Mixed Salts of a Single-Entity Amphetamine Product

Boxed Warning 10/2023 Dosage and Administration ( 2.1 , 2.2 ) 10/2023 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.4 , 5.6 , 5.10 ) 10/2023

1 INDICATIONS AND USAGE Mixed Salts of a Single-Entity Amphetamine Product 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 )] . Mixed Salts of a Single-Entity Amphetamine Product 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 )

2 DOSAGE AND ADMINISTRATION Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules [see Warnings and Precautions ( 5.10 )] 2.2 General Administration Instructions Because the effects of Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules orally with or without food. Advise patients to take Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules consistently either with food or without food [see Clinical Pharmacology ( 12.3 )] . Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules may be administered in one of the following ways: Swallow Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 alte …

3 DOSAGE FORMS AND STRENGTHS Extended-release capsules 12.5 mg: opaque yellow body/opaque yellow cap (imprinted with "12.5 mg" and "M" in a box) Extended-release capsules 25 mg: opaque white body/opaque white cap (imprinted with "25 mg" and "M" in a box) Extended-release capsules 37.5 mg: opaque pink body/opaque blue cap (imprinted with "37.5 mg" and "M" in a box) Extended-release capsules 50 mg: opaque blue body/opaque blue cap (imprinted with "50 mg" and "M" in a box) Extended-release capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg ( 3 )

4 CONTRAINDICATIONS Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are contraindicated in patients with: Known hypersensitivity to amphetamine, or other components of Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules. ( 4 ) Use with monoamine oxidase (MAO) inhibitors, or within 14 days of the last MAO inhibitor dose. ( 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 )] Hypersensitivity to amphetamine products or other ingredients of Mixed Salts of a Single-Entity Amphetamine Product 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 Mallinckrodt at 1-800-778-7898 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. Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules-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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules-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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules-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 …

7 DRUG INTERACTIONS 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue Mixed Salts of a Single-Entity Amphetamine Product 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 co-administering Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules and gastrointestinal and urinary alkalinizing agents. Acidifying Agents Clinical Impact Lower blood levels and efficacy of amphetamines. Intervention Increase dose of Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended. ( 8.2 ) Pediatric: Safety and effectiveness have not been established in pediatric patients ages 12 years and younger. ( 8.4 ) Renal Impairment: Dose adjustment is needed in patients with severe renal insufficiency. Use of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules in patients with ESRD is not recommended. ( 2.6 , 8.6 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/. Risk Summary The limited available data from published literature and postmarketing reports on use of amphetamine in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines [see Clinical Considerations] . In an embryofetal development study, amphetamine ( d- to l- enantiomer ratio of 3:1, the same as in Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules) had no effects on embryofetal morphological development or survival when administered to pregnant rats and rabbits throughout the period of organogenesis up to doses 10 times the maximum recommended human dose (MRHD) of 25 mg/day given to adolescents, on a mg/m 2 body surface area basis. However, in a pre- and post-natal 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 Mixed Salts of a Single-Entity Amphetamine Product 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 amphetamine-dependent mothers 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, the same as in Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules) 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 10 times, respectively, the maximum recommended human dose (MRHD) of 25 mg/day given to adolescents, on a mg/m 2 body surface area basis. Fetal malformations and death hav …

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

11 DESCRIPTION Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules contain mixed salts of a single-entity amphetamine, a CNS stimulant. Mixed Salts of a Single-Entity Amphetamine Product 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 levoamphetamine base equivalent. The 12.5 mg, 25 mg, 37.5 mg and 50 mg strength capsules are for oral administration. They contain three types of drug-releasing beads, an immediate release and two different types of delayed release (DR) beads. The first DR bead releases amphetamine at pH 5.5 and the other DR bead releases amphetamine at pH 7.0. 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 and Colors: The inactive ingredients in Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules include: hard gelatin capsules, ethylcellulose, medium-chain triglycerides, oleic acid, hydroxypropyl cellulose, magnesium stearate, Methacrylic Acid and Ethyl Acrylate Copolymer, sodium lauryl sulfate, polysorbate, sucrose, corn starch, talc, triethyl citrate, and (poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1; 280000 mw)). The gelatin capsules for all four strengths contain gelatin, Sodium lauryl sulfate, titanium dioxide, and edible inks which contain shellac glaze, propylene glycol, potassium hydroxide, and black iron oxide. The 12.5 mg strength gelatin capsules also contain yellow iron oxide. The 37.5 mg strength contains FD&C Blue No. 1 and FD&C Red No. 3. The 50 mg strength capsule also contains FD&C Blue No. 1.

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 Mixed Salts of a Single-Entity Amphetamine Product 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 How Supplied Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are available as: Extended-release capsules 12.5 mg: opaque yellow body/opaque yellow cap (imprinted with "12.5 mg" and "M" in a box) Bottles of 100............................................................................................. NDC 0406-0805-01 Extended-release capsules 25 mg: opaque white body/opaque white cap (imprinted with "25 mg" and "M" in a box) Bottles of 100............................................................................................. NDC 0406-0803-01 Extended-release capsules 37.5 mg: opaque pink body/opaque blue cap (imprinted with "37.5 mg" and "M" in a box) Bottles of 100............................................................................................. NDC 0406-0807-01 Extended-release capsules 50 mg: opaque blue body/opaque blue cap (imprinted with "50 mg" and "M" in a box) Bottles of 100............................................................................................. NDC 0406-0804-01 Storage and Handling Dispense in a tight, light-resistant container as defined in the USP. Store at room temperature, 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] .