HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` ADZENYS ER safely and effectively. See full prescribing information for
`
`
`
`
` ADZENYS ER.
`
`
`
` ADZENYS ER (amphetamine) extended-release oral suspension, CII
`
`
`
` Initial U.S. Approval: 1960
`
`
`
`
`
`
`
`
`
`
`
`
` WARNING: ABUSE AND DEPENDENCE
`
` See full prescribing information for complete boxed warning.
`
`
`
` CNS stimulants, including ADZENYS ER, 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
` ADZENYS ER is a central nervous system (CNS) stimulant indicated for the
`
`
`
`
` treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6
`
`
` years and older. (1)
`
`
` _______________DOSAGE AND ADMINISTRATION ______________
` Shake bottle before administering the dose. (2.2)
`
`
`
`
`
`•
`
`
`May be taken with or without food. (2.2)
`
`•
`Do not mix with food or other liquids before consuming. (2.2)
`
`
`
`
`
`•
`
`
`
`Pediatric patients (ages 6 to 17 years): Starting dose is 6.3 mg (5 mL)
`
`•
`once daily in the morning. Maximum dose is 18.8 mg (15 mL) for
`
`
`
`
`
`
`patients 6 to 12 years, and 12.5 mg (10 mL) once daily for patients 13 to
`
`17 years. (2.3)
`Adults: 12.5 mg (10 mL) once daily in the morning. (2.4)
`
`
`To avoid substitution errors and overdosage, do not substitute for other
`amphetamine products on a milligram-per-milligram basis because of
`
`
`
`
`
`different amphetamine salt compositions and differing pharmacokinetic
`
`
`
`profiles. (2.5, 5.8)
` ______________
` _____________
`DOSAGE FORMS AND STRENGTHS
`
`
`Extended-release oral suspension containing 1.25 mg amphetamine per mL.
`
`(3)
` ___________________
` ___________________ CONTRAINDICATIONS
`
`
` Known hypersensitivity to amphetamine products or other ingredients in
`
`
`•
`
`
` ADZENYS ER. (4)
`
`
`
`Use of monoamine oxidase inhibitor (MAOI) or within 14 days of the
`last MAOI dose. (4)
`
`
`
`
`_______________ 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)
`
`
`Serotonin Syndrome: Increased risk when co-administered with
`
`
` serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during
`
`overdosage situations. If it occurs, discontinue ADZENYS ER and
`
`
`
`initiate supportive treatment. (5.7)
`
`
`
`
`___________________ ADVERSE REACTIONS ___________________
`
`
`Pediatric patients ages 6 to 12 years: Most common adverse reactions
`
`
`
`
`
`
`
`•
` (≥5% and with a higher incidence than on placebo) were loss of appetite,
`
`insomnia, abdominal pain, emotional lability, vomiting, nervousness,
`
`
`nausea, and fever. (6.1)
`
`
`Pediatric patients ages 13 to 17 years: Most common adverse reactions
`
`
`
`
`(≥5% and with a higher incidence than on placebo) were loss of appetite,
`
`
`insomnia, abdominal pain, weight loss, and nervousness. (6.1)
`
`
`
`Adults: Most common adverse reactions (≥5% and with a higher
`
`
`
`
`
`
`incidence than on placebo) were dry mouth, loss of appetite, insomnia,
`
`
`
`
`
`headache, weight loss, nausea, anxiety, agitation, dizziness, tachycardia,
`diarrhea, asthenia, and urinary tract infections. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Neos
`
`Therapeutics, Inc. at 1-888-219-1789 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch.
`
`
`___________________ DRUG INTERACTIONS____________________
`
`Acidifying and Alkalinizing Agents: Agents that alter urinary pH can alter
`
`
`
`
`blood levels of amphetamine. Acidifying agents can decrease amphetamine
`blood levels, while alkalinizing agents can increase amphetamine blood
`
`
`
`
`levels. Adjust ADZENYS ER dosage accordingly. (7.1)
`
`
` ______________
` _______________
`USE IN SPECIFIC POPULATIONS
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`
`
`•
`Lactation: Breastfeeding not recommended. (8.2)
`
`
`
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 9/2017
`
`
`
`
`Reference ID: 4153413
`
`
`
`
`
`
`
`
`
`
`
`KVK-TECH EXHIBIT 1056
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: ABUSE AND DEPENDENCE
`
`
`1
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`Pre-Treatment Screening
`
`2.1
`
`
`2.2 Dosing Considerations for All Patients
`
`
`
`2.3
`Pediatric Patients
`
`
`
`2.4 Adults
`
`
`
`2.5
`Switching from Other Amphetamine Products
`
`
`
`
`2.6 Dosage Modifications Due to Drug Interactions
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Potential for Abuse or Dependence
`
`5.1
`
`
`Serious Cardiovascular Reactions
`
`5.2
`
`
`
`5.3 Blood Pressure and Heart Rate Increases
`
`
`
`
`5.4
`Psychiatric Adverse Events
`
`
`
`5.5 Long-Term Suppression of Growth
`
`
`
`5.6
`Peripheral Vasculopathy, including Raynaud’s Phenomenon
`
`
`
`
`5.7
`Serotonin Syndrome
`
`
`5.8
`Potential for Overdose Due to Medication Errors
`
`
`
`5.9
`Potential for Intestinal Necrosis
`
`
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Adverse Reactions from Clinical Trials and Spontaneous
`
`
`
`Postmarketing Reports of Other Amphetamine Products
`
`
`
`
`6
`
`
`
`
`
`
`
`
`7
`
`
`8
`
`
`9
`
`
`DRUG INTERACTIONS
`
`7.1 Drugs Having Clinically Important Interactions with
`
`
`
`
`
`Amphetamines
`
`
`
`7.2 Drug/Laboratory Test Interactions
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`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
`*Sections or subsections omitted from full prescribing information are
`
`
`
`
`
`not listed.
`
`
`Reference ID: 4153413
`
`
`
`
`
` 2
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` WARNING: ABUSE AND DEPENDENCE
`
`
` CNS stimulants, including ADZENYS ER, 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) and Drug Abuse and Dependence (9.2, 9.3)].
`
`
`
` INDICATIONS AND USAGE
`
`1
`
`
` ADZENYS ER is indicated for the treatment of Attention Deficit Hyperactivity Disorder
` (ADHD) in patients 6 years and older [see Clinical Studies (14)].
`
`
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
`2
`
`
`2.1
` Pre-Treatment Screening
`
` Prior to treating patients with ADZENYS ER, 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)].
`
`
`
`
`
`
` 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 ADZENYS ER use
` [see Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)].
`
`
`
`
`
`
` Dosing Considerations for All Patients
`
`2.2
`
`
`
`
` Administer ADZENYS ER orally once daily in the morning with or without food. The dose
` should be individualized according to the therapeutic needs and response of the patient.
`
`
`
`
`
`
` Shake the bottle of ADZENYS ER before administering the dose. Do not add ADZENYS ER to
`
` food or mix ADZENYS ER with other liquids before consuming.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.3
` Pediatric Patients
`
`
`
`
` The recommended starting dose for patients 6 to 17 years of age is 6.3 mg (5 mL) once daily in
` the morning. Increase in increments of 3.1 mg (2.5 mL) or 6.3 mg (5 mL) at weekly intervals.
`
`
`
` The maximum dose is 18.8 mg (15 mL) daily for patients 6 to 12 years, and 12.5 mg (10 mL)
`
`
`
` daily for patients 13 to 17 years.
`
`
` Adults
`
`2.4
`
` The recommended dose of ADZENYS ER for adults is 12.5 mg (10 mL) daily.
`
`
`
`
`
`
`
`
`
`Reference ID: 4153413
`
`
`
`3
`
`
`

`

`
`
`
`2.5
` Switching from Other Amphetamine Products
`
` Patients taking ADDERALL XR may be switched to ADZENYS ER at the equivalent dose taken
`
`
`
`
`
` once daily [see Clinical Pharmacology (12)]. Refer to Table 1 for equivalent doses of
`
` ADZENYS ER and ADDERALL XR. ADDERALL XR (dextroamphetamine sulfate,
`
`
`
` dextroamphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate
`
`
` extended-release capsules) is also referred to as mixed salts of a single-entity amphetamine
`
` product extended-release capsules (MAS ER).
`
`
`
`
`Table 1:
`
`
`
`
`
`
`Equivalent Doses of ADZENYS ER and ADDERALL XR (Mixed Salts of a
`
`
`Single-Entity Amphetamine Product) Extended-Release Capsules
`
` 6.3 mg
`
` ADZENYS ER
` 3.1 mg
`
`
` 9.4 mg
`
` 12.5 mg
`
` 15.7 mg
`
` (5 mL)
` (2.5 mL)
` (7.5 mL)
`
` (10 mL)
` (12.5 mL)
`
`
`
` Amphetamine extended-
`
` release oral suspension
`
`ADDERALL XR
`
`Mixed salts of a single-
`entity amphetamine
`product extended-release
`capsules (MAS ER)
`
`
`
`
`
` 18.8 mg
`
` (15 mL)
`
`5 mg
`
`
`10 mg
`
`
`15 mg
`
`
`20 mg
`
`
`25 mg
`
`
`30 mg
`
`
`
`
`
` If switching from any other amphetamine products, discontinue that treatment, and titrate with
`
` ADZENYS ER using the titration schedule [see Dosage and Administration (2.3, 2.4)].
`
`
`
` Do not substitute for other amphetamine products on a milligram-per-milligram basis because of
`
`
` different amphetamine salt compositions and differing pharmacokinetic profiles [see Warnings
`
`
` and Precautions (5.8)].
`
` Dosage Modifications Due to Drug Interactions
`
`
`2.6
`
`
` Agents that alter 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 ADZENYS ER dosage accordingly [see Drug
`
`
`
` Interactions (7.1)].
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`3
`
` Extended-release oral suspension contains 1.25 mg amphetamine per mL.
`
`
`
`
`
` CONTRAINDICATIONS
`4
`
`
` ADZENYS ER is contraindicated:
`
`
`Reference ID: 4153413
`
`
`
`4
`
`
`

`

`
`
`
`•
`
`
`•
`
`In patients known to be hypersensitive to amphetamine, or other components of ADZENYS
`
`
`ER. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been
`
`reported in patients treated with other amphetamine products [see Adverse Reactions (6.2)].
`
`
`
`
`
`In patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping
`
`MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an
`increased risk of hypertensive crisis [see Warnings and Precautions (5.7) Drug Interactions
`
`
`
`
`
`(7.1)].
`
`
`
`
` WARNINGS AND PRECAUTIONS
`
`5
`
` Potential for Abuse or Dependence
`
`
`5.1
`
`
` CNS stimulants, including ADZENYS ER, 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)].
`
`
`
`
` Serious Cardiovascular Reactions
`
`5.2
`
`
` Sudden death, stroke, and myocardial infarction have been reported in adults with CNS stimulant
` treatment at recommended doses. Sudden death has been reported in children and adolescents
`
`
` with structural cardiac abnormalities and other serious heart problems 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 ADZENYS ER treatment.
`
`
`
`
`
` Blood Pressure and Heart Rate Increases
`
`
`5.3
`
`
` 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.
`
`
`
`
` Psychiatric Adverse Events
`5.4
`
`
` 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 Illness
`
` CNS stimulants may induce a mixed or 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 has a history of depressive symptoms or a family history of suicide, bipolar
`
` disorder, and depression).
` New Psychotic or Manic Symptoms
`
`
`
`
`
`
`Reference ID: 4153413
`
`
`
`5
`
`
`

`

`
`
`
`CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g.,
`
`
`
`hallucinations, delusional thinking, or mania) in patients without prior history of psychotic
`
`
`illness or mania. If such symptoms occur, consider discontinuing ADZENYS ER. 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 ADZENYS ER.
`
` Patients who are not growing or gaining height or weight as expected may need to have their
`
`
` treatment interrupted [Use in Specific Populations (8.4)].
`
`
`
`
`
`
`
`
`
` Peripheral Vasculopathy, including Raynaud’s Phenomenon
`
`5.6
`
`
`
`
` Stimulants, including ADZENYS ER, 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 for digital changes is necessary during treatment
`
`
`with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be
`
`
`appropriate for certain patients.
`
` Serotonin Syndrome
`
`5.7
`
` 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 ADZENYS ER. 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 ADZENYS ER with MAOI drugs is contraindicated [see Contraindications
`
`
` (4)].
`
`
`
`
`
`Reference ID: 4153413
`
`
`
`6
`
`
`

`

`
`
` Discontinue treatment with ADZENYS ER and any concomitant serotonergic agents
`
`
`
`
`
`
`
`
` immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If
`
` concomitant use of ADZENYS ER with other serotonergic drugs or CYP2D6 inhibitors is
`
`
` clinically warranted, initiate ADZENYS ER 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.
`
`
`
`
`
`
` Potential for Overdose Due to Medication Errors
`
`5.8
`
` Medication errors, including substitution and dispensing errors, between ADZENYS ER 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 salt compositions and differing
`
`
`
`
`pharmacokinetic profiles [see Dosage and Administration (2.5)].
`
`
`
`
`
`
` Potential for Intestinal Necrosis
`
`
`
`5.9
`
`
`Cases of intestinal necrosis, including some deaths, have been reported with the concomitant use
`
`of sodium polystyrene sulfonate and sorbitol, two of the inactive ingredients in ADZENYS
`
`
`
`ER. In these cases, patients were administered sodium polystyrene sulfonate to treat
`
`
`
`
`hyperkalemia at doses greater than 200 times the amount present in Adzenys ER. However, no
`
`
`
`
`absolute safe levels for the interaction of sodium polystyrene sulfonate and sorbitol have been
`
`established.
`
`
`
`
`
`
`
`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, or other components of ADZENYS ER [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)]
`
`
` • Serotonin Syndrome [see Warnings and Precautions (5.7)]
`
`
` • Potential for Intestinal Necrosis [see Warnings and Precautions (5.9)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4153413
`
`
`
`7
`
`
`
`
`
`
`

`

`
`
`
`
`
`
` Clinical Trials Experience
`
`
`6.1
`
`
`
` 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.
`
`
`
` The safety of ADZENYS ER has been established from adequate and well-controlled studies of
`
`
`
` single-entity amphetamine product extended-release (MAS ER) capsules [see Clinical Studies
`
`
` (14)]. The adverse reactions of MAS ER capsules in these adequate and well-controlled studies
`
`
` are described below.
`The premarketing development program for MAS ER included exposures in a total of 1315
`participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients,
`and 82 healthy adult subjects). Of these, 635 patients (ages 6 to 12) were evaluated in two
`
`controlled clinical studies, one open-label clinical study, and two single-dose clinical
`
`pharmacology studies (N= 40).
`
`Adverse Reactions Leading to Discontinuation of Treatment
`
`
`
`The most frequent adverse reactions leading to discontinuation of MAS ER in controlled and
`
`
`uncontrolled, multiple-dose clinical trials of pediatric patients ages 6 to 12 years (N=595) were
`
`
`
`anorexia (loss of appetite) (2.9%), insomnia (1 5%), weight loss (1.2%), emotional lability (1%),
`and depression (0.7%).
`
`In a separate placebo-controlled 4-week study in pediatric patients 13 to 17 years with ADHD,
`
`
`
`five patients (2.1%) discontinued treatment due to adverse events among MAS ER-treated
`
`
`
`patients (N=233) compared to none who received placebo (N=54). The most frequent adverse
`
`
`event leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation
`in at least 1% of MAS ER-treated patients and at a rate at least twice that of placebo) was
`
`
`
`insomnia (1.3%, n=3).
`
`In one placebo-controlled 4-week study among adults with ADHD with doses 20 mg to 60 mg,
`
`23 patients (12.0%) discontinued treatment due to adverse events among MAS ER-treated
`
`
`patients (N=191) compared to one patient (1.6%) who received placebo (N=64). The most
`
`
`
`frequent adverse events leading to discontinuation and considered to be drug-related (i.e. leading
`
`
`
`to discontinuation in at least 1% of MAS ER-treated patients and at a rate at least twice that of
`
`placebo) were insomnia (5.2%, n=10), anxiety (2.1%, n=4), nervousness (1.6%, n=3), dry mouth
`
`(1.6%, n=3), anorexia (1.6%, n=3), tachycardia (1.6%, n=3), headache (1.6%, n=3), and asthenia
`
`(1.0%, n=2).
`
`Adverse Reactions Occurring in Controlled Trials
`
`
`Adverse reactions reported in a 3-week clinical trial of pediatric patients 6 to 12 years and a 4­
`
`
`
`
`week clinical trial in pediatric patients 13 to 17 years of age and adults, respectively, treated with
`
`
`
`MAS ER or placebo are presented in the tables below.
`
`
`
`
`Reference ID: 4153413
`
`
`
`8
`
`
`

`

` Adverse Reactions Reported by 2% or More of Children (6-12 years old)
`
`
`
` Receiving MAS ER with Higher Incidence than on Placebo in a 584-Patient
` Clinical Study
`
` Preferred Term
`
`
`
`
`Abdominal Pain (stomachache)
`
`Fever
`
`Infection
`
`Accidental Injury
`
`Asthenia (fatigue)
`
`Loss of Appetite
`
`Vomiting
`
`Nausea
`
`Dyspepsia
`
`Insomnia
`
`Emotional Lability
`
`Nervousness
`
`Dizziness
` Weight Loss
`
`
`
` MAS ER
`
` (n=374)
`
`14%
`
`5%
`
`4%
`
`3%
`
`2%
`
`22%
`
`7%
`
`5%
`
`2%
`
`17%
`
`9%
`
`6%
`
`2%
`
` 4%
`
`
` Placebo
`
` (n=210)
`
`10%
`
`2%
`
`2%
`
`2%
`
`0%
`
`2%
`
`4%
`
`3%
`
`1%
`
`2%
`
`2%
`
`2%
`0%a
`
`
` 0%
`
`
`
`
`
`
`
` Table 2:
`
`
`
` Body System
`
`General
`
`
`Digestive System
`
`
`Nervous System
`
`
`
`
` Metabolic/Nutritional
`
`Table 3:
`
`
`
`
`
` Body System
`
`General
`
`Digestive System
`
`Nervous System
`
`
`Adverse Reactions Reported by 5% or More of Adolescents (13-17 Years
`
`Old) Weighing ≤ 75kg Receiving MAS ER with Higher Incidence than
`
`
`Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study*
`
`
` Placebo
` Preferred Term
`
`
` MAS ER
`
` (n=54)
`
` (n=233)
`
`
`2%
`11%
`
`
`2%
`36%
`
`
`4%
`12%
`
`
` 0%
` 9%
`
`Metabolic/Nutritional
`
`
`
`
` * Included doses up to 40 mg
`
`b Dose-related adverse reactions
`
`
`Note: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adolescent patients receiving
`
`
`
`
`
`
`MAS ER with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia,
`
`
`
`
`
`emotional lability, nausea, somnolence, and vomiting.
`
`
`
`
`
`
`
`Abdominal Pain (stomachache)
`Loss of Appetite b
`
`
`Insomnia b
`
`
`Weight Loss b
`
`
`Reference ID: 4153413
`
`
`
`9
`
`
`

`

`
` Adverse Reactions Reported by 5% or More of Adults Receiving MAS ER
` with Higher Incidence Than Placebo in a 255 Patient Clinical Forced
`
`
` Weekly-Dose Titration Study*
` Preferred Term
`
`
`
`
`
`
`
`
` Table 4:
`
`
`
` Body System
`
`General
`
`
`Digestive System
`
`
`Nervous System
`
`
`Cardiovascular System
`
`Metabolic/Nutritional
`
`Urogenital System
`
`
` MAS ER
`
`
` (n=191)
`
`26%
`
`6%
`
`35%
`
`33%
`
`8%
`
`6%
`
`27%
`
`8%
`
`8%
`
`7%
`
`
`6%
`
`10%
`
`5%
`
`
`Headache
`
`Asthenia
`
`Dry Mouth
`
`Loss of Appetite
`
`Nausea
`
`Diarrhea
`
`Insomnia
`
`Agitation
`
`Anxiety
`
`Dizziness
`
`
`Tachycardia
`
`Weight Loss
`
`Urinary Tract
`
`Infection
`
`
` Placebo
`
` (n=64)
`
`13%
`
`5%
`
`5%
`
`3%
`
`3%
`
`0%
`
`13%
`
`5%
`
`5%
`
`0%
`
`
`3%
`
`0%
`
`0%
`
`
`
`
`
`
`
` * Included doses up to 60 mg.
`
`
`
`6.2
`
`
`
`
`
`
` Note: The following reactions did not meet the criterion for inclusion in Table 4 but were reported by 2% to 4% of adult patients receiving MAS
`
`
`
`
`
`
`
`
`
`
`
` ER with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g.
` teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation,
`
`
`
`
` twitching, dyspnea, sweating, dysmenorrhea, and impotence.
`Adverse Reactions from Clinical Trials and Spontaneous
`
`
` Postmarketing Reports of Other Amphetamine Products
`
` The following adverse reactions are from clinical trials and spontaneous postmarketing reports of
`
`
`
` other amphetamine products in pediatric patients and adults with ADHD. Because some of these
`
` reactions were reported voluntarily from a population of uncertain size, it is not always possible
`
`
` to estimate their frequency reliably or to establish a causal relationship to drug exposure.
`
`
`
`
` Cardiovascular: Palpitations, sudden death, myocardial infarction. There have been isolated
`
`
`
` reports of cardiomyopathy associated with chronic amphetamine use.
`Central Nervous System: Restlessness, irritability, euphoria, dyskinesia, dysphoria, depression,
`tremor, aggression, anger, logorrhea, and paresthesia (including formication).
`
`Eye Disorders: Vision blurred, mydriasis.
`
`Gastrointestinal: Unpleasant taste, constipation, other gastrointestinal disturbances.
`
`
`
`Reference ID: 4153413
`
`
`
`10
`
`
`

`

`
`
` 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, change in libido, frequent or prolonged erections.
`
`
` Skin: Alopecia.
`
`
` Musculoskeletal, Connective Tissue, and Bone Disorders: Rhabdomyolysis.
`
`
` Psychiatric Disorders: Dermatillomania, bruxism.
`
`
` Vascular Disorders: Raynaud’s phenomenon
`
`
`
`
`
`
`
`
`
`
`
`7
`
`7.1
`
` Table 5:
`
`
`
`
`
`
`
` DRUG INTERACTIONS
`
`
`
` Drugs Having Clinically Important Interactions with Amphetamines
`
` Drugs Having Clinically Important Interactions with Amphetamines
`
`
`
` MAO Inhibitors (MAOI)
`
`
`
`Clinical Impact
`
`
`MAOI antidepressants slow amphetamine metabolism, increasing
`
`amphetamines effect on the release of norepinephrine and other
`
`
`
`monoamines from adrenergic nerve endings causing headaches and other
`
`signs of hypertensive crisis. Toxic neurological effects and malignant
`
`
`hyperpyrexia can occur, sometimes with fatal results.
`
`
`Intervention
`
`
`Do not administer ADZENYS ER during or within 14 days following the
`
`
`
`administration of MAOI [see Contraindications (4)].
`
`
`
`Examples
`
`
`selegiline, isocarboxazid, phenelzine, tranylcypromine
`
`
`Serotonergic Drugs
`
`
`Clinical Impact
`
`
`
`Intervention
`
`
`Examples
`
`Alkalinizing Agents
`
`
`The concomitant use of ADZENYS ER 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 ADZENYS ER initiation or dosage
`
`
`
`increase. If serotonin syndrome occurs, discontinue ADZENYS ER and the
`
`
`
`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
`
`
`Reference ID: 4153413
`
`
`
`11
`
`
`

`

` Increase blood levels and potentiate the action of amphetamine.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Clinical Impact
`
`Intervention
`
`
`Examples
`
`
`Acidifying Agents
`
`
`Co-administration of ADZENYS ER and gastrointestinal alkalinizing
`
`
`
`agents should be avoided.
`
`
`Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate).
`
`Urinary alkalinizing agents (e.g., acetazolamide, some thiazides).
`
`
`
`Clinical Impact
`
`
`Lower blood levels and efficacy of amphetamines.
`
`
`
`Intervention
`
`
`Examples
`
`
`Tricyclic Antidepressants
`
`
`Clinical Impact
`
`
`Increase dose based on clinical response.
`
`
`
`Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic
`acid HCl, ascorbic acid).
`
`
`May enhance the activity of tricyclic or sympathomimetic agents causing
`
`striking and sustained increases in the concentration of d-amphetamine in
`
`
`
`the brain; cardiovascular effects can be potentiated.
`
`
`
`
`Intervention
`
`
`Monitor frequently and adjust or use alternative therapy based on clinical
`
`
`response.
`
`
`Examples
`
`
`desipramine, protriptyline
`
`
`CYP2D6 Inhibitors
`
`
`
`
` Clinical Impact
`
`
`
` May increase the exposure of amphetamine.
`
`Intervention
`
`
`Start with lower doses and monitor frequently and adjust ADZENYS ER
`
`
`
`dose or use alternative therapy based on clinical response.
`
`
`
`Examples
`
`
`paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir.
`
`
`
`Gastric pH Modulators
`
`
`Clinical Impact
`
`
`May change the release profile, shape of pharmacokinetic profile and
`
`
`
`
`exposure to ADZENYS ER resulting in the potential for dose dumping.
`
`
`
`
`Intervention
`
`
`Concomitant use of ADZENYS ER with a gastric pH modulator (i.e. H2
`
`
`
`
`blocker or proton pump inhibitor) is not recommended.
`
`
`Examples
`
`
`omeprazole, esomeprazole, pantoprazole, cimetidine
`
`
`Reference ID: 4153413
`
`
`
`12
`
`
`

`

`
`
`
`
` Drug/Laboratory Test Interactions
`
`7.2
`
`
` Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is
` greatest in the evening. Amphetamines may interfere with urinary steroid determinations.
`
`
`
`
`
`
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`8
`
` Pregnancy
`
`8.1
`
`Pregnancy Exposure Registry
`
`
` There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
`
` ADZENYS ER during pregnancy. Healthcare providers are encouraged to register patients by
`
`
` calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.
`
`
` Risk Summary
`
`
`
` The limited available data from published literature and postmarketing reports on the use of
`
` prescription amphetamine in pregnant women are insufficient to inform a drug-associated risk
`
`
`
`
` for major congenital malformation