MYDAYIS (dextroamphetamine sulfate 9.375 mg dextroamphetamine saccharate 9.375 mg amphetamine aspartate monohydrate 9.375 mg amphetamine sulfate 9.375 mg) Dailymed

Recent Major Changes Section

Boxed Warning	10/2023
Dosage and Administration (2.1, 2.2)	10/2023
Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.6, 5.10)	10/2023

Warning: Abuse, Misuse, And Addiction

MYDAYIS has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including MYDAYIS, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing MYDAYIS, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout MYDAYIS treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)].


WARNING: ABUSE, MISUSE, AND ADDICTION

See full prescribing information for complete boxed warning.

MYDAYIS has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including MYDAYIS, can result in overdose and death (5.1, 9.2, 10):

• Before prescribing MYDAYIS, assess each patient’s risk for abuse, misuse, and addiction.
• Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug.
• Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

• 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. (2.2)
• Administer upon awakening because the effects may last up to 16 hours and there is the potential for insomnia. (2.2)
• Prior to treatment, assess for presence of cardiac disease. (2.1)
• 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. (2.7)

2.1 Pretreatment 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) [see Warnings and Precautions (5.2)]
• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating MYDAYIS [see Warnings and Precautions (5.10)]

2.2 General 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 [see Adverse Reactions (6.1), Clinical Studies (14)].

2.3Administration Instructions

Administer MYDAYIS orally with or without food. Advise patients to take MYDAYIS consistently either with food or without food [see Clinical Pharmacology (12.3)].

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.

2.4 Recommended 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.

2.5 Dosage 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 [see Drug Interactions (7.1)].

2.6 Dosage in Patients with Renal Impairment

In adult patients with severe renal impairment (GFR between 15 to <30 mL/min/1.73 m²), 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 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)].

2.7 Switching 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 [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)].

3 Dosage Forms And Strengths

• Extended-release capsules 12.5 mg: green body/green cap (imprinted with SHIRE 465 and 12.5 mg)
• Extended-release capsules 25 mg: ivory body/green cap (imprinted with SHIRE 465 and 25 mg)
• Extended-release capsules 37.5 mg: ivory body/light caramel cap (imprinted with SHIRE 465 and 37.5 mg)
• Extended-release capsules 50 mg: ivory body/purple cap (imprinted with SHIRE 465 and 50 mg)

Extended-release capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg (3)

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 [see Adverse Reactions (6.2)].
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor, because of an increased risk of hypertensive crisis [see Drug Interactions (7.1)].

• Known hypersensitivity to amphetamine products or other ingredients in MYDAYIS. (4)
• Use with monoamine oxidase (MAO) inhibitors, or within 14 days of the last MAO inhibitor dose. (4, 7.1)

5 Warnings And Precautions

• 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. (5.2)
• Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. (5.3)
• 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. (5.4)
• Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.5)
• 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. (5.6)
• Seizures: May lower the convulsive threshold. If a seizure occurs, discontinue MYDAYIS. (5.7)
• Serotonin Syndrome: Increased risk when coadministered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue MYDAYIS and initiate supportive treatment. (5.8)
• 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. (5.10)

5.1 Abuse, 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 [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including MYDAYIS, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing 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.

5.2 Risks 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.

5.3 Increased 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 [see Adverse Reactions (6.1)].

5.4 Psychiatric 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.

5.5 Long-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 [see Adverse Reactions (6.1)].

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 [see Use in Specific Populations (8.4)].

5.6 Peripheral Vasculopathy, Including Raynauds 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 [see Drug Interactions (7.1)]. 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 [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 MYDAYIS with MAOI drugs is contraindicated [see Contraindications (4)].

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 [see Dosage and Administration (2.7), Overdosage (10)].

5.10 Motor and Verbal Tics, and Worsening of Tourettes 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 [see Adverse Reactions (6.2)] .

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.

6 Adverse Reactions

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

• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
• Hypersensitivity to amphetamine products or other ingredients of MYDAYIS [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4), Drug Interactions (7.1)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, Including Raynaud's Phenomenon [see Warnings and Precautions (5.6)]
• Seizures [see Warnings and Precautions (5.7)]
• Serotonin Syndrome [see Warnings and Precautions (5.8)]
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.10)]

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. (6.1)
• Adults: insomnia, decreased appetite, decreased weight, dry mouth, increased heart rate, and anxiety. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-800-828-2088 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 [see Clinical Studies (14)].

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 uls 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	MYDAYISIncludes 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
	DysmenorrheaDysmenorrhea was observed in 11 females.	4%	2%
	Erectile DysfunctionErectile 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 uls 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%
	InsomniaInsomnia 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.