Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Capsule, Extended Release
FDA Label NDC 57664-951

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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, amphetamine sulfate extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)].

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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)].

Prior to treating patients with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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, amphetamine sulfate extended-release capsules [see Warnings and Precautions (5.10)]

Because the effects of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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)].

Administer dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules orally with or without food. Advise patients to take dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules consistently either with food or without food [see Clinical Pharmacology (12.3)].

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules may be administered in one of the following ways:

• Swallow dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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.

Adult (18 to 55 years)

The recommended starting dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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.

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, amphetamine sulfate extended-release capsules dosage accordingly [see Drug Interactions (7.1)].

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, 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, amphetamine sulfate extended-release capsules is 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)].

For patients switching from another medication or any other amphetamine products, discontinue that treatment, and titrate with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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)].

• Extended-release capsules 12.5 mg: green cap and green body imprinted with “950” on cap and “12.5 mg” on body in black ink containing light orange to orange colored pellets
• Extended-release capsules 25 mg: green opaque cap and ivory body imprinted with “951” on cap and “25 mg” on body in black ink containing light orange to orange colored pellets
• Extended-release capsules 37.5 mg: light caramel cap and ivory body imprinted with “952” on cap and “37.5 mg” on body in black ink containing light orange to orange colored pellets
• Extended-release capsules 50 mg: purple cap and ivory body imprinted with “953” on cap and “50 mg” on body in black ink containing light orange to orange colored pellets

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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, 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)].

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules has a high potential for abuse and misuse. The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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, 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, 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, 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, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules in a safe place, preferably locked, and instruct patients to not give dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules to anyone else. Throughout dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.

Avoid dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease

CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mmHg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases.

Monitor all dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules-treated patients for potential tachycardia and hypertension [see Adverse Reactions (6.1)].

Exacerbation of Pre-Existing Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder

CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, and depression).

New Psychotic or Manic Symptoms

CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

In a 4 week, placebo-controlled trial of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules in patients ages 6 to 17 years old with ADHD, there was a decrease in weight in the dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules groups compared to weight gain in the placebo group [see Adverse Reactions (6.1)].

Closely monitor growth (weight and height) in dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules-treated pediatric patients. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules are not approved for use in pediatric patients 12 years and younger [see Use in Specific Populations (8.4)].

CNS stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant.

Careful observation for digital changes is necessary during dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules-treated patients who develop signs or symptoms of peripheral vasculopathy.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules may lower the convulsive threshold in patients with prior history of seizure, in patients with prior EEG abnormalities in the absence of seizures, and in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules should be discontinued.

Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort [ see Drug Interactions (7.1)]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [ see Drug Interactions (7.1)].

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules with MAOI drugs is contraindicated [see Contraindications (4)].

Discontinue treatment with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome.

Medication errors, including substitution and dispensing errors, between dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules and other amphetamine products could occur, leading to possible overdosage. 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 [see Dosage and Administration (2.7)and Overdosage (10)] .

CNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

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),and Drug Abuse and Dependence ( 9.2, 9.3)]
• Hypersensitivity to amphetamine products or other ingredients of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and 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)]

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, 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, 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, amphetamine sulfate 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate 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.e. leading to discontinuation in at least 1% of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules-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, Amphetamine Sulfate Extended-Release Capsules-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, amphetamine sulfate extended-release capsules.

• Table 1 Adverse Reactions Reported by 2% or More of Adults Taking Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, 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, 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 1	4%	2%
	Erectile Dysfunction 2	2%	1%

• *Includes doses up to 75 mg (1.5 times the maximum recommended dosage).
• ¹Dysmenorrhea was observed in 11 females
• ²Erectile 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, Amphetamine Sulfate Extended-Release Capsules-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, 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, 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.

The following adverse reactions have been associated with the use of amphetamines. The following adverse reactions have been identified during post approval 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.

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.

Eye Disorders:Mydriasis.

Gastrointestinal: Unpleasant taste, constipation, intestinal ischemia.

Allergic: Urticaria, rash, hypersensitivity reactions, including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported.

Endocrine: Impotence, changes in libido, frequent or prolonged erections.

Skin: Alopecia.

Vascular Disorders: Raynaud’s phenomenon.

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.

Table 3 Drugs Having Clinically Important Interactions with Amphetamines

Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate 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 2-4% and 15- 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Amphetamines, such as dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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 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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate 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 have been reported in mice following parenteral administration of d- amphetamine doses of 50 mg/kg/day (approximately 8 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 pre- and postnatal development study was conducted with amphetamine ( d-to l-enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. These doses are approximately 0.6, 2, and 3 times the MRHD of 25 mg/day amphetamine ( d-to l-ratio of 3:1) 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 was seen at all doses. A decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg.

A number of studies from the literature in rodents indicate that prenatal or early postnatal exposure to amphetamine ( d-or d, l-) at doses similar to those used clinically can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

Risk Summary

Based on limited case reports in published literature, amphetamine ( d-or d, l-) is present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of dextroamphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, including serious cardiovascular reactions, blood pressure and heart rate increase, suppression of growth, and peripheral vasculopathy, advise patients that breastfeeding is not recommended during treatment with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules.

Safety and effectiveness of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules in pediatric patients with ADHD ages 13 to 17 years have been established in two placebo-controlled clinical studies [see Adverse Reactions (6.1),Clinical Pharmacology (12.3),Clinical Studies (14)].

Safety and effectiveness of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules have not been established in pediatric patients ages 12 years and younger.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules have been studied for the treatment of ADHD in pediatric patients 6 to 12 years in two placebo controlled safety and efficacy trials. In the first trial, pediatric patients 6 to 12 years experienced higher rates of adverse reactions in some cases compared to patients 13 years and older, including higher rates of insomnia (30% versus 8%) and appetite decreased (43% versus 22%). In addition, amphetamine systemic exposures (both d- and l-) in pediatric patients 6 to 12 years following a single dose were higher than those observed in adults at the same dose (72-79% higher Cmax and approximately 83% higher AUC). A second trial evaluated a lower dose than those approved for pediatric patients 13 to 17 years; efficacy was not demonstrated for the lower dose. Therefore, a safe and effective dose cannot be established in pediatric patients 12 years and younger.

Growth Suppression

Growth should be monitored during treatment with stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules, in pediatric patients 13 to 17 years who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.5),Adverse Reactions (6.1)].

Juvenile Animal Toxicity Data

Juvenile rats treated with mixed amphetamine salts (same as in dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules) early in the postnatal period through sexual maturation demonstrated transient changes in motor activity. Learning and memory was impaired at approximately 8 times the maximum recommended human dose (MRHD) given to children on a mg/m ²basis. No recovery was seen following a drug free period. A delay in sexual maturation was observed at a dose approximately 8 times the MRHD given to children on a mg/m ²basis, although there was no effect on fertility.

In a juvenile developmental study, rats received daily oral doses of amphetamine ( dto lenantiomer ratio of 3:1, the same as in dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules) of 2, 6, or 20 mg/kg on days 7-13 of age; from day 14 to approximately day 60 of age these doses were given b.i.d. for total daily doses of 4, 12, or 40 mg/kg. The latter doses are approximately 0.8, 2, and 8 times the MRHD of 25 mg/day given to children on a mg/m ²basis. Post-dosing hyperactivity was seen at all doses; motor activity measured prior to the daily dose was decreased during the dosing period but the decreased motor activity was largely absent after an 18 day drug-free recovery period. Performance in the Morris water maze test for learning and memory was impaired at the 40 mg/kg dose, and sporadically at the lower doses, when measured prior to the daily dose during the treatment period; no recovery was seen after a 19 day drug-free period. A delay in the developmental milestones of vaginal opening and preputial separation was seen at 40 mg/kg but there was no effect on fertility.

Clinical studies of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Due to reduced clearance of amphetamine in patients with severe renal insufficiency (GFR 15 to < 30 mL/min/1.73 m ²), the maximum dose in adults should be reduced. Pediatric patients ages 13 to 17 years with severe renal insufficiency can be given the recommended starting dose if tolerated, but the dose should not be escalated. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules are not recommended in patients with ESRD (GFR < 15 mL/min/1.73 m ²) [see Dosage and Administration (2.6),Clinical Pharmacology (12.3)].

d-amphetamine is not dialyzable.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules contain mixed amphetamine salts, a Schedule II controlled substance.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of amphetamine may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, 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.

Physical Dependence

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

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 dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release 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.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules contain mixed salts of a single-entity amphetamine, a CNS stimulant. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules contains 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 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.

Inactive Ingredients and Colors: The inactive ingredients in dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules include: ammonio methacrylate copolymer (Type B), dibutyl sebacate, ethylcellulose, FD&C Yellow #6, FD&C Blue #2, gelatin, hypromellose, methacrylic acid copolymer (Type-C), polyethylene glycol, sugar spheres, talc, titanium dioxide, triethyl citrate, yellow iron oxide and edible inks. The 37.5 mg strength capsule also contains red iron oxide. The 50 mg strength capsule also contains D&C Red #28, D&C Red #33, and FD&C Blue #1.

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

Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Pharmacokinetic studies of d-and l-amphetamine after oral administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules have been conducted in healthy adults (19 to 52 years) and pediatric patients (6 to 17 years) with ADHD. Following administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules, the peak plasma concentrations occurred in about 7 to 10 hours in pediatric patients and about 8 hours in adults for both d-amphetamine and l-amphetamine. The mean plasma elimination half-life for d- amphetamine ranges from about 10 to 11 hours and l-amphetamine from 10 to 13 hours in both pediatric and adult patients.

Absorption

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules exhibit linear dose proportionality over the range of 12.5 to 50 mg. Steady-state is achieved between Days 7 and 8 of dosing with mean accumulation ratio of 1.6. A single dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules 37.5 mg capsules provided comparable plasma concentration profiles of both d-and l-amphetamine to mixed amphetamine salts extended release (MAS-ER) 25 mg followed by 12.5 mg immediate release amphetamine administered 8 hours later (Figure 1).

• Figure 1 Mean Plasma Concentrations of d- and l-amphetamine Following Oral Administration of Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release Capsules 37.5 mg vs MAS-ER 25 mg Followed by Immediate-Release MAS-IR 12.5 mg 8 Hours Later in Adults


Figure 1 (Mixedamphetamine 01)

Effect of Food

High fat meal does not affect the extent of absorption of d-and l-amphetamine when taken with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules. Tmax is prolonged by 5 hours (from 7.0 hours at fasted state to 12.0 hours after a high-fat meal) for d-amphetamine and 4.5 hours (from 7.5 hours at fasted state to 12 hours after a high-fat meal) for l-amphetamine after administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules 50 mg with high fat meal. Opening the capsule and sprinkling the contents on applesauce results in comparable absorption and exposure to the intact capsule taken in the fasted state [see Dosage and Administration (2.3)]

Effect of Alcohol

The in vitrotesting showed increases in amphetamine release rate from dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules in the presence of 20% and, more noticeably, 40% alcohol. There is no in vivostudy conducted for the effect of alcohol on drug exposure.

Elimination

Metabolism

Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy- amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy- amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not yet been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-aphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

Amphetamine is known to inhibit monoamine oxidase. Amphetamines are not an in vitroinhibitor of the major human CYP450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), nor was it an in vitroinducer of CYP1A2, CYP2B6 or CYP3A4/5. Amphetamines are not an in vitrosubstrate for P-gp.

Excretion

The renal excretion is the primary route for elimination of d- and l-amphetamine and its metabolites after administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules.

At normal urine pHs, approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30% to 40% of the dose is recoverable in urine as amphetamine itself. Urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination. Urinary recovery of amphetamine has been reported to range from 1% to 75%, and the fraction of a dose hepatically metabolized is dependent on urine pH. Consequently, both hepatic and renal dysfunctions have the potential to alter the elimination of amphetamine and could result in prolonged exposures [see Drug Interactions (7.1)].

Specific Populations

Age

Comparison of the pharmacokinetics of d- and l-amphetamine after oral administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules in pediatric patients with ADHD 13 to 17 years old and healthy adult subjects (19 to 52 years) indicates that body weight is the primary determinant of apparent differences in the pharmacokinetics of d-and l-amphetamine across the age range.

PK data from patients age 13 to 17 years (n=14) who received a single 25 mg dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules was scaled (based on PK proportionality) and compared with PK data from adult patients 19 to 51 years (n =20) who received 37.5 mg. Based on dose proportionality, a single dose dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsule administered to pediatric patients age 13 to 17 years (n=14) would produce about 21 to 31% higher Cmax for d-and l-amphetamine and 21-31% higher AUC for d-and l-amphetamine, compared to the same dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsule administered to adults (age 19 to 51 years).

Male and Female Patients

In pharmacokinetic studies, systemic exposure to d-and l-amphetamine was similar in women (N=41) and in men (N=61).

Racial Groups

Formal pharmacokinetic studies for race have not been conducted. However, amphetamine pharmacokinetics appeared to be comparable among Whites (N=41), Blacks (N=27), and Hispanics (N=34).

Patients with Renal impairment

The effect of renal impairment on d- and l-amphetamine after administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules has not been studied.

In a pharmacokinetic study of lisdexamfetamine in adult subjects with normal and impaired renal function mean d-amphetamine clearance was reduced from 0.7 L/hr/kg in normal subjects to 0.4 L/hr/kg in subjects with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m ²) patients. Dialysis did not significantly affect the clearance of d-amphetamine. The impact of renal impairment on the disposition of amphetamine would be expected to be similar between oral administration of lisdexamfetamine and dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules [see Use in Specific Populations (8.6)].

Carcinogenesis

No evidence of carcinogenicity was found in studies in which d, l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 3, 2, and 1 times, respectively, the maximum recommended human dose of 50 mg/day on a mg/m ²body surface area basis in adults.

Mutagenesis

Amphetamine, in the enantiomer ratio present, d-to l-ratio of 3:1, was not clastogenic in the mouse bone marrow micronucleus test in vivoand was negative when tested in the E. coli component of the Ames test in vitro. d, l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitrosister chromatid exchange and chromosomal aberration assays.

Impairment of Fertility

Amphetamines, in the enantiomer ratio, d-to l-ratio of 3:1, did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day (approximately 6 times the maximum recommended human dose of 25 mg/day given to adolescents on a mg/m ²body surface area basis).

Acute administration of high doses of amphetamine ( d-or d, l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

Efficacy of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules in the treatment of ADHD was established in the following trials:

• Three short-term trials in adults (18 to 55 years, Studies 1, 2, and 3)
• Two short-term trials in pediatric patients (13 to 17 years, Studies 4 and 5)

Adult patients (18 to 55 years) with ADHD

The approved adult doses, 12.5 mg, 25 mg, and 37.5 mg are based on Studies 1 and 3 and the 50 mg dose efficacy is based on Study 2. Doses up to 75 mg per day (1.5 times the maximum recommended adult dosage) were evaluated, but demonstrated no additional clinical benefit.

A 4-week, randomized, double-blind, multi-center, placebo-controlled, forced-dose titration, safety and efficacy study (Study 1) was conducted in adults aged 18 to 55 years (N=275) who met DSM-5 criteria for ADHD. Patients were randomized in a 1:1:1 ratio, to two dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules treatment groups and a placebo group. Group 1 received a dose of 12.5 mg/day throughout the study. Group 2 were titrated on a weekly basis from the initial dose 12.5 mg until target dose of 37.5 mg/day was reached by Week 3 and were maintained at 37.5 mg throughout the study. Group 3 received placebo.

The primary efficacy endpoint was defined as the change from baseline of the adult ADHD-Rating Scale (RS) with prompts total score at Week 4. Baseline adult ADHD-RS with prompts total score was defined as the last valid adult ADHD-RS with prompts total score assessment prior to taking the first dose of double-blind investigational product, usually at Visit 2. The primary comparison of interest was at Week 4 for each dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules dose compared with placebo. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules demonstrated a statistically significant treatment effect compared with placebo on change of ADHD-RS total score from baseline at visit 6 (Week 4), for both 12.5 mg and 37.5 mg doses respectively (Study 1 in Table 4). Patients on dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules also showed statistically significantly greater improvement on the Clinical Global Impression of Improvement (CGI-I) score compared with placebo treatment.

Two multi-center, randomized, double-blind, placebo-controlled, crossover studies of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules 25 mg/day (Study 3) and 50 mg/day (Study 2) were conducted in adult patients who met DSM-IV TR criteria for ADHD. The efficacy was determined using the Permanent Product Measure of Performance (PERMP), a skill-adjusted math test that measures attention in ADHD. PERMP total score results from the sum of the number of math problems attempted plus the number of math problems answered correctly. Efficacy assessments were conducted at 2, 4, 8, 12, 14, and 16 hours post-dose using the PERMP. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules treatment, compared to placebo, reached statistical significance at either 2 hours (Study 2) or 4 hours (Study 3) post-dose to 16 hours post-dose in both studies. In a pre-specified supplementary analysis for Study 2, the maximum approved dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules (50 mg) demonstrated a statistically significant treatment effect compared with placebo beginning at 2 to 16 hours post-dose (Study 2 and Study 3 in Table 4).

Pediatric patients (13 to 17 years) with ADHD

A 4-week, randomized, double-blind, multi-center, placebo-controlled, dose-optimization, safety and efficacy study (Study 4) was conducted. In Study 4, the 157 pediatric patients 13 to 17 years old who met DSM-IV TR criteria for ADHD, were randomized in a 1:1 ratio to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules or placebo group. Subjects were titrated from a dose of 12.5 mg/day until an optimal dose was reached (up to a maximum dose of 25 mg); this dose was maintained during the dose-maintenance period (Study 4 in Table 4).

The primary efficacy endpoint was defined as the change from baseline of the ADHD-RS-IV Total Score at Week 4. The baseline ADHD-RS-IV Total Score was defined as the last valid ADHD-RS-IV Total Score assessment prior to taking the first dose of double-blind investigational product, usually at Visit 2. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules demonstrated a statistically significant treatment effect compared with placebo on the change of ADHD RS-IV total scores from baseline at Visit 6 (Week 4). Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules also showed statistically significantly greater improvement on the Clinical Global Impression of Improvement (CGI-I) score at Visit 6 (Week 4).

A multi-center, randomized, double-blind, placebo-controlled, crossover study of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules 25 mg/day (Study 5) was conducted in adolescent patients who met DSM-IV TR criteria for ADHD. The efficacy was determined using the Permanent Product Measure of Performance (PERMP), a skill-adjusted math test that measures attention in ADHD. PERMP total score results from the sum of the number of math problems attempted plus the number of math problems answered correctly. Efficacy assessments were conducted at 2, 4, 8, 12, 14, and 16 hours post-dose using the PERMP. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules treatment, compared to placebo, reached statistical significance at 2 to 16 hours post-dose (Study 5 in Table 4, Figure 2).

• Figure 2 LS Mean (SE) PERMP Total score by Treatment and Time-point for Adolescents Ages 13 to 17 with ADHD after 1 Week of Double Blind Treatment (Study 5)


Figure 2 (Mixedamphetamine 02)

In both adults and pediatric patients, examination of a population subset based on gender or race did not reveal any differences.

Table 4:Summary of Primary Efficacy Results from Short-term Studies of Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release Capsules in Adult and Pediatric Patients with ADHD

Study Number (Age range)	Primary Endpoint	Treatment Group	Mean Baseline Score (SD)	LS Mean Change from Baseline	Placebo-subtracted Difference a(95% CI)
Adult Studies
Study 1 (18-55 years)	ADHD-RS	Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules (12.5 mg/day)*	39.8 (6.38)	-18.5	-8.1 (-11.7, -4.4)
		Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules (37.5 mg/day)*	39.9 (7.07)	-23.8	-13.4 (-17.1, -9.7)
		Placebo	40.5 (6.52)	-10.4
Study 2 (18-55 years)	Average PERMP	Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules (50mg/day)*	239.2 (75.6) b	293.23 c	18.38 (11.28, 25.47)
		Placebo	249.6 (76.7)b	274.85 c
Study 3 (18-55 years)	Average PERMP	Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules (25 mg/day)*	217.5 (59.6) b	267.96 c	19.29 (10.95, 27.63)
		Placebo	226.9 (61.7) b	248.67 c
Pediatric Studies
Study 4 (13-17 years)d	ADHD-RS-IV	Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules (12.5-25 mg/day)*	36.7 (6.15)	-20.3	-8.7 (-12.6, -4.8)
		Placebo	38.3 (6.67)	-11.6
Study 5 (13-17 years)	Average PERMP	Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules (25 mg/day)*	214.5 (87.8) b	272.67 c	41.26 (32.24, 50.29)
		Placebo	228.7 (101) b	231.41 c

• SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval.
• a Difference (drug minus placebo) in least-squares mean change from baseline.
• b Pre-dose PERMP total score.
• c LS Mean for PERMP is post-dose average score over all sessions of the treatment day, rather than change from baseline.
• d Results represent subgroup of study 4 and not the total population.
• * Doses statistically significantly superior to placebo.

How Supplied

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules are available as:

• 12.5 mg: green cap and green body imprinted with “950” on cap and “12.5 mg” on body in black ink containing light orange to orange colored pellets, bottles of 100 CRC, NDC 57664-950-88
• 25 mg: green opaque cap and ivory body imprinted with “951” on cap and “25 mg” on body in black ink containing light orange to orange colored pellets, bottles of 100 CRC, NDC 57664-951-88
• 37.5 mg: light caramel cap and ivory body imprinted with “952” on cap and “37.5 mg” on body in black ink containing light orange to orange colored pellets, bottles of 100 CRC, NDC 57664-952-88
• 50 mg: purple cap and ivory body imprinted with “953” on cap and “50 mg” on body in black ink containing light orange to orange colored pellets, bottles of 100 CRC, NDC 57664-953-88

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].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Abuse, Misuse, and Addiction

Educate patients and their families about the risks of abuse, misuse, and addiction of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), Overdosage (10)] . Advise patients to store dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules in a safe place, preferably locked, and instruct patients to not give dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules to anyone else.

Risks to Patients with Serious Cardiac Disease

Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)]. Increased Blood Pressure and Heart Rate Instruct patients that dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules can cause elevations of their blood pressure and pulse rate and they should be monitored for such effects [see Warnings and Precautions (5.3)].

Psychiatric Adverse Reactions

Advise patients that dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules, at recommended doses, may cause psychotic or manic symptoms even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].

Long-Term Suppression of Growth in Pediatric Patients

Advise patients, family members, and caregivers that dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules may cause slowing of growth including weight loss [see Warnings and Precautions (5.5)].

Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including Raynaud’s Phenomenon]

Instruct patients beginning treatment with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].

Seizures

Caution patient that dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules may lower the convulsive threshold. Advise patients to contact their healthcare provider immediately and to discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules if a seizure occurs [see Warnings and Precautions (5.7)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see Contraindications (4), Warnings and Precautions (5.8), Drug Interactions (7.1)]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

Advise patients that motor and verbal tics and worsening of Tourette’s syndrome may occur during treatment with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.10)] .

Concomitant Medications

Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs because there is a potential for interactions [see Drug Interactions (7.1)] .

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules during pregnancy [see Use in Specific Populations (8.1)] .

Pregnancy

Advise patients of the potential fetal effects from the use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules during pregnancy. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules [see Use in Specific Populations (8.1)] .

Lactation

Advise women not to breastfeed if they are taking dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules [see Use in Specific Populations (8.2)] .

Alcohol

Advise patients to avoid alcohol while taking dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules. Consumption of alcohol while taking dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release capsules may result in a more rapid release of the dose of mixed amphetamine salts [see Clinical Pharmacology (12.3)] .

Manufactured by:

Ohm Laboratories Inc.

New Brunswick, NJ 08901

Distributed by:

Sun Pharmaceutical Industries, Inc.,

Cranbury, NJ 08512

Rev. 01/2024

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Iss. 01/2024