Adzenys Drug Information

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. 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 Study Included 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 Study Included 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%

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, 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.

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. 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) . 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. Acidifying Agents Clinical Impact Lower blood levels and efficacy of amphetamines. Intervention Increase dose based on clinical response.

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.

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.

Pregnancy 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.

Pediatric Use 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. 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. 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. 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/m 2 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.

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. 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. Known hypersensitivity to amphetamine products or other ingredients in ADZENYS XR-ODT. Use of monoamine oxidase inhibitor (MAOI) or within 14 days of the last MAOI dose.

• 10. OVERDOSAGE 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 104ºF) 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.