` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`022063Orig1s000
`
`
`LABELING
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to
`use MYDAYIS safely and effectively. See full prescribing
`information for MYDAYIS.
`
`MYDAYIS (mixed salts of a single-entity amphetamine
`product) extended-release capsules, for oral use, CII
`Initial U.S. Approval: 2001
`
`
`WARNING: ABUSE AND DEPENDENCE
`See full prescribing information for complete boxed warning.
`
`
` CNS stimulants, including MYDAYIS, other amphetamine -
`containing products, and methylphenidate, have a high
`potential for abuse and dependence (5.1, 9.3)
` Assess the risk of abuse prior to prescribing and
`monitor for signs of abuse and dependence while on
`therapy (9.2, 9.3)
`
`--------------------------INDICATIONS AND USAGE---------------------------
`
`MYDAYIS is a central nervous system (CNS) stimulant indicated
`for the treatment of Attention Deficit Hyperactivity Disorder
`(ADHD) in patients 13 years and older. (1)
`
`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. (8.4)
`
`---------------------DOSAGE AND ADMINISTRATION----------------------
`
`----------------------WARNINGS AND PRECAUTIONS-----------------------
`
` Serious Cardiovascular Reactions Sudden death has been reported
`in association with CNS stimulant treatment at recommended doses
`in pediatric patients with structural cardiac abnormalities or other
`serious heart problems. In adults, sudden death, stroke, and
`myocardial infarction have been reported. Avoid use in patients
`with known structural cardiac abnormalities, cardiomyopathy,
`serious heart arrhythmia, or coronary artery disease. (5.2)
` Blood Pressure and Heart Rate Increases Monitor blood
`pressure and pulse. Consider benefits and risks before use in
`patients for whom blood pressure increases may be problematic.
`(5.3)
` Psychiatric Adverse Reactions May cause psychotic or manic
`symptoms in patients with no prior history, or exacerbation of
`symptoms in patients with pre-existing psychosis. Evaluate for
`bipolar disorder prior to stimulant use. (5.4)
` Long-Term Suppression of Growth Monitor height and weight in
`pediatric patients during treatment. (5.5)
` Peripheral Vasculopathy, including Raynaud’s phenomenon
`Stimulants used to treat ADHD are associated with peripheral
`vasculopathy, including Raynaud’s phenomenon. Careful
`observation for digital changes is necessary during treatment with
`ADHD stimulants. (5.6)
` Seizures May lower the convulsive threshold. If a seizure occurs,
`discontinue MYDAYIS. (5.7)
` Serotonin Syndrome Increased risk when co-administered with
`serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during
`overdosage situations. If it occurs, discontinue MYDAYIS and
`initiate supportive treatment. (5.8)
`
` MYDAYIS should be taken once daily upon awakening.
`
` --------------------------ADVERSE REACTIONS-------------------------
`
`
`
`Maximum
`Titration
`Recommended
`Daily Dose
`Schedule
`Starting Dose
`50 mg
`12.5 mg weekly
`12.5 mg
`Adults
`25 mg
`12.5 mg weekly
`12.5 mg
`Pediatrics (13 to 17)
` 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)
`
`--------------------DOSAGE FORMS AND STRENGTHS---------------------
`
` Extended-release capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg (3)
`
`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
`Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088
`or www.fda.gov./medwatch
`
`--------------------------DRUG INTERACTIONS--------------------------
`
`Acidifying and Alkalinizing Agents Agents that alter GI and
`urinary pH can alter blood levels of amphetamine. Acidifying
`agents (GI and urinary) decrease amphetamine blood levels, while
`alkalinizing agents (GI and urinary) increase amphetamine blood
`levels. Adjust MYDAYIS dosage accordingly. (2.5, 7.1)
`
`-------------------USE IN SPECIFIC POPULATIONS-------------------
`
` Pregnancy Based on animal data, may cause fetal harm. (8.1)
` Lactation Breastfeeding not recommended. (8.2)
` Renal Impairment Dose adjustment is needed in patients with
`severe renal insufficiency. Use of MYDAYIS in patients with
`ESRD is not recommended. (2.6, 8.6)
`
`-----------------------------CONTRAINDICATIONS-----------------------------
`
`
`
` 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)
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide.
`
`Revised: 06/2017
`
`
`
`
`Reference ID: 4114154
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: ABUSE AND DEPENDENCE
`
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Important Information Prior to Initiating Treatment
`
`2.2 General Instructions for Use
`
`2.3 Dosing Information
`2.4 Maintenance Treatment
`2.5 Dosage Modifications due to Drug Interactions
`
`2.6 Dosage in Patients with Renal Impairment
`
`2.7 Switching from other Amphetamine Products
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Potential for Abuse and Dependence
`
`5.2 Serious Cardiovascular Reactions
`
`5.3 Blood Pressure and Heart Rate Increases
`
`5.4 Psychiatric Adverse Reactions
`
`5.5 Long-Term Suppression of Growth
`
`5.6 Peripheral Vasculopathy, including Raynaud’s
`Phenomenon
`
`5.7 Seizures
`
`5.8 Serotonin Syndrome
`
`5.9 Potential for Overdose Due to Medication Errors
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Renal Impairment
`
`9 DRUG ABUSE AND DEPENDENCE
`
`9.1 Controlled Substance
`
`9.2 Abuse
`
`9.3 Dependence
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`
`
`
`6.2 Adverse Reactions Associated with the Use of
`Amphetamines
`
`7 DRUG INTERACTIONS
`
`7.1 Drugs Having Clinically Important Interactions with
`Amphetamines
`
`7.2 Drug/Laboratory Test Interactions
`
`
`
`*Sections or subsections omitted from full the prescribing information
`are not listed
`
`
`
`
`Reference ID: 4114154
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: ABUSE AND DEPENDENCE
`including MYDAYIS, other amphetamine-containing products, and
`stimulants,
`CNS
`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), and Drug Abuse and Dependence (9.2, 9.3)].
`
`1
`
`INDICATIONS AND USAGE
`
`MYDAYIS is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 13 years and
`older [see Clinical Studies (14)].
`
`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 [see Use in Specific
`Populations (8.4)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Important Information Prior to Initiating Treatment
`
`Prior to initiating treatment with MYDAYIS, 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 MYDAYIS use [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].
`
`2.2
`
`General Instructions for Use
`
`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)].
`
`Pharmacological treatment of ADHD may be needed for an extended period. Periodically re-evaluate the long-term use of
`MYDAYIS and adjust dosage as needed.
`
`2.3
`
`Administration 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.
`
`Dosing Information
`
`2.4
`
`Adult Use (18 to 55 years)
`
`
`Reference ID: 4114154
`
`
`
`
`
`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 Use (13 to 17 years)
`
`The recommended starting does 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)
`
`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)].
`
`
`Reference ID: 4114154
`
`
`
`
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Potential for Abuse and Dependence
`
`CNS stimulants, including MYDAYIS, 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)].
`
`5.2
`
`Serious Cardiovascular Reactions
`
`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
`MYDAYIS treatment.
`
`5.3
`
`Blood Pressure and Heart Rate Increases
`
`CNS stimulants cause an increase in blood pressure (mean increase about 2-4 mm Hg) and heart rate (mean increase about
`3-6 bpm). Monitor all 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 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 MYDAYIS. 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.
`
`5.5
`
`Long-Term Suppression of Growth
`
`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 MYDAYIS. 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)].
`
`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 [Use in Specific Populations (8.4)].
`
`5.6
`
`Peripheral Vasculopathy, including Raynaud’s Phenomenon
`
`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, very rare sequelae include digital
`ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were
`observed in post-marketing 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
`
`
`Reference ID: 4114154
`
`
`
`
`
`for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology
`referral) may be appropriate for certain patients.
`
`5.7
`
`Seizures
`
`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.
`
`5.8
`
`Serotonin 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
`co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to
`MYDAYIS. 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 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.
`
`5.9
`
`Potential 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) and Overdosage (10)].
`
`6
`
`ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
`
` Drug Dependence [see Boxed Warning, Warnings and Precautions (5.1), and 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)
`and Drug Interactions (7.1)]
` Serious Cardiovascular Reactions [see Warnings and Precautions (5.2)]
` Blood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3)]
` Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
` Long-Term Suppression of Growth [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)]
`
`
`Reference ID: 4114154
`
`
`
`
`
`6.1
`
`Clinical Trial 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, 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 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 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
`
`Nervous System
`
`
`
`
`Psychiatric disorders
`
`
`Metabolism and nutritional
`disorders
`
`Adverse
`Reaction
`
`
`Anxiety
`Feeling Jittery
`Agitation
`Bruxism
`
`Insomnia
`Depression
`
`
`
`MYDAYIS*
`(N= 626)
`
`Placebo
`(N= 328)
`
`
`
`
`
`7%
`2%
`2%
`2%
`
`31%
`3%
`
`
`
`3%
`1%
`0%
`0%
`
`8%
`0%
`
`
`
`
`Reference ID: 4114154
`
`
`
`
`
`
`
`
`Gastrointestinal System
`
`
`Cardiovascular System
`
`Decreased
`Appetite
`Weight
`Decreased
`
`Dry Mouth
`Diarrhea
`
`
`Heart Rate
`Increased
`
`
`
`Genitourinary System
`
`
`Palpitations
`
`Dysmenorrhea1
`Erectile
`Dysfunction2
`
`*Includes doses up to 75 mg (1.5 times the maximum recommended dosage).
`1 Dysmenorrhea was observed in 11 females
`2 Erectile dysfunction was observed in 6 males
`
`30%
`
`9%
`
`
`23%
`3%
`
`
`9%
`
`4%
`
`4%
`
`2%
`
`4%
`
`0%
`
`
`4%
`1%
`
`
`0%
`
`2%
`
`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
`
`Metabolism and nutrition disorders
`
`Decreased appetite
`
`Weight decreased
`Psychiatric disorders
`
`Irritability
`
`Insomnia*
`Gastrointestinal disorders
`
`Nausea
`
`
`
`
`
`
`
`4%
`
`22%
`5%
`
`6%
`8%
`
`8%
`
`
`
`
`
`
`
`0%
`
`6%
`1%
`
`3%
`3%
`
`4%
`
`Abdominal pain
`1%
`4%
`upper
`
`*Insomnia includes terms: initial insomnia, middle insomnia, terminal insomnia and insomnia.
`
`6.2
`
`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 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.
`
`
`Reference ID: 4114154
`
`
`
`
`
`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.
`
`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.
`
`7
`
`DRUG INTERACTIONS
`
`7.1
`
`Drugs Having Clinically Important Interactions with Amphetamines
`
`Table 3 Drugs Having Clinically Important Interactions with Amphetamines
`
`
`MAO Inhibitors (MAOI)
`
`Clinical Impact
`
`Intervention
`
`Examples
`Serotonergic Drugs
`
`Clinical Impact
`
`Intervention
`
`Examples
`
`Alkalinizing Agents
`
`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.
`Do not administer MYDAYIS during or within 14 days following the administration of
`MAOI [see Contraindications (4)].
`selegiline, isocarboxazid, phenelzine, tranylcypromine
`
`The concomitant use of amphetamines and serotonergic drugs increases the risk of
`serotonin syndrome.
`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) [see
`Warnings and Precautions 5.7].
`Selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake
`inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl,
`lithium, tramadol,
`tryptophan, buspirone, St. John’s Wort
`
`Clinical Impact
`
`May increase exposure to amphetamine and exacerbate the action of amphetamine.
`
`Caution should be taken when co-administering MYDAYIS and gastrointestinal and
`urinary alkalinizing agents.
`
`Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate; proton pump inhibitors
`[e.g. omeprazole])
`Urinary alkalinizing agents (e.g. acetazolamide, some thiazides)
`
`Lower blood levels and efficacy of amphetamines.
`Increase dose of MYDAYIS based on clinical response.
`
`Intervention
`
`Examples
`
`Acidifying Agents
`
`Clinical Impact
`Intervention
`
`
`Reference ID: 4114154
`
`
`
`
`
`Examples
`
`Tricyclic Antidepressants
`
`Clinical Impact
`
`Intervention
`
`Examples
`CYP2D6 Inhibitors
`
`Clinical Impact
`Intervention
`
`Examples
`Gastric pH Modulators
`
`Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl,
`ascorbic acid)
`Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate,
`methenamine salts)
`
`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.
`Monitor frequently and adjust MYDAYIS dose or use alternative therapy based on
`clinical response.
`desipramine, protriptyline
`
`May increase the exposure of amphetamine
`Start with lower doses and monitor frequently and adjust MYDAYIS dose or use
`alternative therapy based on clinical response.
`paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir.
`
`Clinical Impact
`Intervention
`
`Examples
`
`Potential change in shape of PK profile and exposure may occur
`Monitor patients for changes in clinical effect and use alternative therapy based on
`clinical response.
`omeprazole, esomeprazole, pantoprazole, cimetidine
`
`
`7.2
`
`Drug/Laboratory Test Interactions
`
`Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening.
`Amphetamines may interfere with urinary steroid determinations.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`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 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/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