These Highlights Do Not Include All The Information Needed To Use Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate And Amphetamine Sulfate Extended-release Capsules Safely And Effectively. See Full Prescribing Information For Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, And Amphetamine Sulfate Extended-release Capsules.

Exacerbation of Pre-Existing Psychosis

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

Dispense in a tightly-closed, light-resistant container as defined in the USP, with a child-resistant closure, as required.

Store at 20ºC to 25°C (68°F to 77ºF) [see USP Controlled Room Temperature].

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have 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, and 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, and amphetamine sulfate extended-release capsules, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in the absence of seizures, and very rarely, 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, and amphetamine sulfate extended-release capsules should be discontinued.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules contain mixed salts of a single-entity amphetamine, a CNS stimulant. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules contain equal amounts (by weight) of four salts: dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate. This results in a 3.1:1 mixture of dextro- to levo-amphetamine base equivalent.

The 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg strength extended-release capsules are for oral administration. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are a once daily extended-release, single-entity amphetamine product. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules combine the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate monohydrate. The dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are a dose proportional composition using a multi-layer fluid bed bead coating process, followed by encapsulation using hard gelatin capsules. The dosage utilizes a bead that is coated with an extended-release drug layer, that is then coated with an enteric polymer to control drug release, and finally coated with an immediate-release drug layer.

The safety and effectiveness of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have not been established in pediatric patients less than 6 years of age.

The safety and effectiveness of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have been established in pediatric patients with ADHD 6 years of age and older.

In studies evaluating extended-release amphetamine products, patients 4 to <6 years of age had higher systemic amphetamine exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have not been studied in the geriatric population.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules administration is contraindicated in patients:

• known to be hypersensitive to amphetamine, or other components of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see Adverse Reactions (6.2)].
• taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.8), Drug Interactions (7.1)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5)]
• Seizures [see Warnings and Precautions (5.6)]
• Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.7)]
• Serotonin Syndrome [see Warnings and Precautions (5.8)]
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.9)]

• Alkalinizing agents (GI antacids and urinary): These agents increase blood levels of amphetamine. (2.7, 7.1)
• Acidifying agents (GI and urinary): These agents reduce blood levels of amphetamine. (7.1)

Due to reduced clearance of amphetamines in patients with severe renal impairment (GFR 15 to <30 mL/min/1.73m²), the recommended dose should be reduced. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are not recommended in patients with ESRD (GFR <15 mL/min/1.73m²) [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

d-Amphetamine is not dialyzable.

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

Pharmacokinetic studies of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have been conducted in healthy adult and pediatric (children aged 6 to 12 yrs) subjects, adolescent (13 to 17 yrs), and children with ADHD. Both dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release) and dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release), the peak plasma concentrations occurred in about 3 hours for both d-amphetamine and l-amphetamine.

The time to reach maximum plasma concentration (T_max) for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules is about 7 hours, which is about 4 hours longer compared to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release). This is consistent with the extended-release nature of the product.

Figure 1: Mean d-amphetamine and l-amphetamine Plasma Concentrations Following Administration of Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Extended-Release Capsules 20 mg (8 am) and Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Tablets (immediate-release) 10 mg Twice Daily (8 am and 12 noon) in the Fed State.

A single dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended release 20 mg capsules provided comparable plasma concentration profiles of both d-amphetamine and l-amphetamine to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release) 10 mg twice daily administered 4 hours apart.

The mean elimination half-life for d-amphetamine is 10 hours in adults; 11 hours in adolescents aged 13 to 17 years and weighing less than or equal to 75 kg/165 lbs; and 9 hours in children aged 6 to 12 years. For the l-amphetamine, the mean elimination half-life in adults is 13 hours; 13 to 14 hours in adolescents; and 11 hours in children aged 6 to 12 years. On a mg/kg body weight basis, children have a higher clearance than adolescents or adults (see Special Populations below).

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules demonstrate linear pharmacokinetics over the dose range of 20 to 60 mg in adults and adolescents weighing greater than 75 kg/165 lbs, over the dose range of 10 to 40 mg in adolescents weighing less than or equal to 75 kg/165 lbs, and 5 to 30 mg in children aged 6 to 12 years. There is no unexpected accumulation at steady state in children.

Food does not affect the extent of absorption of d-amphetamine and l-amphetamine, but prolongs T_max by 2.5 hours (from 5.2 hrs. at fasted state to 7.7 hrs. after a high-fat meal) for d-amphetamine and 2.7 hours (from 5.6 hrs. at fasted state to 8.3 hrs. after a high-fat meal) for l-amphetamine after administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release, 30 mg capsule. Opening the capsule and sprinkling the contents on applesauce results in comparable absorption to the intact capsule taken in the fasted state. Equal doses of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules strengths are bioequivalent.

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 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)]. Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism [see Clinical Pharmacology (12.3)]. The potential for a pharmacokinetic interaction exists with the coadministration of CYP2D6 inhibitors which may increase the risk with increased exposure to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. In these situations, consider an alternative nonserotonergic 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, and amphetamine sulfate extended-release capsules with MAOI drugs is contraindicated [see Contraindications (4)].

Discontinue treatment with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. Concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules with other serotonergic drugs or CYP2D6 inhibitors should be used only if the potential benefit justifies the potential risk. If clinically warranted, consider initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules with lower doses, monitoring patients for the emergence of serotonin syndrome during drug initiation or titration, and informing patients of the increased risk for serotonin syndrome.

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

Limitations of Use

The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage. (5.5, 8.4)

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

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

Prior to treating patients with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess:

• for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules use [see Warnings and Precautions (5.9)].

• Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. (5.2)
• Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse at appropriate intervals. (5.3)
• Psychiatric Adverse Reactions: Prior to initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. (5.4)
• Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.5)
• Seizures: May lower the convulsive threshold. Discontinue in the presence of seizures. (5.6)
• Peripheral Vasculopathy, Including Raynaud's Phenomenon: Careful observation for digital changes is necessary during dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. (5.7)
• Serotonin Syndrome: Increased risk when coadministered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and initiate supportive treatment. (4, 5.8, 10)
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. (5.9)

• Pediatric patients (ages 6 to 17): 10 mg once daily in the morning. Maximum dose for children 6 to 12 years of age is 30 mg once daily. (2.2, 2.3, 2.4)
• Adults: 20 mg once daily in the morning. (2.5)
• Pediatric patients (ages 6 to 17) with severe renal impairment: 5 mg once daily in the morning. Maximum dose for children 6 to 12 years of age with severe renal impairment is 20 mg once daily. (2.6, 8.6)
• Adults with severe renal impairment: 15 mg once daily in the morning. (2.6, 8.6)
• Patients with end stage renal disease (ESRD): Not recommended. (2.6, 8.6)

• Pregnancy: May cause fetal harm. (8.1)
• Lactation: Breastfeeding not recommended. (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The premarketing development program for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules included exposures in a total of 1,315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects). Of these, 635 patients (ages 6 to 12) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N=40). Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse reactions.

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

In adults with ADHD who are either starting treatment for the first time or switching from another medication, the recommended dose is 20 mg/day.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have a high potential for abuse and misuse. The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules in a safe place, preferably locked, and instruct patients to not give dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules to anyone else. Throughout dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and 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.

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

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

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have 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, and amphetamine sulfate extended-release capsules, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and 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)].

Individualize the dosage according to the therapeutic needs and response of the patient. Administer dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules at the lowest effective dosage.

Based on bioequivalence data, patients taking divided doses of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release), (for example, twice daily), may be switched to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules at the same total daily dose taken once daily. Titrate at weekly intervals to appropriate efficacy and tolerability as indicated.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules may be taken whole, or the capsule may be opened and the entire contents sprinkled on applesauce. If the patient is using the sprinkle administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules may be taken orally with or without food.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules should be given upon awakening. Afternoon doses should be avoided because of the potential for insomnia.

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.

CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm).

Monitor all dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules-treated patients for hypertension and tachycardia.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients 6 years and older.

Limitations of Use

The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.5), Use in Specific Populations (8.4)].

In adult patients with severe renal impairment (GFR 15 to <30 mL/min/1.73m²), the recommended dose is 15 mg once daily in the morning. In pediatric patients (6 to 17 years of age) with severe renal impairment, the recommended dose is 5 mg once daily. The maximum dose for children 6 to 12 years of age with severe renal impairment is 20 mg once daily. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are not recommended in patients with end stage renal disease (ESRD) (GFR <15 mL/min/1.73m²) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Agents that alter urinary pH can impact excretion and alter blood levels of amphetamines. Acidifying agents (e.g., ascorbic acid) decrease blood levels; adjust dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules dosage based on clinical response [see Drug Interactions (7)].

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, and 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.

NDC 42858-055-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

5 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-610-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

10 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-215-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

15 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-720-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

20 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-325-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

25 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-930-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

30 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are not approved for use and are not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules-treated pediatric patients treated with CNS stimulants. In a controlled trial of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was -1.1 lbs. and -2.8 lbs., respectively, for patients receiving 10 mg and 20 mg dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment. Chronic use of amphetamines can be expected to cause a similar suppression of growth [see Adverse Reactions (6.1)].

Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

In pediatric patients 6 to 12 years of age with ADHD and are either starting treatment for the first time or switching from another medication, start with 10 mg once daily in the morning; daily dosage may be adjusted in increments of 5 mg or 10 mg at weekly intervals. When in the judgment of the clinician a lower initial dose is appropriate, patients may begin treatment with 5 mg once daily in the morning. The maximum recommended dose for children 6 to 12 years of age is 30 mg/day; doses greater than 30 mg/day have not been studied in children. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have not been studied in children under 6 years of age.

The recommended starting dose for pediatric patients 13 to 17 years of age with ADHD and are either starting treatment for the first time or switching from another medication is 10 mg/day. The dose may be increased to 20 mg/day after one week if ADHD symptoms are not adequately controlled.

CNS stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and 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, and amphetamine sulfate extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules-treated patients who develop signs or symptoms of peripheral vasculopathy.

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, and 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, and 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 have been identified during postapproval use of amphetamine; dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules; or dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Exacerbation of Pre-Existing Psychosis

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

Dispense in a tightly-closed, light-resistant container as defined in the USP, with a child-resistant closure, as required.

Store at 20ºC to 25°C (68°F to 77ºF) [see USP Controlled Room Temperature].

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have 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, and 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, and amphetamine sulfate extended-release capsules, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in the absence of seizures, and very rarely, 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, and amphetamine sulfate extended-release capsules should be discontinued.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules contain mixed salts of a single-entity amphetamine, a CNS stimulant. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules contain equal amounts (by weight) of four salts: dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate. This results in a 3.1:1 mixture of dextro- to levo-amphetamine base equivalent.

The 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg strength extended-release capsules are for oral administration. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are a once daily extended-release, single-entity amphetamine product. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules combine the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate monohydrate. The dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are a dose proportional composition using a multi-layer fluid bed bead coating process, followed by encapsulation using hard gelatin capsules. The dosage utilizes a bead that is coated with an extended-release drug layer, that is then coated with an enteric polymer to control drug release, and finally coated with an immediate-release drug layer.

The safety and effectiveness of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have not been established in pediatric patients less than 6 years of age.

The safety and effectiveness of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have been established in pediatric patients with ADHD 6 years of age and older.

In studies evaluating extended-release amphetamine products, patients 4 to <6 years of age had higher systemic amphetamine exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have not been studied in the geriatric population.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules administration is contraindicated in patients:

• known to be hypersensitive to amphetamine, or other components of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see Adverse Reactions (6.2)].
• taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.8), Drug Interactions (7.1)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5)]
• Seizures [see Warnings and Precautions (5.6)]
• Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.7)]
• Serotonin Syndrome [see Warnings and Precautions (5.8)]
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.9)]

• Alkalinizing agents (GI antacids and urinary): These agents increase blood levels of amphetamine. (2.7, 7.1)
• Acidifying agents (GI and urinary): These agents reduce blood levels of amphetamine. (7.1)

Due to reduced clearance of amphetamines in patients with severe renal impairment (GFR 15 to <30 mL/min/1.73m²), the recommended dose should be reduced. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are not recommended in patients with ESRD (GFR <15 mL/min/1.73m²) [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

d-Amphetamine is not dialyzable.

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

Pharmacokinetic studies of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have been conducted in healthy adult and pediatric (children aged 6 to 12 yrs) subjects, adolescent (13 to 17 yrs), and children with ADHD. Both dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release) and dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release), the peak plasma concentrations occurred in about 3 hours for both d-amphetamine and l-amphetamine.

The time to reach maximum plasma concentration (T_max) for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules is about 7 hours, which is about 4 hours longer compared to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release). This is consistent with the extended-release nature of the product.

Figure 1: Mean d-amphetamine and l-amphetamine Plasma Concentrations Following Administration of Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Extended-Release Capsules 20 mg (8 am) and Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate Tablets (immediate-release) 10 mg Twice Daily (8 am and 12 noon) in the Fed State.

A single dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended release 20 mg capsules provided comparable plasma concentration profiles of both d-amphetamine and l-amphetamine to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release) 10 mg twice daily administered 4 hours apart.

The mean elimination half-life for d-amphetamine is 10 hours in adults; 11 hours in adolescents aged 13 to 17 years and weighing less than or equal to 75 kg/165 lbs; and 9 hours in children aged 6 to 12 years. For the l-amphetamine, the mean elimination half-life in adults is 13 hours; 13 to 14 hours in adolescents; and 11 hours in children aged 6 to 12 years. On a mg/kg body weight basis, children have a higher clearance than adolescents or adults (see Special Populations below).

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules demonstrate linear pharmacokinetics over the dose range of 20 to 60 mg in adults and adolescents weighing greater than 75 kg/165 lbs, over the dose range of 10 to 40 mg in adolescents weighing less than or equal to 75 kg/165 lbs, and 5 to 30 mg in children aged 6 to 12 years. There is no unexpected accumulation at steady state in children.

Food does not affect the extent of absorption of d-amphetamine and l-amphetamine, but prolongs T_max by 2.5 hours (from 5.2 hrs. at fasted state to 7.7 hrs. after a high-fat meal) for d-amphetamine and 2.7 hours (from 5.6 hrs. at fasted state to 8.3 hrs. after a high-fat meal) for l-amphetamine after administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release, 30 mg capsule. Opening the capsule and sprinkling the contents on applesauce results in comparable absorption to the intact capsule taken in the fasted state. Equal doses of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules strengths are bioequivalent.

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 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)]. Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism [see Clinical Pharmacology (12.3)]. The potential for a pharmacokinetic interaction exists with the coadministration of CYP2D6 inhibitors which may increase the risk with increased exposure to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. In these situations, consider an alternative nonserotonergic 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, and amphetamine sulfate extended-release capsules with MAOI drugs is contraindicated [see Contraindications (4)].

Discontinue treatment with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. Concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules with other serotonergic drugs or CYP2D6 inhibitors should be used only if the potential benefit justifies the potential risk. If clinically warranted, consider initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules with lower doses, monitoring patients for the emergence of serotonin syndrome during drug initiation or titration, and informing patients of the increased risk for serotonin syndrome.

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

Limitations of Use

The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage. (5.5, 8.4)

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

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

Prior to treating patients with dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess:

• for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules use [see Warnings and Precautions (5.9)].

• Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. (5.2)
• Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse at appropriate intervals. (5.3)
• Psychiatric Adverse Reactions: Prior to initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. (5.4)
• Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.5)
• Seizures: May lower the convulsive threshold. Discontinue in the presence of seizures. (5.6)
• Peripheral Vasculopathy, Including Raynaud's Phenomenon: Careful observation for digital changes is necessary during dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. (5.7)
• Serotonin Syndrome: Increased risk when coadministered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules and initiate supportive treatment. (4, 5.8, 10)
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. (5.9)

• Pediatric patients (ages 6 to 17): 10 mg once daily in the morning. Maximum dose for children 6 to 12 years of age is 30 mg once daily. (2.2, 2.3, 2.4)
• Adults: 20 mg once daily in the morning. (2.5)
• Pediatric patients (ages 6 to 17) with severe renal impairment: 5 mg once daily in the morning. Maximum dose for children 6 to 12 years of age with severe renal impairment is 20 mg once daily. (2.6, 8.6)
• Adults with severe renal impairment: 15 mg once daily in the morning. (2.6, 8.6)
• Patients with end stage renal disease (ESRD): Not recommended. (2.6, 8.6)

• Pregnancy: May cause fetal harm. (8.1)
• Lactation: Breastfeeding not recommended. (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The premarketing development program for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules included exposures in a total of 1,315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects). Of these, 635 patients (ages 6 to 12) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N=40). Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse reactions.

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

In adults with ADHD who are either starting treatment for the first time or switching from another medication, the recommended dose is 20 mg/day.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have a high potential for abuse and misuse. The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules in a safe place, preferably locked, and instruct patients to not give dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules to anyone else. Throughout dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and 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.

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

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

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have 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, and amphetamine sulfate extended-release capsules, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and 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)].

Individualize the dosage according to the therapeutic needs and response of the patient. Administer dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules at the lowest effective dosage.

Based on bioequivalence data, patients taking divided doses of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release), (for example, twice daily), may be switched to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules at the same total daily dose taken once daily. Titrate at weekly intervals to appropriate efficacy and tolerability as indicated.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules may be taken whole, or the capsule may be opened and the entire contents sprinkled on applesauce. If the patient is using the sprinkle administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules may be taken orally with or without food.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules should be given upon awakening. Afternoon doses should be avoided because of the potential for insomnia.

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.

CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm).

Monitor all dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules-treated patients for hypertension and tachycardia.

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients 6 years and older.

Limitations of Use

The use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.5), Use in Specific Populations (8.4)].

In adult patients with severe renal impairment (GFR 15 to <30 mL/min/1.73m²), the recommended dose is 15 mg once daily in the morning. In pediatric patients (6 to 17 years of age) with severe renal impairment, the recommended dose is 5 mg once daily. The maximum dose for children 6 to 12 years of age with severe renal impairment is 20 mg once daily. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are not recommended in patients with end stage renal disease (ESRD) (GFR <15 mL/min/1.73m²) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Agents that alter urinary pH can impact excretion and alter blood levels of amphetamines. Acidifying agents (e.g., ascorbic acid) decrease blood levels; adjust dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules dosage based on clinical response [see Drug Interactions (7)].

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, and 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.

NDC 42858-055-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

5 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-610-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

10 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-215-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

15 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-720-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

20 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-325-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

25 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

NDC 42858-930-01

CII

Dextroamphetamine

Saccharate, Amphetamine

Aspartate Monohydrate,

Dextroamphetamine Sulfate,

and Amphetamine Sulfate

Extended-Release Capsules

(Mixed Salts of a Single-Entity

Amphetamine Product)

30 mg*

R_x only

PHARMACIST: Dispense the Accompanying

Medication Guide to Each Patient.

Marketed by:

Rhodes Pharmaceuticals, Wilson, NC 27893

100 Capsules

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules are not approved for use and are not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules-treated pediatric patients treated with CNS stimulants. In a controlled trial of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was -1.1 lbs. and -2.8 lbs., respectively, for patients receiving 10 mg and 20 mg dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment. Chronic use of amphetamines can be expected to cause a similar suppression of growth [see Adverse Reactions (6.1)].

Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

In pediatric patients 6 to 12 years of age with ADHD and are either starting treatment for the first time or switching from another medication, start with 10 mg once daily in the morning; daily dosage may be adjusted in increments of 5 mg or 10 mg at weekly intervals. When in the judgment of the clinician a lower initial dose is appropriate, patients may begin treatment with 5 mg once daily in the morning. The maximum recommended dose for children 6 to 12 years of age is 30 mg/day; doses greater than 30 mg/day have not been studied in children. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules have not been studied in children under 6 years of age.

The recommended starting dose for pediatric patients 13 to 17 years of age with ADHD and are either starting treatment for the first time or switching from another medication is 10 mg/day. The dose may be increased to 20 mg/day after one week if ADHD symptoms are not adequately controlled.

CNS stimulants, including dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and 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, and amphetamine sulfate extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules-treated patients who develop signs or symptoms of peripheral vasculopathy.

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, and 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, and 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 have been identified during postapproval use of amphetamine; dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules; or dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate tablets (immediate-release). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.