Dyanavel XR

1 INDICATIONS AND USAGE DYANAVEL XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older . Limitations of Use The use of DYANAVEL XR 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 . DYANAVEL XR is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older Limitations of Use The use of DYANAVEL XR 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 ( 5.5 , 8.4 ).

Recommended starting dosage is 2.5 mg or 5 mg once daily in the morning Dosage may be increased in increments of 2.5 mg to 10 mg per day every 4 to 7 days up to a maximum daily dose of 20 mg May be taken with or without food Extended-release oral suspension: Shake bottle before administering Extended-release tablets: May be chewed or swallowed whole DYANAVEL XR oral suspension can be substituted with DYANAVEL XR tablets on a milligram per milligram basis Do not substitute for other amphetamine products on a milligram-per-milligram basis, because of different amphetamine salt compositions and differing pharmacokinetic profiles

2.1Pretreatment Screening Prior to

treating patients with DYANAVEL XR, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating DYANAVEL XR .

2.2Recommended Dosage The

recommended starting dosage is 2.5 mg or 5 mg once daily in the morning. The dosage may be increased in increments of 2.5 mg to 10 mg per day every 4 to 7 days based on clinical response. The maximum recommended dosage is 20 mg once daily.

2.3Administration Information Administer

DYANAVEL XR orally once daily in the morning with or without food. DYANAVEL XR Extended-Release Oral Suspension Instruct patients to read the “Instructions for Use” for complete administration instructions. Ensure that the bottle adapter is firmly inserted into the bottle and do not remove once inserted.

Shake the bottle of DYANAVEL XR extended-release oral suspension well before every administration. Use with the oral dosing dispenser provided by the pharmacist. DYANAVEL XR Extended-Release Tablets May be chewed or swallowed whole . The 5 mg extended-release tablet is functionally scored and may be divided into equal halves (2.5 mg) at the score line.

2.4Switching from Other Amphetamine Products

DYANAVEL XR extended-release oral suspension can be substituted with DYANAVEL XR extended-release tablets on a milligram-per-milligram basis . If switching from other amphetamine products, discontinue that treatment, and titrate with DYANAVEL XR using the above titration schedule. Do not substitute for other amphetamine products on a milligram-per-milligram basis, because of different amphetamine salt compositions and differing pharmacokinetic profiles .

2.5Dosage 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 DYANAVEL XR dosage accordingly .

Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. Psychiatric Adverse Reactions: Prior to initiating DYANAVEL XR, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing DYANAVEL XR Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted Peripheral Vasculopathy, including Raynaud’s phenomenon: Careful observation for digital changes is necessary during DYANAVEL XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy Serotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue DYANAVEL XR and initiate supportive treatment. Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating DYANAVEL XR, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate.

5.1Abuse, Misuse, and Addiction

DYANAVEL XR has a high potential for abuse and misuse. The use of DYANAVEL XR exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. DYANAVEL XR can be diverted for non-medical use into illicit channels or distribution . Misuse and abuse of CNS stimulants, including DYANAVEL XR, can result in overdose and death , and this risk is increased with higher doses and or unapproved methods of administration, such as snorting or injection.

Before prescribing DYANAVEL XR, 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 DYANAVEL XR in a safe place, preferably locked, and instruct patients to not give DYANAVEL XR to anyone else.

Throughout DYANAVEL XR treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2Risks for Patients with Serious Cardiac Disease

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

5.3Increased Blood Pressure and Heart Rate

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). Monitor all DYANAVEL XR-treated patients for potential tachycardia and hypertension.

5.4Psychiatric Adverse Reactions Exacerbation of Pre-existing

Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disease CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating DYANAVEL XR treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, 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 approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing DYANAVEL XR.

5.5Long-Term Suppression of Growth in Pediatric Patients

DYANAVEL XR is not approved for use and is not recommended in pediatric patients below 6 years of age . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in DYANAVEL XR-treated pediatric patients treated with CNS stimulants. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.6Peripheral Vasculopathy,

including Raynaud's Phenomenon CNS stimulants, including DYANAVEL XR, 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 stimulant. Careful observation for digital changes is necessary during DYANAVEL XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for DYANAVEL XR-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.7Serotonin 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 . The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to DYANAVEL XR. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 . 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 DYANAVEL XR with MAOI drugs is contraindicated . Discontinue treatment with DYANAVEL XR and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment.

If concomitant use of DYANAVEL XR with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate DYANAVEL XR 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.

5.8Motor and Verbal Tics, and Worsening of Tourette’s

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

4 CONTRAINDICATIONS DYANAVEL XR is contraindicated: In patients known to be hypersensitive to amphetamine, or other components of DYANAVEL XR. 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 as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis . Known hypersensitivity to amphetamine products or other ingredients in DYANAVEL XR Use of monoamine oxidase inhibitor (MAOI) or within 14 days of the last MAOI dose ( 4 , 7.1 )

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DYANAVEL XR during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/. Risk Summary There are limited published data on the use of amphetamines in pregnant women. These data are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage.

Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines. No effects on morphological development were observed in embryo-fetal development studies with oral administration of amphetamine to rats and rabbits during organogenesis at doses that are approximately 3 and 16 times, respectively, the maximum recommended human dose (MRHD) of 20 mg/day (as base equivalents) on a mg/m 2 basis, given to adults. However, long-term neurochemical and behavioral effects have been reported in published animal developmental studies using clinically relevant doses of amphetamine . 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 DYANAVEL XR, 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. Data Animal Data Amphetamine ( d - to l - enantiomer 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 3 and 16 times, respectively, the MRHD of 20 mg/day (as base equivalents) on a mg/m 2 basis, given to adults.

Fetal malformations and death have been reported in mice following parenteral administration of d -amphetamine doses of 50 mg/kg/day (approximately 12 times the MRHD) given to adults on a mg/m 2 basis or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity. 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.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Abuse, Misuse, and Addiction Hypersensitivity to amphetamine, or other components of DYANAVEL XR Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors Risks to Patients with Serious Cardiac Disease Increased Blood Pressure and Heart Rate Psychiatric Adverse Reactions Long-Term Suppression of Growth in Pediatric Patients Peripheral Vasculopathy, including Raynaud's phenomenon Serotonin Syndrome Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Most common adverse reactions observed with amphetamine products: dry mouth, anorexia, weight loss, abdominal pain, nausea, insomnia, restlessness, emotional lability, dizziness, tachycardia To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc. at 1-732-940-0358 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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. Adverse Reactions in Studies with Other Amphetamine Products in Pediatric Patients and Adults with ADHD Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.

Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea. Eye Disorders: Vision blurred, mydriasis. Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances.

Anorexia and weight loss may occur as undesirable effects. 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, changes in libido.

Skin: Alopecia. Adverse Reactions in Studies with DYANAVEL XR in Pediatric Patients with ADHD There is limited experience with DYANAVEL XR in controlled trials. Based on this limited experience, the adverse reaction profile of DYANAVEL XR appears similar to other amphetamine extended-release products.

The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted with DYANAVEL XR extended-release oral suspension in 108 patients with ADHD (aged 6 to 12 years) were: epistaxis, allergic rhinitis, and upper abdominal pain. Table 1. Common Adverse Reactions Occurring in ≥2% of Patients on DYANAVEL XR Extended-Release Oral Suspension and Greater than Placebo During the Double Blind Phase.

Preferred Term DYANAVEL XR (N=52) Placebo (N=48) Respiratory, thoracic and mediastinal disorders Epistaxis 3.8% 0% Rhinitis allergic 3.8% 0% Gastrointestinal disorders Abdominal pain upper 3.8% 2.1%

6.2Postmarketing Experience The

following adverse reactions have been identified during post approval use of other amphetamine products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic : urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis.

Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported 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), motor and verbal tics Endocrine : impotence, changes in libido, frequent or prolonged erections Eye Disorders : vision blurred, mydriasis Gastrointestinal : unpleasant taste, constipation, intestinal ischemia, and other gastrointestinal disturbances Musculoskeletal, Connective Tissue, and Bone Disorders : rhabdomyolysis Psychiatric Disorders : dermatillomania, bruxism Skin : alopecia Vascular Disorders : Raynaud’s phenomenon