Adzenys Xr-odt Tablet, Orally Disintegrating
FDA Label NDC 70165-005

ADZENYS XR-ODT has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including ADZENYS XR-ODT, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Before prescribing ADZENYS XR-ODT, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout ADZENYS XR-ODT treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)].

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)].

Limitations of Use

The use of ADZENYS XR-ODT is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g. weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.5). Use in Specific Populations (8.4)].

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)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating ADZENYS XR-ODT [see Warnings and Precautions (5.9)].

ADZENYS XR-ODT may be taken orally with or without food. Individualize the dosage according to the therapeutic needs and response of the patient.

ADZENYS XR-ODT supplied in blister form 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.

ADZENYS XR-ODT supplied in bottle form should be taken as follows:

• The tablet should remain in the bottle until the patient is ready to take it.
• The patient or caregiver should use dry hands to open the bottle.

As soon as the bottle 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.

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)].

The recommended dose is ADZENYS XR-ODT 12.5 mg daily.

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 (5.9)].

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)].

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)

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].

ADZENYS XR-ODT has a high potential for abuse and misuse. The use of ADZENYS XR-ODT exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. ADZENYS XR-ODT can be diverted for nonmedical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including ADZENYS XR-ODT, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing ADZENYS XR-ODT, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store ADZENYS XR-ODT in a safe place, preferably locked, and instruct patients to not give ADZENYS XR-ODT to anyone else. Throughout ADZENYS XR-ODT treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.

Avoid ADZENYS XR-ODT use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases.

Monitor all ADZENYS XR-ODT-treated patients for potential tachycardia and hypertension.

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 Disorder

CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating ADZENYS XR-ODT 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 the recommended dosages, may cause psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients without prior history of psychotic illness or mania. 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% of placebo-treated patients. If such symptoms occur, conisder discontinuing ADZENYS XR-ODT.

Physical Dependence
ADZENYS XR-ODT may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including ADZENYS XR-ODT include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance
ADZENYS XR-ODT may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

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 3.1 mg extended-release orally disintegrating tablet: round, orange to light orange mottled (debossed A1 on one side), bottle containing 30 tablets each, for a total of 30 tablets, NDC 70165-005-31

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 6.3 mg extended-release orally disintegrating tablet: round, orange to light orange mottled (debossed A2 on one side), bottle containing 30 tablets each, for a total of 30 tablets, NDC 70165-010-31

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 9.4 mg extended-release orally disintegrating tablet: round, orange to light orange mottled (debossed A3 on one side), bottle containing 30 tablets each, for a total of 30 tablets, NDC 70165-015-31

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 12.5 mg extended-release orally disintegrating tablet: round, orange to light orange mottled (debossed A4 on one side), bottle containing 30 tablets each, for a total of 30 tablets, NDC 70165-020-31

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 15.7 mg extended-release orally disintegrating tablet: round, orange to light orange mottled (debossed A5 on one side), bottle containing 30 tablets each, for a total of 30 tablets, NDC 70165-025-31

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

ADZENYS XR-ODT 18.8 mg extended-release orally disintegrating tablet: round, orange to light orange mottled (debossed A6 on one side), bottle containing 30 tablets each, for a total of 30 tablets, NDC 70165-030-31

Abuse, Misuse, and Addiction

Educate patients and their families about the risks of abuse, misuse, and addiction of ADZENYS XR-ODT, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), Overdosage (10)]. Advise patients to store ADZENYS XR-ODT in a safe place, preferably locked, and instruct patients to not give ADZENYS XR-ODT to anyone else.

Risks to Patients with Serious Cardiac Disease

Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with ADZENYS XR-ODT use. 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)].

Dosage and Administration Instructions

Provide the following instructions on administration to the patient in the blister packaging:

• 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.

Provide the following instructions on administration to the patient in the bottle packaging form:

• The tablet should remain in the bottle until the patient is ready to take it.
• The tablet should be taken immediately after removing it from bottle. It should not be stored for future use.
• The patient or caregiver should use dry hands to open the bottle.
• As soon as the tablet is removed from the bottle, 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.

Increased Blood Pressure and Heart Rate

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

Psychiatric Adverse Reactions

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

Motor and Verbal Tics, and Worsening of Tourette’s Syndrome
Advise patients that motor and verbal tics and worsening of Tourette’s syndrome may occur during treatment with ADZENYS XR-ODT. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.8)].

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 that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADZENYS XR-ODT during 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. [seeUse in Specific Populations (8.1) ] .

Lactation

Advise patients not to breastfeed if they are taking ADZENYS XR-ODT [see Use in Specific Populations (8.2)].

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., Denver, CO 80237. Made in USA.

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

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

Copyright ^© 2017, Neos Therapeutics, Inc.

Patent Number 8,709,491 B2

ADZENYS XR-ODT is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Population (8.4)].

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in ADZENYS XR-ODT-treated pediatric patients treated with CNS stimulants.

Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted.

CNS 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, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulants.

Careful observation for digital changes is necessary during ADZENYS XR-ODT-treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for ADZENYS XRODT-treated patients who develop signs or symptoms of peripheral vasculopathy.

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.

CNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating ADZENYS XR-ODT, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor ADZENYS XR-ODT-treated patients for the emergence or worsening of tics or Tourette’s syndrome and discontinue treatment if clinically appropriate.

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)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Abuse, Misuse, and Addiction [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)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Long-Term Suppression of Growth in Pediatric Patients [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)]
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome [ see Warnings and Precautions ( 5.8) ]

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).

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, paresthesia (including formication), motor and verbal tics.

Eye Disorders: Vision blurred, mydriasis.

Gastrointestinal: Unpleasant taste, constipation, intestinal ischemia, 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.

Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors outcomes in women exposed to ADHD medications, including ADZENYS XR-ODT, during pregnancy. Healthcare providers are encouraged to advise patients to register by contacting the National Pregnancy Registry for ADHD Medication at 1-866-961-2388 or online at www.womensmentalhealth.org/pregnancyregistry.

Risk Summary

Available data from epidemiologic studies and postmarketing reports on the use of amphetamine in pregnant women over decades of use have not identified a drug-associated risk of major birth defects or miscarriage. Neonates exposed to amphetamine in utero are at risk for withdrawal symptoms following delivery. Adverse pregnancy outcomes including premature delivery and low birth weight have been seen in infants born to mothers taking amphetamines during pregnancy (see Clinical Considerations).

No apparent effects on morphological development were observed in embryo-fetal development studies, with oral administration of amphetamine to rats and rabbits during organogenesis. However, in a pre- and post-natal development study, amphetamine (d- to l- ratio of 3:1) administered orally to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Amphetamines, such as ADZENYS XR-ODT, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions, increasing the risk of premature delivery. Infants born to mothers taking amphetamines during pregnancy have an increased risk of premature delivery and low birth weight.

Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.

Data

Animal Data

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.

Risk Summary

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. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of amphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, advise patients that breastfeeding is not recommended during treatment with ADZENYS XR-ODT.

The 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)].

The safety and efficacy of ADZENYS XR-ODT in pediatric patients less than 6 years have not been established.

In studies evaluating extended-release amphetamine products, patients 4 to <6 years of age had higher systemic amphetamine exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss.

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

ADZENYS XR-ODT contains amphetamine, a Schedule II controlled substance.

ADZENYS XR-ODT has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. ADZENYS XR-ODT can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of amphetamine may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including ADZENYS XRODT, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Clinical Effects of Overdose
Overdose of CNS stimulants is characterized by the following sympathomimetic effects:

• Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.

• CNS effects including psychomotor agitation, confusion, and hallucination. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur.
• Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.

Overdose Management
Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of ADZENYS XR-ODT should be considered when treating patients with overdose. Damphetamine is not dialyzable. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

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:

Structural Formula (Adzenys Xr Odt 1)

C ₉H ₁₃N MW 135.21

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 3350.

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.

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.

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

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 bottle packaging in a cool, dry place 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.

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

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.

Adzenys Xr-odt 3.1 mg (Adzenys Xr Odt 3)

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.

Adzenys Xr-odt 6.3 mg (Adzenys Xr Odt 4)

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.

Adzenys Xr-odt 9.4 mg (Adzenys Xr Odt 5)

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.

Adzenys Xr-odt 12.5 mg (Adzenys Xr Odt 6)

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.

Adzenys Xr-odt 15.7 mg (Adzenys Xr Odt 7)

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.

Adzenys Xr-odt 18.8 mg (Adzenys Xr Odt 8)

NDC 70165-005-31

Contains:

30 Tablets (1 x 30-count bottle)

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.

3.1 mg Tablet Bottle (Adzenys Xr Odt 9)

NDC 70165-010-31

Contains:

30 Tablets (1 x 30-count bottle)

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.

6.3 mg Tablet Bottle (Adzenys Xr Odt 10)

NDC 70165-015-31

Contains:

30 Tablets (1 x 30-count bottle)

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.

9.4 mg Tablet Bottle (Adzenys Xr Odt 11)

NDC 70165-020-31

Contains:

30 Tablets (1 x 30-count bottle)

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.

12.5 mg Tablet Bottle (Adzenys Xr Odt 12)

NDC 70165-025-31

Contains:

30 Tablets (1 x 30-count bottle)

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.

15.7 mg Tablet Bottle (Adzenys Xr Odt 13)

NDC 70165-030-31

Contains:

30 Tablets (1 x 30-count bottle)

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.

18.8 mg Tablet Bottle (Adzenys Xr Odt 14)