Contents

DYANAVEL XR (amphetamine) extended-release CII

DYANAVEL XR (amphetamine) extended-release oral suspension and DYANAVEL XR (amphetamine) extended-release tablets contain amphetamine, a CNS stimulant, in a 3.2:1 ratio of d– to l– amphetamine.

There are three active ingredients: amphetamine (complexed with sodium polystyrene sulfonate), dextroamphetamine sulfate and amphetamine aspartate. The dosage strengths are expressed in terms of amphetamine base.

DYANAVEL XR contains both immediate-release and extended-release components.

Active Ingredients:

DYANAVEL XR extended-release oral suspension 2.5 mg/mL:

Each 1 mL contains 2 mg of amphetamine (in a 3.2 to 1 ratio of d– to l-amphetamine complexed with sodium polystyrene sulfonate), and 0.5 mg amphetamine (present as 0.5 mg of amphetamine aspartate and 0.3 mg of dextroamphetamine sulfate).

DYANAVEL XR extended-release tablets:

Each 5 mg strength tablet contains 4 mg of amphetamine (in a 3.2 to 1 ratio of d- to lamphetamine complexed with sodium polystyrene sulfonate), and 1 mg of amphetamine (present as 1 mg of amphetamine aspartate and 0.7 mg of dextroamphetamine sulfate).
Each 10 mg strength tablet contains 8 mg of amphetamine (in a 3.2 to 1 ratio of d– to lamphetamine complexed with sodium polystyrene sulfonate), and 2 mg of amphetamine (present as 2 mg amphetamine aspartate and 1.4 mg dextroamphetamine sulfate).
Each 15 mg strength tablet contains 12 mg of amphetamine (in a 3.2 to 1 ratio of d– to lamphetamine complexed with sodium polystyrene sulfonate), and 3 mg of amphetamine (present as 3 mg amphetamine aspartate and 2 mg dextroamphetamine sulfate).
Each 20 mg strength tablet contains 16 mg of amphetamine (in a 3.2 to 1 ratio of d– to lamphetamine complexed with sodium polystyrene sulfonate), and 4 mg of amphetamine (present as 4 mg amphetamine aspartate and 2.7 mg dextroamphetamine sulfate).

DYANAVEL XR extended-release oral suspension and DYANAVEL XR extended-release tablets are intended for oral administration.

INDICATIONS AND USAGE

DYANAVELXR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older.

Mechanism of Action

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known.

DOSAGE AND ADMINISTRATION

Prior to initiating treatment 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)

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 DYANAVEL XR use

Recommended 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.

Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-evaluate the long-term use of DYANAVEL XR, and adjust dosage as needed.

Administration 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.

Switching from Other Amphetamine Products

DYANAVEL XR extended-release oral suspension can be substituted with DYANAVEL XR extendedrelease 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-permilligram basis, because of different amphetamine salt compositions and differing pharmacokinetic profiles.

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 DYANAVEL XR dosage accordingly.

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

WARNINGS AND PRECAUTIONS

Potential for Abuse and Dependence: CNS stimulants, including DYANAVEL XR, other amphetamine-containing products, andmethylphenidate, have a high potential for abuse and dependence. Assess the risk of abuse prior toprescribing, and monitor for signs of abuse and dependence while on therapy

Serious Cardiovascular Reactions: Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulanttreatment at recommended doses. Sudden death has been reported in pediatric patients with structuralcardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses forADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heartarrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients whodevelop exertional chest pain, unexplained syncope, or arrhythmias during DYANAVEL XR treatment.

Blood Pressure and Heart Rate Increases: 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 patients for potential tachycardia and hypertension.

Psychiatric Adverse Reactions: Exacerbation of Preexisting Psychosis. CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

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, includingDYANAVEL XR. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Peripheral Vasculopathy, including Raynaud’s Phenomenon: 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, veryrare 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 attherapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generallyimprove after reduction in dose or discontinuation of drug. Careful observation for digital changes isnecessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral)may be appropriate for certain patients.

Serotonin Syndrome: Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used incombination with other drugs that affect the serotonergic neurotransmitter systems such as monoamineoxidase 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.

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.

DRUG INTERACTIONS

MAO Inhibitors (MAOI): MAOI antidepressants slow amphetamine metabolism, increasing amphetamineseffect 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.

Do not administer DYANAVEL XR concomitantly or within 14 days following administration of MAOI.

Serotonergic Drugs: The concomitant use of DYANAVEL XR and serotonergic drugs increases the risk ofserotonin syndrome.

Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during DYANAVEL XR initiation or dosage increase. If serotonin syndrome occurs, discontinue DYANAVEL XR and the concomitant serotonergic drug(s).

CYP2D6 Inhibitors: The concomitant use of DYANAVEL XR and CYP2D6 inhibitors may increase the exposure of DYANAVEL XR compared to the use of the drug alone and increase the risk of serotonin syndrome.

Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during DYANAVEL XR initiation and after a dosage increase. If serotonin syndrome occurs, discontinue DYANAVEL XR and the CYP2D6 inhibitor

Alkalinizing Agents (Urinary and Gastrointestinal): Increase blood levels and potentiate the action of amphetamine.

Co-administration of DYANAVEL XR and gastrointestinal or urinary alkalinizing agents should be avoided.

Acidifying Agents (Urinary and Gastrointestinal): Lower blood levels and efficacy of amphetamines.

Increase dose based on clinical response.

Tricyclic Antidepressants: 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.

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.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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/m2 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.

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.

Lactation: 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 ratioranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant and noeffects on milk production. However, long term neurodevelopmental effects on infants from stimulantexposure are unknown. Because of the potential for serious adverse reactions in a breastfed infant,advise patients that breastfeeding is not recommended during treatment with DYANAVEL XR.

Pediatric Use

Safety and effectiveness have been established in pediatric patients with ADHD ages 6 to 17 years. Safety and efficacy in pediatric patients younger than 6 years with ADHD have not been established.

Long-Term Growth Suppression: Growth should be monitored during treatment with stimulants, including DYANAVEL XR, and pediatricpatients who are not growing or gaining weight as expected may need to have their treatment interrupted.

Geriatric Use: DYANAVEL XR has not been studied in the geriatric population.

DRUG ABUSE AND DEPENDENCE

Controlled Substance: DYANAVEL XR contains amphetamine, a Schedule II controlled substance.

Abuse: DYANAVELXR, is a CNS stimulant that contains amphetamine which has a high potential for abuse.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. 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 higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking DYANAVELXR as prescribed.

Tolerance: Tolerance is a physiological state characterized by a reduced response to a drug after repeatedadministration (i.e., a higher dose of a drug is required to produce the same effect that was once obtainedat a lower dose). Tolerance may occur during the chronic therapy of CNS stimulants including DYANAVEL XR.

Dependence: Physical dependence is a state that develops as a result of physiological adaptation in response torepeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation, asignificant dose reduction of a drug, or administration of an antagonist and may occur in patients treatedwith CNS stimulants including DYANAVEL XR. Withdrawal symptoms after abrupt cessation followingprolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid,unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation oragitation.

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.

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DYANAVEL XR (amphetamine) extended-release CII

DYANAVEL XR (amphetamine) extended-release CII