Mydayis Drug Information

is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 13 years and older . MYDAYIS is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 13 years and older. Limitations of Use : Pediatric patients 12 years and younger experienced higher plasma exposure than patients 13 years and older at the same dose and experienced higher rates of adverse reactions, mainly insomnia and decreased appetite. Limitations of Use : Pediatric patients 12 years and younger experienced higher plasma exposure than patients 13 years and older at the same dose, and experienced higher rates of adverse reactions, mainly insomnia and decreased appetite .

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. MYDAYIS was studied in adults (18 to 55 years) and pediatric patients (13 to 17 years) who met Diagnostic and Statistical Manual of Mental Disorders, 4 th or 5 th editions (DSM-IV-TR ® or DSM-5) criteria for ADHD. The safety data for adults were pooled from three randomized, double-blind, placebo-controlled studies in doses of 12.5 mg to 75 mg per day (1.5 times the maximum recommended dosage). Doses higher than 50 mg per day did not demonstrate additional clinical benefit and are not recommended. The safety data for pediatric patients (13 to 17 years) is from 1 randomized, double-blind, placebo-controlled study of doses of 12.5 mg to 25 mg.

The total exposure in patients treated with MYDAYIS 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 . Adverse Reactions Leading to Discontinuation of Treatment In pooled controlled trials of adult patients, 9% (54/626) of MYDAYIS-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 MYDAYIS-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 MYDAYIS-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 MYDAYIS-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 MYDAYIS-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 MYDAYIS. Table 1: Adverse Reactions Reported by 2% or More of Adults Taking MYDAYIS and at Least Twice the Incidence in Patients Taking Placebo in 3 Clinical Trials (4, 6, and 7 Weeks) Body System Adverse Reaction MYDAYIS 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 MYDAYIS-Treated Adolescents (13 to 17 years) in a 4-Week Clinical Trial The most common adverse reactions reported in adolescents were decreased appetite, nausea, insomnia, abdominal pain upper, irritability, and weight decreased.

Table 2 lists the adverse reactions that occurred ≥2% compared to placebo. Table 2: Adverse Reactions Reported by ≥2% or More of Adolescents Taking MYDAYIS and at Least Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial Body System Adverse Reaction MYDAYIS (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%

Adverse Reactions Associated with the Use of Amphetamines

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

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

There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, euphoria, dyskinesia, dysphoria, headache, tics, fatigue, aggression, anger, logorrhea, dermatillomania, and paresthesia (including formication), motor and verbal tics. Endocrine: Impotence, changes in libido, frequent or prolonged erections.

Eye Disorders: Mydriasis. Gastrointestinal: Unpleasant taste, constipation, intestinal ischemia. Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.

Skin: Alopecia. Vascular Disorders: Raynaud’s phenomenon.

Drugs Having Clinically Important Interactions with Amphetamines Table 3: Drugs Having Clinically

Important Interactions with Amphetamines Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. Intervention Do not administer MYDAYIS during or within 14 days following the administration of MAOI . 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 MYDAYIS initiation or dosage increase. If serotonin syndrome occurs, discontinue MYDAYIS and concomitant serotonergic drug(s) . Alkalinizing Agents Clinical Impact May increase exposure to amphetamine and exacerbate the action of amphetamine. Intervention Caution should be taken when coadministering MYDAYIS and gastrointestinal and urinary alkalinizing agents.

Acidifying Agents Clinical Impact Lower blood levels and efficacy of amphetamines. Intervention Increase dose of MYDAYIS based on clinical response. Tricyclic Antidepressants Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.

Intervention Monitor frequently and adjust MYDAYIS dose or use alternative therapy based on clinical response. CYP2D6 Inhibitors Clinical Impact May increase the exposure of amphetamine. Intervention Start with lower doses and monitor frequently and adjust MYDAYIS dose or use alternative therapy based on clinical response.

Gastric pH Modulators Clinical Impact Potential change in shape of PK profile and exposure may occur. Intervention Monitor patients for changes in clinical effect and use alternative therapy based on clinical response.

Interference with Laboratory Tests Amphetamines can cause a significant elevation in plasma

corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.

Allow for an adequate washout period between administration of MYDAYIS and radioactive diagnostic agents used for dopamine transporter (DAT) visualization. MYDAYIS can interfere with the test results of a radioactive diagnostic agent (ioflupane I-123) that is used for DAT visualization by binding and internalization of the DAT, which may result in lower DAT in the striatum. This may lead to false-positive diagnostic results.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MYDAYIS 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 . In an embryofetal development study, amphetamine (d- to l- enantiomer ratio of 3:1, the same as in MYDAYIS) had no effects on embryofetal morphological development or survival when administered to pregnant rats and rabbits throughout the period of organogenesis up to doses 10 times the maximum recommended human dose (MRHD) of 25 mg/day given to adolescents, on a mg/m 2 body surface area basis.

However, in a pre- and postnatal development study, amphetamine (d- to l- ratio of 3:1) administered orally to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine . 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 MYDAYIS, cause vasoconstriction and thereby may decrease placental perfusion.

In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Infants born to amphetamine-dependent mothers have an increased risk of premature delivery and low birth weight. Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.

Data Animal Data Amphetamine (d- to l- enantiomer ratio of 3:1, the same as in MYDAYIS) had no apparent effects on embryofetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 2 and 10 times, respectively, the maximum recommended human dose (MRHD) of 25 mg/day given to adolescents, on a mg/m 2 body surface area basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 8 times the MRHD given to adolescents on a mg/m 2 basis) or greater to pregnant animals.

Administration of these doses was also associated with severe maternal toxicity. A pre- and postnatal development study was conducted with amphetamine (d- to l- enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and 10 mg/kg from gestation Day 6 to lactation Day 20. These doses are approximately 0.6, 2, and 3 times the MRHD of 25 mg/day amphetamine (d- to l- ratio of 3:1) given to adolescents, on a mg/m 2 basis. All doses caused hyperactivity and decreased weight gain in the dams.

A decrease in pup survival was seen at all doses. A decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on Day 22 postpartum but not at 5 weeks postweaning.

When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg. A number of studies from the literature in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d, l-) at doses similar to those used clinically can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

Pediatric Use The safety and effectiveness of MYDAYIS in pediatric patients with ADHD ages 13 to 17 years have been established in two placebo-controlled clinical studies . The safety and effectiveness of MYDAYIS have not been established in pediatric patients ages 12 years and younger. MYDAYIS has 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% vs 8%) and appetite decreased (43% vs 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 to 79% higher C max 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 MYDAYIS, in pediatric patients 13 to 17 years who are not growing or gaining weight as expected may need to have their treatment interrupted . Juvenile Animal Toxicity Data Juvenile rats treated with mixed amphetamine salts (same as in MYDAYIS) early in the postnatal period through sexual maturation demonstrated transient changes in motor activity. Learning and memory was impaired at approximately 8 times the maximum recommended human dose (MRHD) given to children on a mg/m 2 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/m 2 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 MYDAYIS) 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/m 2 basis. Postdosing 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.

is contraindicated in patients with: Known hypersensitivity to amphetamine, or other components of MYDAYIS. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products . Concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis . Known hypersensitivity to amphetamine products or other ingredients in MYDAYIS. Use with monoamine oxidase (MAO) inhibitors, or within 14 days of the last MAO inhibitor dose.

Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.

CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.

Overdose Management Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of MYDAYIS should be considered when treating patients with overdose. D-amphetamine is not dialyzable.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.