ADZENYS XR-ODT

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Dosage and administration

2. DOSAGE AND ADMINISTRATION May be taken with or without food. Allow tablet to disintegrate in saliva then swallow. (2.2) Pediatric patients (ages 6 to 17 years): Starting dose is 6.3 mg once daily in the morning. Maximum dose is 18.8 mg once daily for patients 6 to 12 years, and 12.5 mg once daily for patients 13 to 17 years. (2.3) Adults: 12.5 mg 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 base compositions and differing pharmacokinetic profiles. (2.5, 5.7) 2.1 Pre-treatment Screening Prior to treating patients with ADZENYS XR-ODT, 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 XR-ODT use [see Warnings and Precautions (5.1), and Drug Abuse and Dependence (9) ]. 2.2 Dosing Considerations for All Patients ADZENYS XR-ODT may be taken with or without food. Individualize the dosage according to the therapeutic needs and response of the patient. ADZENYS XR-ODT should be taken as follows: The tablet should remain in the blister pack until the patient is ready to take it. The patient or caregiver should use dry hands to open the blister. Tear along the perforation, bend the blister where indicated and peel back the blister's labeled backing to take out the tablet. The tablet should not be pushed through the foil. As soon as the blister is opened, the tablet should be removed and placed on the patient's tongue. The whole tablet should be placed on the tongue and allowed to disintegrate without chewing or crushing. The tablet will disintegrate in saliva so that it can be swallowed. 2.3 Pediatric Patients The recommended starting dosage is 6.3 mg once daily in the morning. Increase in increments of 3.1 mg or 6.3 mg at weekly intervals. The maximum recommended dose is 18.8 mg daily for patients 6 to 12 years, and 12.5 mg daily for patients 13 to 17 years [see Use in Specific Populations (8.3), Clinical Studies (14) ]. 2.4 Adults The recommended dose is ADZENYS XR-ODT 12.5 mg daily. 2.5 Switching from Other Amphetamine Products Patients taking ADDERALL XR may be switched to ADZENYS XR-ODT at the equivalent dose taken once daily [see Clinical Pharmacology (12.3) ]. Refer to Table 1 for equivalent doses of ADZENYS XR-ODT 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 XR-ODT and ADDERALL XR (Mixed Salts of a Single-Entity Amphetamine Product) Extended-Release Capsules ADZENYS XR-ODT Amphetamine extended-release orally disintegrating tablets 3.1 mg 6.3 mg 9.4 mg 12.5 mg 15.7 mg 18.8 mg ADDERALL XR Mixed salts of a single-entity amphetamine product extended-release capsules (MAS ER) 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 XR-ODT 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 base compositions and differing pharmacokinetic profiles [see Warnings and Precautions (5.7) ]. 2.6 Dosage Modifications Due to Drug Interactions 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 XR-ODT dosage accordingly [see Drug Interactions (7.1) ].

Table 1: Equivalent Doses of ADZENYS XR-ODT and ADDERALL XR (Mixed Salts of a Single-Entity Amphetamine Product) Extended-Release Capsules
ADZENYS XR-ODT Amphetamine extended-release orally disintegrating tablets 3.1 mg 6.3 mg 9.4 mg 12.5 mg 15.7 mg 18.8 mg
ADDERALL XR Mixed salts of a single-entity amphetamine product extended-release capsules (MAS ER) 5 mg 10 mg 15 mg 20 mg 25 mg 30 mg

Pregnancy

8.1 Pregnancy Teratogenic Effects Pregnancy Category C. Amphetamine, in the enantiomer ratio present in ADZENYS XR-ODT (d- to l- ratio of 3:1), had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 2 and 12 times, respectively, the maximum recommended human dose (MRHD) for adolescents of 12.5 mg/day (as base), on a mg/m2 body surface area basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 10 times the MRHD for adolescents on a mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity. A study was conducted in which pregnant rats received daily oral doses of amphetamine (d- to l- enantiomer ratio of 3:1, the same as in ADZENYS XR-ODT) of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. These doses are approximately 0.8, 2, and 4 times the MRHD for adolescents of 12.5 mg/day (as base), on a mg/m2 basis. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup bodyweight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks post-weaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg. A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d, l-), at doses similar to those used clinically, can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function. There are no adequate and well-controlled studies in pregnant women. There are limited published data on the use of amphetamine in pregnant women. These data are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Amphetamines, such as ADZENYS XR-ODT, may cause vasoconstriction, including vasoconstriction of placental blood vessels, and may increase the risk for intrauterine growth restriction. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Monitor infants born to mothers taking amphetamines for symptoms of withdrawal, such as feeding difficulties, irritability, agitation, and excessive drowsiness.

Drug Interactions

7. 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 XR-ODT dosage accordingly. (7.1 ) 7.1 Drugs Having Clinically Important Interactions with Amphetamines Table 5: 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 XR-ODT during or within 14 days following the administration of MAOI [see Contraindications (4) ]. Examples selegiline, isocarboxazid, phenelzine, tranylcypromine Serotonergic Drugs Clinical Impact The concomitant use of ADZENYS XR-ODT and serotonergic drugs increases the risk of serotonin syndrome. Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADZENYS XR-ODT initiation or dosage increase. If serotonin syndrome occurs, discontinue ADZENYS XR-ODT and the concomitant serotonergic drug(s) [see Warnings and Precautions (5.7)]. Examples selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort Alkalinizing Agents Clinical Impact Increase blood levels and potentiate the action of amphetamine. Intervention Co-administration of ADZENYS XR-ODT and gastrointestinal alkalinizing agents should be avoided. Examples Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g., acetazolamide, some thiazides). Acidifying Agents Clinical Impact Lower blood levels and efficacy of amphetamines. Intervention Increase dose based on clinical response. Examples Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Tricyclic Antidepressants Clinical Impact 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 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.

Indications And Usage

1. INDICATIONS AND USAGE ADZENYS XR-ODT is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies (14) ]. ADZENYS XR-ODT is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older. (1)

Clinical Studies

14. CLINICAL STUDIES The safety and efficacy of ADZENYS XR-ODT has been established based on adequate and well-controlled studies of mixed salts of a single-entity amphetamine product extended-release capsules in the treatment of ADHD. Below is a description of the results of the adequate and well-controlled studies of mixed salts of a single-entity amphetamine product extended-release capsules (MAS ER) in the treatment of ADHD. Pediatric Patients A double-blind, randomized, placebo-controlled, parallel-group study was conducted in pediatric patients 6 to 12 years of age (N=584) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Patients were randomized to fixed-dose treatment groups receiving final doses of 10, 20 or 30 mg of mixed salts of a single-entity amphetamine product extended-release capsules or placebo once daily in the morning for three weeks. The primary efficacy variable was the Attention Deficit Hyperactivity Disorder-Rating Scale IV (ADHD-RS-IV) total score for the primary cohort. The ADHD-RS-IV is an 18-item scale that measures the core symptoms of ADHD. Significant improvements on the ADHD-RS-IV, based upon teacher ratings of attention and hyperactivity, were observed for all doses compared to patients who received placebo, for all three weeks, including the first week of treatment, when all subjects were receiving a dose of 10 mg/day. Patients who received MAS ER showed improvements on the ADHD-RS-IV total score in both morning and afternoon assessments compared to patients on placebo. In a classroom analogue study, patients (N=51) receiving fixed doses of 10 mg, 20 mg or 30 mg MAS ER demonstrated statistically significant improvements on teacher-rated Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scale Attention and Deportment variables and Permanent Product Measure of Performance (PERMP) scales compared to patients treated with placebo. SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting. PERMP is a skill-adjusted math test that measure attention in ADHD. A double-blind, randomized, multi-center, parallel-group, placebo-controlled study was conducted in pediatric patients 13 to 17 years of age (N=327) who met DSM-IV criteria for ADHD. The primary cohort of patients (n=287, weighing ≤ 75kg) was randomized to fixed-dose treatment groups and received four weeks of treatment. Patients were randomized to receive final doses of 10 mg, 20 mg, 30 mg, and 40 mg MAS ER or placebo once daily in the morning. Patients randomized to doses greater than 10 mg were titrated to their final doses by 10 mg each week. Improvements in the primary cohort were statistically significantly greater in all four primary cohort active treatment groups (MAS ER 10 mg, 20 mg, 30 mg, and 40 mg) compared with the placebo group. There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit. Adult Patients A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adults (N=255) who met DSM-IV criteria for ADHD. Patients were randomized to fixed-dose treatment groups receiving final doses of 20, 40, or 60 mg of MAS ER or placebo once daily in the morning for four weeks. Improvements, measured with the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS) were observed at endpoint for MAS ER 20, 40 and 60 mg, compared to patients who received placebo for all four weeks. However, there was not adequate evidence that doses greater than 20 mg/day conferred additional benefit.

Warnings And Cautions

5. 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 XR-ODT and initiate supportive treatment. (5.7, 17) 5.1 Potential for Abuse and Dependence CNS stimulants, including ADZENYS XR-ODT, 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 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 XR-ODT 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. 5.4 Psychiatric Adverse Reactions Exacerbation 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 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 XR-ODT. 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 XR-ODT. 5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon Stimulants, including ADZENYS XR-ODT, 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. 5.7 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 ADZENYS XR-ODT. 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 XR-ODT with MAOI drugs is contraindicated [see Contraindications (4)]. Discontinue treatment with ADZENYS XR-ODT and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of ADZENYS XR-ODT with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate ADZENYS XR-ODT 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. 5.8 Potential for Overdose Due to Medication Errors Medication errors, including substitution and dispensing errors, between ADZENYS XR-ODT 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 (2.5) ].

Overdosage

10. OVERDOSAGE Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice for treatment of overdosage. Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses. Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Other reactions include arrhythmias, hypertension or hypotension, circulatory collapse, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.

Adverse Reactions

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 XR-ODT [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) ] 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 1-888-319-1789 or http://www.adzenysxrodt.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ADZENYS XR-ODT 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 years) 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 ages 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 0% 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 Clinical Trials Adverse reactions reported in a 3-week clinical trial of pediatric patients 6 to 12 years of age 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. Table 2: Adverse Reactions Reported by 2% or More of Pediatric Patients (6-12 years old) Receiving MAS ER with Higher Incidence than on Placebo in a 584-Patient Clinical Study Body System Adverse Reaction MAS ER (n=374) Placebo (n=210) General Abdominal Pain (stomachache) 14% 10% Fever 5% 2% Infection 4% 2% Accidental Injury 3% 2% Asthenia (fatigue) 2% 0% Digestive System Loss of Appetite 22% 2% Vomiting 7% 4% Nausea 5% 3% Dyspepsia 2% 1% Nervous System Insomnia 17% 2% Emotional Lability 9% 2% Nervousness 6% 2% Dizziness 2% 0% Metabolic/Nutritional Weight Loss 4% 0% Table 3: Adverse Reactions Reported by 5% or More of Pediatric Patients (13-17 Years Old) Weighing ≤ 75kg Receiving MAS ER with Higher Incidence than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration StudyIncluded doses up to 40 mg Body System Preferred Term MAS ER (n=233) Placebo (n=54) 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. General Abdominal Pain (stomachache) 11% 2% Digestive System Loss of Appetite Dose-related adverse reactions 36% 2% Nervous System Insomnia 12% 4% Metabolic/Nutritional Weight Loss 9% 0% Table 4: 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 StudyIncluded doses up to 60 mg. Body System Preferred Term MAS ER (n=191) Placebo (n=64) 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. General Headache 26% 13% Asthenia 6% 5% Digestive System Dry Mouth 35% 5% Loss of Appetite 33% 3% Nausea 8% 3% Diarrhea 6% 0% Nervous System Insomnia 27% 13% Agitation 8% 5% Anxiety 8% 5% Dizziness 7% 0% Cardiovascular System Tachycardia 6% 3% Metabolic/Nutritional Weight Loss 10% 0% Urogenital System Urinary Tract Infection 5% 0% 6.2 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. 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.

Recent major changes

Contraindications (4) 10/2016 Warnings and Precautions (5.7) 10/2016

Mechanism

12.1 Mechanism of Action Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known. Amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Contraindications

4. CONTRAINDICATIONS ADZENYS XR-ODT is contraindicated: In patients known to be hypersensitive to amphetamine, or other components of ADZENYS XR-ODT. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see Adverse Reactions (6.2) ]. Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such a linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.7) , Drug Interactions 7.1] Known hypersensitivity to amphetamine products or other ingredients in ADZENYS XR-ODT. (4) Use of monoamine oxidase inhibitor (MAOI) or within 14 days of the last MAOI dose. (4)

Nursing Mothers

8.3 Nursing Mothers Based on limited case reports in published literature, amphetamine (d- or d, l-) is present in human milk at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant and no effects on milk production. However, long-term neurodevelopmental effects on infants from stimulant exposure are unknown. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ADZENYS XR-ODT.