The following Structured Product Label (SPL) was submitted to the FDA by Specgx Llc for the product Mixed Salts Of A Single-entity Amphetamine Product (NDC 0406-0803). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding warning: abuse and dependence, 1 indications and usage, 2.1 important information prior to initiating treatment, 2.2 general instructions for use, 2.3 administration instructions, 2.4 dosing information, 2.5 dosage modifications due to drug interactions, 2.6 dosage in patients with renal impairment, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
CNS stimulants, including Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules, other amphetamine-containing products, and methylphenidate, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions (5.1, 9.3), Drug Abuse and Dependence (9.2, 9.3)].
Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 13 years and older [see Clinical Studies (14)].
Prior to initiating treatment with Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules, assess for the presence of cardiac disease (e.g., a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
Assess the risk of abuse, prior to prescribing and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules use [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].
Because the effects of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules may last up to 16 hours and there is potential for insomnia, administer once daily in the morning upon awakening. In the event of a missed dose, do not administer later in the day. Do not administer additional medication to make up for the missed dose [see Adverse Reactions (6.1), Clinical Studies (14)].
Pharmacological treatment of ADHD may be needed for an extended period. Periodically re-evaluate the long-term use of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules and adjust dosage as needed.
Administer Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules orally with or without food. Advise patients to take Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules consistently either with food or without food [see Clinical Pharmacology (12.3)].
Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules may be administered in one of the following ways:
Adult Use (18 to 55 years)
The recommended starting dose of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules is 12.5 mg once daily in the morning upon awakening. Initial doses of 25 mg once daily may be considered for some patients. Dosage may be adjusted in increments of 12.5 mg no sooner than weekly, up to a maximum dose of 50 mg once daily, based on the therapeutic needs and response of the patient. Doses above 50 mg daily have shown no additional clinically meaningful benefit.
Pediatric Use (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 Mixed Salts of a Single-Entity Amphetamine Product 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 m2), the recommended starting dose of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules is 12.5 mg daily with a maximum recommended dose of 25 mg daily. Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are not recommended for use in patients with end stage renal disease (ESRD < 15 ml/min/1.73 m2). 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 Mixed Salts of a Single-Entity Amphetamine Product 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)].
Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are contraindicated in patients with:
CNS stimulants, including Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules, other amphetamine-containing products, and methylphenidate, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning, Drug Abuse and Dependence (9.2, 9.3)].
Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems while taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules treatment.
CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Monitor all 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 mixed/manic episode in patients with bipolar disorder. Prior to initiating 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 recommended doses, may cause psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated patients compared to 0% in placebo-treated patients.
CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules. In a 4-week, placebo-controlled trial of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules in patients ages 6 to 17 years old with ADHD, there was a decrease in weight in the Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules groups compared to weight gain in the placebo group [see Adverse Reactions (6.1)].
Patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are not approved for use in pediatric patients 12 years and younger [Use in Specific Populations (8.4)].
Stimulants, including Mixed Salts of a Single-Entity Amphetamine Product 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, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
Mixed Salts of a Single-Entity Amphetamine Product 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, Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules with MAOI drugs is contraindicated [see Contraindications (4)].
Discontinue treatment with Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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), Overdosage (10)].
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules were studied in adults (18 to 55 years) and pediatric patients (13 to 17 years) who met Diagnostic and Statistical Manual of Mental Disorders, 4th or 5th editions (DSM-IV-TR® or DSM-5) criteria for ADHD. The safety data for adults were pooled from three randomized, double-blind, placebo-controlled studies in doses of 12.5 mg to 75 mg per day (1.5 times the maximum recommended dosage). Doses higher than 50 mg per day did not demonstrate additional clinical benefit and are not recommended.
The safety data for pediatric patients (13 to 17 years) is from 1 randomized, double-blind, placebo-controlled study of doses of 12.5 mg to 25 mg. The total exposure in patients treated with Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules totalled 704; this included pediatric patients, 78 adolescent patients and 626 adult patients from multiple well-controlled trials. The duration of use ranged from 4 to 7 weeks [see Clinical Studies (14)].
Adverse Reactions Leading to Discontinuation of Treatment
In pooled controlled trials of adult patients, 9% (54/626) of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules-treated patients discontinued due to adverse reactions compared to 2% (7/328) of placebo-treated patients. The most frequent adverse reactions leading to discontinuation (i.e., leading to discontinuation in at least 1% of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules-treated patients and at a rate at least twice that of placebo) were insomnia (2%, n=15), blood pressure increased (2%, n=10), decreased appetite (1%, n=5), and headache (1%, n=4).
In a controlled trial including adolescent patients (13 to 17 years), 5% (4/78) of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules-treated patients discontinued due to adverse reactions compared to 0% (0/79) of placebo-treated patients. The most frequent adverse reaction leading to discontinuation (i.e., leading to discontinuation in at least 1% of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules-treated patients and at a rate at least twice that of placebo) were 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules.
| Body System | Adverse Reaction | Mixed Salts of aSingle-Entity Amphetamine Product Extended-Release Capsules Includes doses up to 75 mg (1.5 times the maximum recommended dosage). (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 Dysmenorrhea was observed in 11 females | 4% | 2% | |
| Erectile Dysfunction Erectile dysfunction was observed in 6 males | 2% | 1% |
Adverse Reactions Occurring at an Incidence of 2% or More and at Least Twice Placebo Among Mixed Salts of a Single-Entity Amphetamine Product 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.
| Body System | Adverse Reaction | Mixed Salts of aSingle-Entity Amphetamine Product 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 Insomnia includes terms: initial insomnia, middle insomnia, terminal insomnia and insomnia. | 8% | 3% | |
| Gastrointestinal Disorders | |||
| Nausea | 8% | 4% | |
| Abdominal Pain, Upper | 4% | 1% | |
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).
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.
| MAO Inhibitors (MAOI) | |
| Clinical Impact | MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. |
| Intervention | Do not administer Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules during or within 14 days following the administration of MAOI [see Contraindications (4)]. |
| Examples | selegiline, isocarboxazid, phenelzine, tranylcypromine |
| Serotonergic Drugs | |
| Clinical Impact | The concomitant use of amphetamines and serotonergic drugs increases the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules and concomitant serotonergic drug(s) [see Warnings and Precautions 5.7]. |
| Examples | Selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort |
| Alkalinizing Agents | |
| Clinical Impact | May increase exposure to amphetamine and exacerbate the action of amphetamine. |
| Intervention | Caution should be taken when co-administering Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules and gastrointestinal and urinary alkalinizing agents. |
| Examples | Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate; proton pump inhibitors [e.g., omeprazole]) Urinary alkalinizing agents (e.g., acetazolamide, some thiazides) |
| Acidifying Agents | |
| Clinical Impact | Lower blood levels and efficacy of amphetamines. |
| Intervention | Increase dose of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules based on clinical response. |
| Examples | Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) |
| Tricyclic Antidepressants | |
| Clinical Impact | May enhance the activity of tricyclic or sympathomimetic agents causing sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. |
| Intervention | Monitor frequently and adjust Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules dose or use alternative therapy based on clinical response. |
| Examples | desipramine, protriptyline |
| CYP2D6 Inhibitors | |
| Clinical Impact | May increase the exposure of amphetamine |
| Intervention | Start with lower doses and monitor frequently and adjust Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules dose or use alternative therapy based on clinical response. |
| Examples | paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir |
| Gastric pH Modulators | |
| Clinical Impact | Potential change in shape of PK profile and exposure may occur |
| Intervention | Monitor patients for changes in clinical effect and use alternative therapy based on clinical response. |
| Examples | omeprazole, esomeprazole, pantoprazole, cimetidine |
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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/.
Risk Summary
The limited available data from published literature and postmarketing reports on use of amphetamine in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines [see Clinical Considerations].
In an embryofetal development study, amphetamine (d- to l- enantiomer ratio of 3:1, the same as in Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules) had no effects on embryofetal morphological development or survival when administered to pregnant rats and rabbits throughout the period of organogenesis up to doses 10 times the maximum recommended human dose (MRHD) of 25 mg/day given to adolescents, on a mg/m2 body surface area basis. However, in a pre- and post-natal development study, amphetamine (d- to l- ratio of 3:1) administered orally to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Amphetamines, such as Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Infants born to amphetamine-dependent mothers have an increased risk of premature delivery and low birth weight.
Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.
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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules.
Safety and effectiveness of Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules have not been established in pediatric patients ages 12 years and younger.
Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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/m2 basis. 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/m2 basis, although there was no effect on fertility.
In a juvenile developmental study, rats received daily oral doses of amphetamine (d to l enantiomer ratio of 3:1, the same as in Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules) of 2, 6, or 20 mg/kg on days 7 to 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/m2 basis. 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 Mixed Salts of a Single-Entity Amphetamine Product 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 m2), 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. Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are not recommended in patients with ESRD (GFR < 15 mL/min/1.73 m2) [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].
D-amphetamine is not dialyzable.
Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules contain mixed amphetamine salts, which are in Schedule II.
Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are a CNS stimulant that contains mixed amphetamine salts which have a high potential for abuse. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving.
Signs and symptoms of amphetamine abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been seen. Abusers of amphetamine may use unapproved routes of administration which can result in overdose and death [see Overdosage (10)].
To reduce the abuse of CNS stimulants, including Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants. Monitor for signs of abuse while on therapy, and re-evaluate the need for Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules use.
Tolerance
Tolerance (a state of adaptation in which exposure to a specific dose of a drug results in a reduction of the drug's desired and/or undesired effects over time, in such a way that a higher dose of the drug is required to produce the same effect that was once obtained at a lower dose) may occur during the chronic therapy of CNS stimulants including Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules.
Dependence
Physical dependence (a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules. Withdrawal symptoms after abrupt cessation of CNS stimulants include extreme fatigue and depression.
Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice for treatment of overdosage. Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.
Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Other reactions include arrhythmias, hypertension or hypotension, circulatory collapse, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.
The prolonged release of mixed amphetamine salts from Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules should be considered when treating patients with overdose.
D-amphetamine is not dialyzable.
Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules contain mixed salts of a single-entity amphetamine, a CNS stimulant. Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules contain equal amounts (by weight) of four salts: dextroamphetamine sulfate and amphetamine sulfate, dextroamphetamine saccharate and amphetamine aspartate monohydrate. This results in a 3:1 mixture of dextro- to levoamphetamine base equivalent.
The 12.5 mg, 25 mg, 37.5 mg and 50 mg strength capsules are for oral administration. They contain three types of drug-releasing beads, an immediate release and two different types of delayed release (DR) beads. The first DR bead releases amphetamine at pH 5.5 and the other DR bead releases amphetamine at pH 7.0.
| CAPSULE STRENGTHS | ||||
|---|---|---|---|---|
| EACH CAPSULE CONTAINS: | 12.5 mg | 25 mg | 37.5 mg | 50 mg |
| Dextroamphetamine Saccharate | 3.125 mg | 6.250 mg | 9.375 mg | 12.500 mg |
| Amphetamine Aspartate Monohydrate | 3.125 mg | 6.250 mg | 9.375 mg | 12.500 mg |
| Dextroamphetamine Sulfate | 3.125 mg | 6.250 mg | 9.375 mg | 12.500 mg |
| Amphetamine Sulfate | 3.125 mg | 6.250 mg | 9.375 mg | 12.500 mg |
| Total mixed amphetamine salts | 12.500 mg | 25 mg | 37.5 mg | 50 mg |
| Total amphetamine base equivalence | 7.8 mg | 15.6 mg | 23.5 mg | 31.3 mg |
Inactive Ingredients and Colors: The inactive ingredients in Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules include: hard gelatin capsules, ethylcellulose, medium-chain triglycerides, oleic acid, hydroxypropyl cellulose, magnesium stearate, Methacrylic Acid and Ethyl Acrylate Copolymer, sodium lauryl sulfate, polysorbate, sucrose, corn starch, talc, triethyl citrate, and (poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1; 280000 mw)). The gelatin capsules for all four strengths contain gelatin, Sodium lauryl sulfate, titanium dioxide, and edible inks which contain shellac glaze, propylene glycol, potassium hydroxide, and black iron oxide. The 12.5 mg strength gelatin capsules also contain yellow iron oxide. The 37.5 mg strength contains FD&C Blue No. 1 and FD&C Red No. 3. The 50 mg strength capsule also contains FD&C Blue No. 1.
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.
Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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
Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release 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 Mixed Salts of a Single-Entity Amphetamine Product 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 (Mixed Salts Of A Single Entity Amphetamine Product 1) 
Effect of Food
High-fat meal does not affect the extent of absorption of d- and l-amphetamine when taken with Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 vitro testing showed increases in amphetamine release rate from Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules in the presence of 20% and, more noticeably, 40% alcohol. There is no in vivo study 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-amphetamine. 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 vitro inhibitor of the major human CYP450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), nor was it an in vitro inducer of CYP1A2, CYP2B6 or CYP3A4/5. Amphetamines are not an in vitro substrate for P-gp.
Excretion
The renal excretion is the primary route for elimination of d- and l-amphetamine and its metabolites after administration of Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsule 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 of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules 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 to 31% higher AUC for d- and l-amphetamine, compared to the same dose of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules 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 white (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 Mixed Salts of a Single-Entity Amphetamine Product 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 m2) 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 Mixed Salts of a Single-Entity Amphetamine Product 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/m2 body 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 vivo and 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 vitro sister 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/m2 body 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules in the treatment of ADHD was established in the following trials:
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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules dose compared with placebo. Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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. Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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. Mixed Salts of a Single-Entity Amphetamine Product 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). Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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. Mixed Salts of a Single-Entity Amphetamine Product 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 (Mixed Salts Of A Single Entity Amphetamine Product 2) 
LS Mean: least-squares mean; SE: standard error
In both adults and pediatric patients, examination of a population subset based on gender or race did not reveal any differences.
| Study Number (Age range) | Primary Endpoint | Treatment Group | Mean Baseline Score (SD) | LS Mean Change from Baseline | Placebo-Subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI) |
|---|---|---|---|---|---|
| SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval. | |||||
| Adult Studies | |||||
| Study 1 (18 to 55 years) | ADHD-RS | Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules (12.5 mg/day) Doses statistically significantly superior to placebo. | 39.8 (6.38) | -18.5 | -8.1 (-11.7, -4.4) |
| Mixed Salts of a Single-Entity Amphetamine Product 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 to 55 years) | Average PERMP | Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules (50mg/day) | 239.2 (75.6) Pre-dose PERMP total score. | 293.23 LS Mean for PERMP is post-dose average score over all sessions of the treatment day, rather than change from baseline. | 18.38 (11.28, 25.47) |
| Placebo | 249.6 (76.7) | 274.85 | |||
| Study 3 (18 to 55 years) | Average PERMP | Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules (25 mg/day) | 217.5 (59.6) | 267.96 | 19.29 (10.95, 27.63) |
| Placebo | 226.9 (61.7) | 248.67 | |||
| Pediatric Studies | |||||
| Study 4 (13 to 17 years) Results represent subgroup of Study 4 and not the total population. | ADHD-RS-IV | Mixed Salts of a Single-Entity Amphetamine Product 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 to 17 years) | Average PERMP | Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules (25 mg/day) | 214.5 (87.8) | 272.67 | 41.26 (32.24, 50.29) |
| Placebo | 228.7 (101) | 231.41 | |||
How Supplied
Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are available as:
Extended-release capsules 25 mg: opaque white body/opaque white cap (imprinted with "25 mg" and "M" in a box)
Bottles of 100............................................................................................. NDC 0406-0803-01
Extended-release capsules 37.5 mg: opaque pink body/opaque blue cap (imprinted with "37.5 mg" and "M" in a box)
Bottles of 100............................................................................................. NDC 0406-0807-01
Extended-release capsules 50 mg: opaque blue body/opaque blue cap (imprinted with "50 mg" and "M" in a box)
Bottles of 100............................................................................................. NDC 0406-0804-01
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Controlled Substance Status/High Potential for Abuse and Dependence
Advise patients and their caregivers that Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules are a federally controlled substance because it can be abused or lead to dependence. Advise patients to store Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].
Serious Cardiovascular Risks
Advise patients, caregivers, and family members that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with Mixed Salts of a Single-Entity Amphetamine Product 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)].
Blood Pressure and Heart Rate Increases
Instruct patients that Mixed Salts of a Single-Entity Amphetamine Product 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 Risks
Advise patients that Mixed Salts of a Single-Entity Amphetamine Product 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
Advise patients, family members, and caregivers that Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules may lower the convulsive threshold. Advise patients to contact their healthcare provider immediately and to discontinue Mixed Salts of a Single-Entity Amphetamine Product 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 Mixed Salts of a Single-Entity Amphetamine Product 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.
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 Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules during pregnancy [see Use in Specific Populations (8.1)].
Pregnancy
Advise patients of the potential fetal effects from the use of Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules during pregnancy. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules [see Use in Specific Populations (8.1)].
Lactation
Advise women not to breastfeed if they are taking Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules [see Use in Specific Populations (8.2)].
Alcohol
Advise patients to avoid alcohol while taking Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules. Consumption of alcohol while taking Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules may result in a more rapid release of the dose of mixed amphetamine salts [see Clinical Pharmacology (12.3)].
Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company.
© 2023 Mallinckrodt.
Manufactured for:
SpecGx LLC
Webster Groves, MO 63119 USA
Issued 09/2023
Mallinckrodt™
Pharmaceuticals
An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/MG20D13.pdf or by calling 1-800-778-7898 for alternate delivery options.
NDC 0406-0805-01
100 CAPSULES
Dextroamphetamine Saccharate,
Amphetamine Aspartate Monohydrate,
Dextroamphetamine Sulfate, Amphetamine Sulfate
(Mixed Salts of a Single-Entity Amphetamine Product)
Extended-Release Capsules
CII
ONCE-DAILY
12.5 mg
Rx only
Do not substitute for Adderall XR®.
PHARACIST: Dispense the Medication Guide
provided separately to each patient.
Mallinckrodt™
L00D87
Rev 05/2018
Principal Display Panel (12.5 mg Capsule Bottle Label)
NDC 0406-0803-01
100 CAPSULES
Dextroamphetamine Saccharate,
Amphetamine Aspartate Monohydrate,
Dextroamphetamine Sulfate, Amphetamine Sulfate
(Mixed Salts of a Single-Entity Amphetamine Product)
Extended-Release Capsules
CII
ONCE-DAILY
25 mg
Rx only
Do not substitute for Adderall XR®.
PHARACIST: Dispense the Medication Guide
provided separately to each patient.
Mallinckrodt™
L00D88
Rev 09/2023
Principal Display Panel (25 mg Capsule Bottle Label)
NDC 0406-0807-01
100 CAPSULES
Dextroamphetamine Saccharate,
Amphetamine Aspartate Monohydrate,
Dextroamphetamine Sulfate, Amphetamine Sulfate
(Mixed Salts of a Single-Entity Amphetamine Product)
Extended-Release Capsules
CII
ONCE-DAILY
37.5 mg
Rx only
Do not substitute for Adderall XR®.
PHARACIST: Dispense the Medication Guide
provided separately to each patient.
Mallinckrodt™
L00D89
Rev 05/2018
Principal Display Panel (37.5 mg Capsule Bottle Label)
NDC 0406-0804-01
100 CAPSULES
Dextroamphetamine Saccharate,
Amphetamine Aspartate Monohydrate,
Dextroamphetamine Sulfate, Amphetamine Sulfate
(Mixed Salts of a Single-Entity Amphetamine Product)
Extended-Release Capsules
CII
ONCE-DAILY
50 mg
Rx only
Do not substitute for Adderall XR®.
PHARACIST: Dispense the Medication Guide
provided separately to each patient.
Mallinckrodt™
L00D90
Rev 09/2023
Principal Display Panel (25 mg Capsule Bottle Label)
* Please review the disclaimer below.
