amphetamine ( d- to l- enantiomer ratio of 3:1) had no apparent effects on embryofetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 2 and 12 times, respectively, the maximum recommended human dose (MRHD) of 20 mg/day given to adolescents, on a mg/m 2 basis. Fetal malformations and death have been reported in mice following parenteral administration of d- amphetamine doses of 50 mg/kg/day (approximately 10 times the MRHD given to adolescents on a mg/m 2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity. A study was conducted in which pregnant rats received daily oral doses of amphetamine ( d- to l- enantiomer ratio of 3:1) of 2, 6, and 10 mg/kg from gestation Day 6 to lactation Day 20. These doses are approximately 0.8, 2, and 4 times the MRHD of 20 mg/day given …

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 ANI Pharmaceuticals, Inc. at 1-855-204-1431 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, and amphetamine sulfate extended-release capsules 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, and amphetamine sulfate extended-release capsule-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 dis…