`
` ----------------------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)
`
`
`
`
`
`
`
`
`
`
` --------------------------ADVERSE REACTIONS------------------------­
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`
`
`
`
`
`Medication Guide.
`
`
`
`
`Revised: 06/2017
`
`
`
`
`
`
`
`
`
`
` 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----------------------
`
` MYDAYIS should be taken once daily upon awakening.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Maximum
`
` Titration
` Recommended
`
`
` Daily Dose
`
`
` Schedule
`
`
` Starting Dose
` Adults
` 50 mg
`
`
`
` 12.5 mg weekly
`
`
` 12.5 mg
`
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`-----------------------------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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4114154
`
`p.1
`
`SHIRE EX. 2004
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`
`
`
` WARNING: ABUSE AND DEPENDENCE
`
`
`
`
`
`
` 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
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`Reference ID: 4114154
`
`
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`
`
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
` *Sections or subsections omitted from full the prescribing information
`
` are not listed
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`p.2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: ABUSE AND DEPENDENCE
`
` stimulants,
`CNS
`
`
` 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 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
`
`p.3
`
`

`

`
`
`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
`
`p.4
`
`

`

`
`
`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
`
`p.5
`
`

`

`
`
`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
`
`p.6
`
`

`

`
`
`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
`th
`th
`
` ® or
`
`
`
`
`
`
`
`Statistical Manual of Mental Disorders, 4 or 5 editions (DSM-IV-TR
` 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
`
`Adverse
`
` Reaction
`
`
` MYDAYIS *
`
` (N= 626)
`
`
` Placebo
` (N= 328)
`
`
`
`
`
`
`
`
` 7%
`
` 2%
`
` 2%
`
` 2%
`
`
` 31%
`
` 3%
`
`
`
`
` 3%
`
` 1%
`
` 0%
`
` 0%
`
`
` 8%
`
` 0%
`
`
`
`
`
`
` Anxiety
`
` Feeling Jittery
`
` Agitation
`
` Bruxism
`
`Insomnia
`
` Depression
`
`
`
`
`
`
`
` Nervous System
`
`
`
`
` Psychiatric disorders
`
`
` Metabolism and nutritional
`
` disorders
`
`
`
`
`
`
`Reference ID: 4114154
`
`p.7
`
`

`

`
`
`
`
`
`
`
` Gastrointestinal System
`
`
` Cardiovascular System
`
`
`
`
`
` Genitourinary System
`
`
`
`
`
`
`Decreased
`
` Appetite
`
` Weight
` Decreased
`
` Dry Mouth
`
` Diarrhea
`
`
`
`
`Heart Rate
`
` Increased
`
`
`
`
`
`
`
` 30%
`
`
`
` 9%
`
`
`
` 23%
`
` 3%
`
`
`
`
` 9%
`
`
` 4%
`
` 4%
`
`
`
`
`
` 2%
`
`
`
` 4%
`
`
`
` 0%
`
`
`
` 4%
`
` 1%
`
`
`
`
` 0%
`
`
` 2%
`
` 2%
`
`
`
`
`
` 1%
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
` Placebo
`
` (N= 79)
`
`
`
`
`
` Body System
`
`
` Adverse Reaction MYDAYIS
`
` (N= 78)
`
`
`
`
`
` 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
` 4%
`
`
`
`
` 1%
` 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
`
`p.8
`
`

`

`
`
`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
`
`
`
`
`
`
`
`
`
`
` 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
`
`
` If serotonin
`
`
`
` syndrome, particularly during MYDAYIS initiation or dosage increase.
`
`
`
` syndrome occurs, discontinue MYDAYIS and concomitant serotonergic drug(s) [see
`
`
`
`
` Warnings and Precautions 5.7].
`
`
`
`
` Selective serotonin