Mydayis

1 INDICATIONS AND USAGE MYDAYIS 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 .

2 DOSAGE AND ADMINISTRATION MYDAYIS should be administered once daily upon awakening . Recommended Starting Dose Titration Schedule Maximum Daily Dose Adults 12.5 mg 12.5 mg weekly 50 mg Pediatrics (13 to 17) 12.5 mg 12.5 mg weekly 25 mg In adult patients with severe renal impairment the maximum dose should not exceed 25 mg daily. Use in adult patients with ESRD is not recommended. ( 2.6 , 8.6 ) The maximum dose in pediatric patients with severe renal impairment is 12.5 mg daily. Use in pediatric patients with ESRD is not recommended. ( 2.6 , 8.6 ) Patients are advised to take consistently either with or without food. Administer upon awakening because the effects may last up to 16 hours and there is the potential for insomnia. Prior to treatment, assess for presence of cardiac disease. To avoid substitution errors and overdosage, do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles.

2.1Pretreatment Screening Prior to

treating patients with MYDAYIS, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating MYDAYIS

2.2General Administration Information Because the

effects of MYDAYIS 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 .

2.3Administration Instructions Administer

MYDAYIS orally with or without food. Advise patients to take MYDAYIS consistently either with food or without food . MYDAYIS may be administered in one of the following ways: Swallow MYDAYIS capsules whole, or Open capsule and sprinkle the entire contents over a spoonful of applesauce. The sprinkled applesauce should be consumed immediately; it should not be stored.

Patients should take the sprinkled applesauce in its entirety without chewing. The dose of a single capsule should not be divided.

2.4Recommended Dosage Adults

(18 to 55 years) The recommended starting dose of MYDAYIS is 12.5 mg once daily in the morning upon awakening. Initial doses of 25 mg once daily may be considered for some patients. Dosage may be adjusted in increments of 12.5 mg no sooner than weekly, up to a maximum dose of 50 mg once daily, based on the therapeutic needs and response of the patient.

Doses above 50 mg daily have shown no additional clinically meaningful benefit. Pediatric Patients (13 to 17 years) The recommended starting dose is 12.5 mg once daily in the morning upon awakening. Dosage may be adjusted in increments of 12.5 mg no sooner than weekly, up to a recommended maximum dose of 25 mg once daily.

The dose should be individualized according to the needs and response of the patient. Doses higher than 25 mg have not been evaluated in clinical trials in pediatric patients.

2.5Dosage Modifications Due to Drug Interactions

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 MYDAYIS dosage accordingly .

2.6Dosage in Patients with Renal Impairment In

adult patients with severe renal impairment (GFR between 15 to <30 mL/min/1.73 m 2 ), the recommended starting dose of MYDAYIS is 12.5 mg daily with a maximum recommended dose of 25 mg daily. MYDAYIS is not recommended for use in patients with end stage renal disease (ESRD <15 mL/min/1.73 m 2 ). In pediatric patients (13 to 17 years) with severe renal impairment, the maximum dose is 12.5 mg, if tolerated .

2.7Switching From Other Amphetamine Products For

patients switching from another medication or any other amphetamine products, discontinue that treatment, and titrate with MYDAYIS using the titration schedule . Do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles .

Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. Psychiatric Adverse Reactions: Prior to initiating MYDAYIS, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing MYDAYIS. 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. Peripheral Vasculopathy, Including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during MYDAYIS treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. Seizures: May lower the convulsive threshold. If a seizure occurs, discontinue MYDAYIS. Serotonin Syndrome: Increased risk when coadministered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue MYDAYIS and initiate supportive treatment. Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating MYDAYIS, 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.

5.1Abuse, Misuse, and Addiction

MYDAYIS has a high potential for abuse and misuse. The use of MYDAYIS exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. MYDAYIS can be diverted for non-medical use into illicit channels or distribution . Misuse and abuse of CNS stimulants, including MYDAYIS, can result in overdose and death , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing MYDAYIS, 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 MYDAYIS in a safe place, preferably locked, and instruct patients to not give MYDAYIS to anyone else.

Throughout MYDAYIS treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2Risks to Patients with Serious Cardiac Disease

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 MYDAYIS use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3Increased Blood Pressure and Heart Rate

CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mmHg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases. Monitor all MYDAYIS-treated patients for potential tachycardia and hypertension .

5.4Psychiatric Adverse Reactions Exacerbation of Pre-Existing

Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating MYDAYIS treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, and depression).

New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing MYDAYIS.

5.5Long-Term Suppression of Growth in Pediatric Patients

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. In a 4-week, placebo-controlled trial of MYDAYIS in patients ages 6 to 17 years old with ADHD, there was a decrease in weight in the MYDAYIS groups compared to weight gain in the placebo group . Closely monitor growth (weight and height) in MYDAYIS-treated pediatric patients. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

MYDAYIS is not approved for use in pediatric patients 12 years and younger .

5.6Peripheral Vasculopathy, Including Raynaud’s Phenomenon

CNS stimulants, including MYDAYIS, 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 MYDAYIS treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for MYDAYIS-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.7Seizures

MYDAYIS 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, MYDAYIS should be discontinued.

5.8Serotonin Syndrome 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 . The coadministration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to MYDAYIS. In these situations, consider an alternative nonserotonergic drug or an alternative drug that does not inhibit CYP2D6 . 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 MYDAYIS with MAOI drugs is contraindicated . Discontinue treatment with MYDAYIS and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

If concomitant use of MYDAYIS with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate MYDAYIS 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.

5.9Potential for Overdose Due to Medication Errors

Medication errors, including substitution and dispensing errors, between MYDAYIS 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 .

5.10Motor and Verbal Tics, and Worsening of Tourette’s

Syndrome 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 . Before initiating MYDAYIS, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor MYDAYIS-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

4 CONTRAINDICATIONS MYDAYIS 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. ( 4 , 7.1 )

8.1Pregnancy 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.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Abuse, Misuse, and Addiction Hypersensitivity to amphetamine products or other ingredients of MYDAYIS Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors Risks to Patients with Serious Cardiac Disease Increased Blood Pressure and Heart Rate Psychiatric Adverse Reactions Long-Term Suppression of Growth in Pediatric Patients Peripheral Vasculopathy, Including Raynaud's Phenomenon Seizures Serotonin Syndrome Motor and Verbal Tics, and Worsening of Tourette's Syndrome Most common adverse reactions in patients with ADHD (incidence ≥5% and at a rate at least twice placebo) are: Pediatrics (13 years and older): insomnia, decreased appetite, decreased weight, irritability, and nausea. Adults: insomnia, decreased appetite, decreased weight, dry mouth, increased heart rate, and anxiety. To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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%

6.2Adverse 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.