FDA Label for Adzenys Xr-odt

Warning: 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 Warnings and Precautions (5.1, 9.3), and Drug Abuse and Dependence (9.2, 9.3)].

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)].

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).

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)].

3. Dosage Forms And Strengths

ADZENYS XR-ODT 3.1 mg Amphetamine Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A1 on one side)

ADZENYS XR-ODT 6.3 mg Amphetamine Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A2 on one side)

ADZENYS XR-ODT 9.4 mg Amphetamine Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A3 on one side)

ADZENYS XR-ODT 12.5 mg Amphetamine Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A4 on one side)

ADZENYS XR-ODT 15.7 mg Amphetamine Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A5 on one side)

ADZENYS XR-ODT 18.8 mg Amphetamine Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A6 on one side)

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].

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.

Other

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.

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.

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.

Long-Term Growth Suppression

Growth should be monitored during treatment with stimulants, including ADZENYS XR-ODT, in pediatric patients aged 6 to 17 years who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.5)].

Juvenile Animal Data

In a juvenile developmental study, 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, or 20 mg/kg on days 7 to 13 of age; from day 14 to approximately day 60 of age these doses were given twice daily for total daily doses of 4, 12, or 40 mg/kg. The latter doses are approximately 0.6, 2, and 6 times the maximum recommended human dose for children of 18.8 mg/day (as base), on a mg/m² basis. Post dosing hyperactivity was seen at all doses; motor activity measured prior to the daily dose was decreased during the dosing period but the decreased motor activity was largely absent after an 18 day drug-free recovery period. Performance in the Morris water maze test for learning and memory was impaired at the 40 mg/kg dose, and sporadically at the lower doses, when measured prior to the daily dose during the treatment period; no recovery was seen after a 19 day drug-free period. A delay in the developmental milestones of vaginal opening and preputial separation was seen at 40 mg/kg but there was no effect on fertility.

Tolerance

Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug's desired and/or undesired effects over time) may occur during the chronic therapy of CNS stimulants including ADZENYS XR-ODT.

Dependence

Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including ADZENYS XR-ODT. Withdrawal symptoms after abrupt cessation following prolonged high dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Absorption

Following a single, 18.8 mg oral dose of ADZENYS XR-ODT in 40 healthy adult subjects in a crossover study under fasting conditions, d-amphetamine mean (±SD) peak plasma concentrations of 44.9 (±8.9) ng/mL occurred at a median time of 5.0 hours after dosing, and l-amphetamine mean (±SD) peak plasma concentrations of 14.5 (+ 3.0 ng/mL occurred at a median time of 5.25 hours after dosing (Figure 1).

Figure 1: Mean Concentration of D-Amphetamine and L-Amphetamine vs Time for ADZENYS XR-ODT (18.8 mg) and Mixed Salts of a Single-Entity Amphetamine Product Extended-Release Capsules (MAS ER 30 mg) in the Fasted State

The single dose pharmacokinetics of d-amphetamine under fed conditions are summarized (Table 6) from studies in healthy adults following an oral dose of 18.8 mg ADZENYS XR-ODT.

A single dose of ADZENYS XR-ODT 18.8 mg provided comparable plasma concentration profiles of both d-amphetamine and l-amphetamine to mixed salts of a single-entity amphetamine product extended-release capsules (MAS ER) 30 mg.

The mean elimination half-life for d-amphetamine is 11 hours in adults and 9-10 hours in pediatric patients aged 6 to 12 years. For l-amphetamine, the mean elimination half-life in adults is 14 hours and 10-11 hours in pediatric patients aged 6 to 12 years. Mean weight-normalized clearance values for d-amphetamine and l-amphetamine decreased slightly with an increase in age.

Food Effect

Food does not affect the extent of absorption of d-amphetamine and l-amphetamine but caused a 19% reduction in C_max. Food also prolonged the median t_max by approximately 2.0 hours for d-amphetamine and by 2.5 hours for l-amphetamine after administration of ADZENYS XR-ODT. These changes are not considered clinically significant.

Alcohol Effect

In an in vitro alcohol-induced dose dumping study, a substantial increase in amphetamine release occurred in the presence of 40% alcohol but not with 5%, 10% and 20% alcohol.

Elimination

Metabolism and Excretion

Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, due to the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made.

With normal urine pHs, approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30-40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9 .9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that effect urinary pH are known to alter the elimination of amphetamine, and any decrease in amphetamine's metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased [see Drug Interactions (7)].

Specific Populations

Comparison of the pharmacokinetics of d- and l-amphetamine after oral administration of MAS ER in pediatric patients (6-12 years) and adolescent (13-17 years) ADHD patients and healthy adult volunteers indicates that body weight is the primary determinant of apparent differences in the pharmacokinetics of d-and l-amphetamine across the age range. Systemic exposure measured by area under the curve to infinity (AUC_∞) and maximum plasma concentration (C_max) decreased with increases in body weight, while oral volume of distribution (V_Z/F), oral clearance (CL/F), and elimination half-life (t_1/2) increased with increases in body weight.

Pediatric Patients

The pharmacokinetics of ADZENYS XR-ODT in pediatric patients has been established based on the pharmacokinetics of MAS ER in pediatric patients. On a mg/kg weight basis, pediatric patients eliminate amphetamine faster than adults. The elimination half-life (t_1/2) is approximately 1 hour shorter for d-amphetamine and 2 hours shorter for l-amphetamine in pediatric patients than in adults. However, for a given dose of MAS ER, pediatric patients had higher systemic exposure to amphetamine (C_max and AUC) than adults which was attributed to the higher dose administered to pediatric patients on a mg/kg body weight basis compared to adults. Upon dose normalization on a mg/kg basis, pediatric patients showed 30% less systemic exposure compared to adults.

Gender

Systemic exposure to amphetamine was 20-30% higher in women (N=20) than in men (N=20) due to the higher dose administered to women on a mg/kg body weight basis. When the exposure parameters (C_max and AUC) were normalized by dose (mg/kg), these differences diminished. Age and gender had no direct effect on the pharmacokinetics of d- and l-amphetamine.

Race

Formal pharmacokinetic studies for race have not been conducted. However, amphetamine pharmacokinetics appeared to be comparable among Caucasians (N=33), Blacks (N=8) and Hispanics (N=10).

Carcinogenesis

No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose for children of 18.8 mg/day (as base), on a mg/m² body surface area basis.

Mutagenesis

Amphetamine, in the enantiomer ratio present in ADZENYS XR-ODT (d- to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d,l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays.

Amphetamine, in the enantiomer ratio present in ADZENYS XR-ODT (d- to l- ratio of 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day [approximately 8 times the maximum recommended human dose for adolescents of 12.5 mg/day (as base), on a mg/m² body surface area basis].

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.

How Supplied

ADZENYS XR-ODT 3.1 mg Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A1 on one side), carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets, NDC 70165-005-30

ADZENYS XR-ODT 6.3 mg Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A2 on one side), carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets, NDC 70165-010-30

ADZENYS XR-ODT 9.4 mg Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A3 on one side), carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets, NDC 70165-015-30

ADZENYS XR-ODT 12.5 mg Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A4 on one side), carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets, NDC 70165-020-30

ADZENYS XR-ODT 15.7 mg Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A5 on one side), carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets, NDC 70165-025-30

ADZENYS XR-ODT 18.8 mg Extended Release Orally Disintegrating Tablet: round, orange to light orange mottled (debossed A6 on one side), carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets, NDC 70165-030-30

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired ADZENYS XR-ODT at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix ADZENYS XR-ODT with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard ADZENYS XR-ODT in the household trash.

Controlled Substance Status/Potential for Abuse, Misuse, and Dependence

Advise patients that ADZENYS XR-ODT is a federally controlled substance because it can be abused or lead to dependence. Advise patients to store ADZENYS XR-ODT in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired ADZENYS XR-ODT by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

Dosage and Administration Instructions

Provide the following instructions on administration to the patient:

• 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.

Serious Cardiovascular Risks

Advise patients of serious cardiovascular risk (including sudden death, myocardial infarction, stroke, and hypertension) with ADZENYS XR-ODT. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)].

Blood Pressure and Heart Rate Increases

Instruct patients that ADZENYS XR-ODT can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)].

Psychiatric Risks

Advise patients that ADZENYS XR-ODT, at recommended doses, may cause psychotic symptoms or mania [see Warnings and Precautions (5.4)].

Long-Term Suppression of Growth

Advise patients that ADZENYS XR-ODT may cause slowing of growth and weight loss [see Warnings and Precautions (5.5)].

Circulation problems in Fingers and Toes [Peripheral vasculopathy, including Raynaud's phenomenon]

Instruct patients beginning treatment with ADZENYS XR-ODT about the risk of peripheral vasculopathy, including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.

Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.

Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking ADZENYS XR-ODT.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with concomitant use of ADZENYS XR-ODT and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see Contraindications (4), Warnings and Precautions (5.7) and Drug Interactions (7.1)]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Concomitant Medications

Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs because there is a potential for interactions [see Drug Interactions (7.1)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ADZENYS XR-ODT. Advise patients of the potential fetal effects from the use of ADZENYS XR-ODT during pregnancy [see Use in Specific Populations (8.1)].

Nursing

Advise patients not to breastfeed if they are taking ADZENYS XR-ODT [see Use in Specific Populations (8.3)].

Alcohol

Advise patients to avoid alcohol while taking ADZENYS XR-ODT. Consumption of alcohol while taking ADZENYS XR-ODT may result in a more rapid release of the dose of amphetamine [see Clinical Pharmacology (12)].

Manufactured for Neos Therapeutics Brands LLC., Grand Prairie, TX 75050. Made in USA.

For more information call 1-888-319-1789.

Pharmacist: Medication Guide to be dispensed to patients

ADZENYS XR-ODT is a registered trademark of Neos Therapeutics, Inc.

Copyright^© 2016, Neos Therapeutics, Inc.

Patent Number 8,709,491 B2

Rev. 02/2018
PIN020299

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)].

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)]

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).

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.

7.1 Drugs Having Clinically Important Interactions With Amphetamines

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.

Teratogenic Effects

Teratogenic Effects

Nonteratogenic Effects

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.

8.2 Labor And Delivery

The effect of ADZENYS XR-ODT on labor and delivery in humans is unknown.

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.

8.4 Pediatric Use

Safety and effectiveness have been established in pediatric patients with ADHD ages 6 to 17 years of age in three adequate and well-controlled clinical trials of up to 4 weeks in duration [see Adverse Reactions (6.1), Clinical Pharmacology (12), Clinical Studies (14)]. Safety and efficacy in pediatric patients younger than 6 years of age with ADHD have not been established.

8.5 Geriatric Use

ADZENYS XR-ODT has not been studied in the geriatric population.

9.1 Controlled Substance

ADZENYS XR-ODT contains amphetamine, which is a Schedule II controlled substance in the U.S. Controlled Substance Act (CSA).

9.2 Abuse

ADZENYS XR-ODT, is a CNS stimulant that contains amphetamine which has a high potential for abuse. Abuse is characterized by impaired control of drug use, compulsive use despite harm, and craving.

Signs and symptoms of amphetamine abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been observed. Abusers of amphetamines may use other unapproved routes of administration which can result in overdose and death [see Overdosage (10)].

To reduce the abuse of ADZENYS XR-ODT, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and proper storage and disposal of CNS stimulants, monitor for signs of abuse while on therapy, and re-evaluate the need for ADZENYS XR-ODT use.

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.

11. Description

ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.

The labeled strengths reflect the amount of amphetamine base in ADZENYS XR-ODT whereas the strengths of the (mixed salts of a single-entity amphetamine) products are in terms of the amount of amphetamine salts. Table 1 in Section 2.5 details the equivalent amounts of active ingredient in these products.

Structural Formula:

ADZENYS XR-ODT is an extended-release orally disintegrating tablet containing 50% immediate-release and 50% delayed-release amphetamine for once daily dosing.

ADZENYS XR-ODT also contains the following inactive ingredients: Mannitol, Crospovidone, Microcrystalline Cellulose, Methacrylic Acid, Sodium Polystyrene Sulfonate, Citric Acid, Fructose, Orange Flavor, Colloidal Silicon Dioxide, Triethyl Citrate, Sucralose, Lake Blend Orange, Magnesium Stearate, and Polyethylene Glycol.

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.

13.2 Animal Toxicology And/Or Pharmacology

Acute administration of high doses of amphetamine (d- or d, l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

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.

Storage And Handling

Storage

Store at 20°C to 25° C (68°F to 77° F). Excursions permitted to 15-30° C (59-86° F) [see USP Controlled Room Temperature]

Store ADZENYS XR-ODT blister packages in the rigid, plastic travel case provided after removal from the carton. To obtain additional travel cases, patients and health care professionals can call Neos Therapeutics, Inc., at 1-888-236-6816.

17. Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Spl Medguide

• sudden death in patients who have heart problems or heart defects
• sudden death, stroke and heart attack in adults
• increased blood pressure and heart rate

Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or a family history of these problems.

Your doctor should check you or your child carefully for heart problems before starting ADZENYS XR-ODT.

Your doctor should check you or your child's blood pressure and heart rate regularly during treatment with ADZENYS XR-ODT.

Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking ADZENYS XR-ODT.

All Patients

• new or worse behavior and thought problems
• new or worse bipolar illness
• new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms

Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.

Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking ADZENYS XR-ODT, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.

• fingers or toes may feel numb, cool, painful
• fingers or toes may change from pale, to blue, to red

Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes.

Call your doctor right away if you have or your child has any unexplained wounds appearing on fingers or toes while taking ADZENYS XR-ODT.

Principal Display Panel - 3.1 Mg Tablet Blister Pack Carton

NDC 70165-005-30

Contains:
30 Tablets (5 x 6-count blister cards)
Travel Case

Rx Only

Adzenys XR-ODT™CII
Amphetamine Extended-Release
Orally Disintegrating Tablets

Do not crush or chew tablets

Each tablet contains 3.1 mg of amphetamine
(equivalent to that in a 5 mg strength mixed salts
of a single-entity amphetamine product)

3.1 mg

NEOS™
Therapeutics

PHARMACIST: Dispense the enclosed Medication Guide to each patient.

Principal Display Panel - 6.3 Mg Tablet Blister Pack Carton

NDC 70165-010-30

Contains:
30 Tablets (5 x 6-count blister cards)
Travel Case

Rx Only

Adzenys XR-ODT™CII
Amphetamine Extended-Release
Orally Disintegrating Tablets

Do not crush or chew tablets

Each tablet contains 6.3 mg of amphetamine
(equivalent to that in a 10 mg strength mixed salts
of a single-entity amphetamine product)

6.3 mg

NEOS™
Therapeutics

PHARMACIST: Dispense the enclosed Medication Guide to each patient.

Principal Display Panel - 9.4 Mg Tablet Blister Pack Carton

NDC 70165-015-30

Contains:
30 Tablets (5 x 6-count blister cards)
Travel Case

Rx Only

Adzenys XR-ODT™CII
Amphetamine Extended-Release
Orally Disintegrating Tablets

Do not crush or chew tablets

Each tablet contains 9.4 mg of amphetamine
(equivalent to that in a 15 mg strength mixed salts
of a single-entity amphetamine product)

9.4 mg

NEOS™
Therapeutics

PHARMACIST: Dispense the enclosed Medication Guide to each patient.

Principal Display Panel - 12.5 Mg Tablet Blister Pack Carton

NDC 70165-020-30

Contains:
30 Tablets (5 x 6-count blister cards)
Travel Case

Rx Only

Adzenys XR-ODT™CII
Amphetamine Extended-Release
Orally Disintegrating Tablets

Do not crush or chew tablets

Each tablet contains 12.5 mg of amphetamine
(equivalent to that in a 20 mg strength mixed salts
of a single-entity amphetamine product)

12.5 mg

NEOS™
Therapeutics

PHARMACIST: Dispense the enclosed Medication Guide to each patient.

Principal Display Panel - 15.7 Mg Tablet Blister Pack Carton

NDC 70165-025-30

Contains:
30 Tablets (5 x 6-count blister cards)
Travel Case

Rx Only

Adzenys XR-ODT™CII
Amphetamine Extended-Release
Orally Disintegrating Tablets

Do not crush or chew tablets

Each tablet contains 15.7 mg of amphetamine
(equivalent to that in a 25 mg strength mixed salts
of a single-entity amphetamine product)

15.7 mg

NEOS™
Therapeutics

PHARMACIST: Dispense the enclosed Medication Guide to each patient.

Principal Display Panel - 18.8 Mg Tablet Blister Pack Carton

NDC 70165-030-30

Contains:
30 Tablets (5 x 6-count blister cards)
Travel Case

Rx Only

Adzenys XR-ODT™CII
Amphetamine Extended-Release
Orally Disintegrating Tablets

Do not crush or chew tablets

Each tablet contains 18.8 mg of amphetamine
(equivalent to that in a 30 mg strength mixed salts
of a single-entity amphetamine product)

18.8 mg

NEOS™
Therapeutics

PHARMACIST: Dispense the enclosed Medication Guide to each patient.