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

Boxed Warning 10/2023 Indications and Usage ( 1 ) 10/2023 Dosage and Administration ( 2.1 , 2.2 , 2.7 ) 10/2023 Contraindications ( 4 ) 10/2023 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.4 , 5.5 , 5.7 , 5.9 ) 10/2023

1 INDICATIONS AND USAGE DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE MONOHYDRATE, DEXTROAMPHETAMINE SULFATE, AMPHETAMINE SULFATE extended-release capsules (MAS-ER 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 ) 1.1 Attention Deficit Hyperactivity Disorder MAS-ER Capsules are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients 6 years and older.

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 ESRD: Not recommended. ( 2.6 , 8.6 ) 2.1 Pretreatment Screening Prior to treating patients with MAS-ER 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 MAS-ER 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 MAS-ER Capsules at the lowest effective dosage. Based on bioequivalence data, patients taking divided doses of immediate-release Adderall, (for example, twice daily), may be switched to MAS-ER Capsules at the same total daily dose taken once daily. Titrate at weekly intervals to appropriate efficacy and tolerability as indicated. MAS-ER 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. MAS-ER Capsules may be taken orally with or without food. MAS-ER 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 to 12 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. MAS-ER Capsules has not been studied in children under 6 years of age. 2.4 Recommended Dosage in Pediatric Patients 13 to 17 Years The recommended starting dose for pediatric patients 13 to 17 years of age with ADHD and are either starting treatment for the first time or switching from another medication is 10 mg/day. The dose may be increased to 20 mg/day after one week if ADHD symptoms are not adequately controlled. 2.5 Recommended Dosage in Adults In adults with ADHD who are either starting treatment for the first time or switching from another medication, the recommended dose is 20 mg/day. 2.6 Dosage in Patients with Renal Impairment In adult patients with severe renal impairment (GFR 15 to <30 mL/min/1.73 m 2 ), the recommended dose is 15 mg once daily in the morning. In pediatric patients (6 to 17 years of age) with severe renal impairment, the recommended dose is 5 mg once daily. The maximum dose for children 6 to 12 years of age with severe renal impairment is 20 mg once daily. MAS-ER Capsules are not recommended in patients with end stage renal disease (ESRD) (GFR <15 mL/min/1.73 m 2 ) [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . 2.7 Dosage Modi …

3 DOSAGE FORMS AND STRENGTHS 5 mg extended-release capsules: Clear/blue (imprinted M. Amphet Salts 5 mg) 10 mg extended-release capsules: Blue/blue (imprinted M. Amphet Salts 10 mg) 15 mg extended-release capsules: Blue/white (imprinted M. Amphet Salts 15 mg) 20 mg extended-release capsules: Orange/orange (imprinted M. Amphet Salts 20 mg) 25 mg extended-release capsules: Orange/white (imprinted M. Amphet Salts 25 mg) 30 mg extended-release capsules: Natural/orange (imprinted M. Amphet Salts 30 mg) Extended-release capsules: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg ( 3 )

4 CONTRAINDICATIONS MAS-ER Capsules administration is contraindicated in patients: known to be hypersensitive to amphetamine, or other components of MAS-ER 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 )

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 Takeda Pharmaceuticals at 1-800-828-2088 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 MAS-ER 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 MAS-ER 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 discontinuation of MAS-ER Capsules 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 MAS- …

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 MAS-ER Capsules concomitantly or within 14 days after discontinuing MAOI [see Contraindications (4) ] . Serotonergic Drugs Clinical Impact The concomitant use of MAS-ER 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 MAS-ER Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the concomitant serotonergic drug(s) [see Warnings and Precautions (5.8) ] . CYP2D6 Inhibitors Clinical Impact The concomitant use of MAS-ER Capsules and CYP2D6 inhibitors may increase the exposure of MAS-ER 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 MAS-ER Capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue MAS-ER 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 Coadministration of MAS-ER 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 greatest in the evening. Amphetamines may interfere with urinary steroid determinations.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MAS-ER 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 MAS-ER 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 to adolescents, on a mg/m 2 basis. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival …

12.1 Mechanism of Action Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known.

11 DESCRIPTION MAS-ER Capsules contain mixed salts of a single-entity amphetamine, a CNS stimulant. MAS-ER Capsules contain equal amounts (by weight) of four salts: dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate and amphetamine (D, L)-aspartate monohydrate. This results in a 3.1:1 mixture of dextro- to levo-amphetamine base equivalent. The 5 mg, 10 mg, 15 mg, 20 mg, 25 mg and 30 mg strength extended-release capsules are for oral administration. MAS-ER Capsules contain two types of drug-containing beads (immediate-release and delayed-release) which prolong the release of amphetamine compared to the Adderall (immediate-release) tablet formulation. Each capsule contains: Capsule Strength 5 mg 10 mg 15 mg 20 mg 25 mg 30 mg Dextroamphetamine Saccharate 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg Amphetamine (D,L)-Aspartate Monohydrate 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg Dextroamphetamine Sulfate 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg Amphetamine Sulfate 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg Total amphetamine base equivalence 3.1 mg 6.3 mg 9.4 mg 12.5 mg 15.6 mg 18.8 mg d -amphetamine base equivalence 2.4 mg 4.7 mg 7.1 mg 9.5 mg 11.9 mg 14.2 mg l -amphetamine base equivalence 0.75 mg 1.5 mg 2.3 mg 3.0 mg 3.8 mg 4.5 mg Inactive Ingredients and Colors The inactive ingredients in MAS-ER Capsules include: gelatin capsules, hydroxypropyl methylcellulose, methacrylic acid copolymer, opadry beige, sugar spheres, talc, and triethyl citrate. Gelatin capsules contain edible inks, kosher gelatin, and titanium dioxide. The 5, 10, and 15 mg capsules also contain FD&C Blue #2. The 20 mg, 25 mg, and 30 mg capsules also contain red iron oxide and yellow iron oxide.

10 OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of MAS-ER Capsules should be considered when treating patients with overdose. D-amphetamine is not dialyzable. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING 5 mg extended-release capsules: Clear/blue (imprinted M. Amphet Salts 5 mg), bottles of 100, NDC 0781-2329-01 10 mg extended-release capsules: Blue/blue (imprinted M. Amphet Salts 10 mg), bottles of 100, NDC 0781-2335-01 15 mg extended-release capsules: Blue/white (imprinted M. Amphet Salts 15 mg), bottles of 100, NDC 0781-2343-01 20 mg extended-release capsules: Orange/orange (imprinted M. Amphet Salts 20 mg), bottles of 100, NDC 0781-2352-01 25 mg extended-release capsules: Orange/white (imprinted M. Amphet Salts 25 mg), bottles of 100, NDC 0781-2368-01 30 mg extended-release capsules: Natural/orange (imprinted M. Amphet Salts 30 mg), bottles of 100, NDC 0781-2371-01 Dispense in a tight, light-resistant container as defined in the USP. Store at room temperature, 20 to 25°C (68 to 77°F). Excursions permitted to 15 to 30°C (59 to 86° F) [see USP Controlled Room Temperature].