The following Structured Product Label (SPL) was submitted to the FDA by Nextwave Pharmaceuticals, Inc for the product Dyanavel Xr (NDC 24478-110). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding warning: abuse and dependence, 1 indications and usage, 2.1 important information prior to initiating treatment, 2.2 recommended dosage, 2.3 administration information, 2.4 switching from other amphetamine products, 2.5 dosage modifications due to drug interactions, 3 dosage forms and strengths, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
CNS stimulants, including DYANAVEL XR, other amphetamine-containing products, and methylphenidate, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].
DYANAVEL XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies (14)].
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) [see Warnings and Precautions (5.2)].
Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for DYANAVEL XR use [see Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)].
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.
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.
DYANAVEL XR Extended-Release Tablets
DYANAVEL XR extended-release oral suspension can be substituted with DYANAVEL XR extended-release tablets on a milligram-per-milligram basis [see Clinical Pharmacology (12.3)].
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 [see Description (11), Clinical Pharmacology (12.3)].
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 [see Drug Interactions (7.1)].
DYANAVEL XR (amphetamine) extended-release oral suspension:
DYANAVEL XR (amphetamine) extended-release tablets:
All strengths are expressed in terms of amphetamine base equivalents.
DYANAVEL XR is contraindicated:
CNS stimulants, including DYANAVEL XR, other amphetamine-containing products, and methylphenidate, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning, Drug Abuse and Dependence (9.2, 9.3)].
Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during DYANAVEL XR treatment.
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.
Exacerbation of Preexisting Psychosis
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.
Induction of a Manic Episode in Patients with Bipolar Illness
CNS stimulants may induce a mixed or manic episode in patients with bipolar disorder. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).
New Psychotic or Manic Symptoms
CNS stimulants, at recommended doses, may cause psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients without prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing DYANAVEL XR. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated patients compared to 0% in placebo-treated patients.
CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including DYANAVEL XR.
Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted [see Use in Specific Populations (8.4)].
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, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
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 DYANAVEL XR. 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 DYANAVEL XR with MAOI drugs is contraindicated [see Contraindications (4)].
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.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Drug Dependence [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
Hypersensitivity to amphetamine, or other components of DYANAVEL XR [see Contraindications (4)]
Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
Serious Cardiovascular Reactions [see Warnings and Precautions (5.2)]
Blood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3)]
Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
Long-Term Suppression of Growth [see Warnings and Precautions (5.5)]
Peripheral Vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions (5.6)]
Serotonin Syndrome [see Warnings and Precautions (5.7)]
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.
Clinical Trials Experience 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.
Clinical Trials Experience 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% |
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)
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
Table 2. 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 DYANAVEL XR concomitantly or within 14 days following administration of MAOI [see Contraindications (4) and Warnings and Precautions (5.7)]. |
| Serotonergic Drugs | |
| Clinical Impact | The concomitant use of DYANAVEL XR 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 DYANAVEL XR initiation or dosage increase. If serotonin syndrome occurs, discontinue DYANAVEL XR and the concomitant serotonergic drug(s) [see Warnings and Precautions (5.7)]. |
| CYP2D6 Inhibitors | |
| Clinical Impact | 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. |
| Intervention | 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 [see Warnings and Precautions (5.7), Overdosage (10)]. |
| Alkalinizing Agents (Urinary and Gastrointestinal) | |
| Clinical Impact | Increase blood levels and potentiate the action of amphetamine. |
| Intervention | Co-administration of DYANAVEL XR and gastrointestinal or urinary alkalinizing agents should be avoided. |
| Acidifying Agents (Urinary and Gastrointestinal) | |
| 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. |
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 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/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 [see Data]. 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.
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/m2 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/m2 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.
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 and no effects on milk production. However, long term neurodevelopmental effects on infants from stimulant exposure are unknown. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with DYANAVEL XR.
Safety and effectiveness have been established in pediatric patients with ADHD ages 6 to 17 years [see Adverse Reactions (6.1), Clinical Pharmacology (12), and Clinical Studies (14)]. 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 pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.5)].
DYANAVEL XR has not been studied in the geriatric population.
DYANAVEL XR contains amphetamine, a Schedule II controlled substance.
DYANAVEL XR, 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 DYANAVEL XR as prescribed.
Signs and symptoms of amphetamine abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been observed. Individuals who abuse amphetamines may use unapproved routes of administration which can result in overdose and death [see Overdosage (10)].
To reduce the abuse of DYANAVEL XR, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants, monitor for signs of abuse while on therapy, and re-evaluate the need for DYANAVEL XR use.
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). 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 to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation, a significant dose reduction of a drug, or administration of an antagonist and may occur in patients treated with CNS stimulants including DYANAVEL XR. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
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.
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.
Structural Formula:
Dxr Chem Draw Structure (Dyanavel Xr Oral Suspension And Tablets 1)
C9H13N MW 135.21
Active Ingredients:
DYANAVEL XR extended-release oral suspension 2.5 mg/mL:
DYANAVEL XR extended-release tablets:
DYANAVEL XR extended-release oral suspension and DYANAVEL XR extended-release tablets are intended for oral administration.
Inactive Ingredients:
DYANAVEL XR extended-release oral suspension: anhydrous citric acid, bubblegum flavor, glycerin, methylparaben, modified starch, polysorbate 80, povidone, polyvinyl acetate, propylparaben, sodium lauryl sulfate, sodium polystyrene sulfonate, sucralose, triacetin and xanthan gum.
DYANAVEL XR extended-release tablets: bubblegum flavor, crospovidone, guar gum, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl acetate, povidone, silicon dioxide, sodium polystyrene sulfonate, sucralose, talc, triacetin and xanthan gum.
Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known.
Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.
Absorption
Extended-Release Oral Suspension
Following a single 18.8 mg dose of DYANAVEL XR extended-release oral suspension in 29 healthy adult subjects under fasting conditions in a crossover study, the median (range) time to peak plasma concentrations (Tmax) for both d- and l- isomers of amphetamine were 4 (2 to 7) hours after dosing. Peak concentrations (Cmax) of d- and l-amphetamine were 102% and 106%, respectively, of the Cmax of immediate-release (IR) mixed amphetamine salts (MAS) tablets. The relative bioavailability of DYANAVEL XR compared with an equal dose of IR MAS tablets is 106% for d- and 111% for l-amphetamine.
Following a single 18.8 mg dose of DYANAVEL XR extended-release oral suspension in 28 healthy adult subjects in a crossover study under fasting conditions, the median (range) time to peak plasma concentrations (Tmax) were about 4 (2 to 7) hours and 5 (3 to 7) hours for d- and l-amphetamine, respectively. Peak concentration (Cmax) was 93% and 94%, respectively, of the Cmax of extended release (ER) MAS capsules. The relative bioavailability of DYANAVEL XR compared with an equal dose of ER MAS capsules is 94% for both d- and l-amphetamine.
Figure 1. Mean d- and l-Amphetamine Plasma Concentration-Time Profile Following Administration of a Single Dose (18.8 mg amphetamine base) of DYANAVEL XR Extended-Release Oral Suspension and MAS ER Under Fasting Conditions
Figure1 (Dyanavel Xr Oral Suspension And Tablets 2) 
Extended-Release Tablet
Following a single 20 mg dose of DYANAVEL XR extended-release tablets (swallowed whole) to 36 healthy adults under fasted conditions in a crossover study, the median (range) time to peak plasma concentration (Tmax) for both d- and l-amphetamine, were 5.0 (2 to 9) hours after dosing. Peak concentrations (Cmax) for both d- and l-amphetamine, were 101% of the Cmax of DYANAVEL XR oral suspension. The relative bioavailability of DYANAVEL XR tablets compared with an equal dose of DYANAVEL XR oral suspension, for d- and l-amphetamine, were 105% and 106%, respectively.
Dyanavel XR extended-release tablets chewed or swallowed whole under fasted conditions did not significantly affect exposure and Tmax.
Figure 2. Mean Plasma d-and l-Amphetamine Concentration-Time Profiles for DYANAVEL XR Extended-Release Tablet and DYANAVEL XR Extended-Release Oral Suspension
Figure2 (Dyanavel Xr Oral Suspension And Tablets 3) 
Effect of Food
Extended-Release Oral Suspension
Ingestion of 18.8 mg of DYANAVEL XR extended-release oral suspension with a high-fat meal increased the average Cmax of both isomers of DYANAVEL XR by about 2%, decreased the AUC of d- and l-amphetamine by 5.7% and 7.4%, respectively. A delay of Tmax by approximately 1 hour was observed for both isomers.
Extended-Release Tablet
Ingestion of 20 mg DYANAVEL XR extended-release tablets with a high-fat meal decreased the average Cmax of both isomers of amphetamine by about 3%, decreased AUC of d- and l-amphetamine by about 4.0% and 7.3%, respectively. Median Tmax was not delayed for either isomer.
Elimination
The mean plasma terminal elimination half-lives of d- and l-amphetamine were 12.4 hours and 15.1 hours, respectively, following a single 18.8 mg dose of DYANAVEL XR extended-release oral suspension.
The mean plasma terminal elimination half-lives of d- and l-amphetamine were 13.5 hours and 17.3 hours, respectively, following a single 20 mg dose of DYANAVEL XR extended-release tablets.
Metabolism
Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4‑hydroxyamphetamine, or on the side chain A or B carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Because CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.
Excretion
With normal urine pH, approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose is recoverable in urine as amphetamine itself.
Specific Populations
Pediatric Patients
Following a single 10 mg dose of DYANAVEL XR extended-release oral suspension in pediatric subjects with ADHD (aged 6 to 12 years) under fasting conditions, peak plasma concentrations of d-and l-amphetamine occurred at a median time of 3.9 and 4.5 hours after dosing, respectively. The mean plasma terminal elimination half-lives of d- and l-amphetamine were 10.4 hours and 12.1 hours, respectively.
Patients with Hepatic or Renal Impairment
No specific studies have been conducted to evaluate the effect of renal impairment or hepatic impairment on the PK after DYANAVEL XR administration. However, urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunctions have the potential to inhibit the elimination of amphetamine and result in prolonged exposures.
Drug Interaction Studies
CYP Enzymes
In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, because of the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made.
Urine pH Modulators
Because amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pH results in less ionization and reduced renal elimination; acidic pH and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. In addition, any decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased [see Drug Interactions (7.1)].
Alcohol Effect
There is no in vivo study conducted for the effect of alcohol on drug exposure. An in vitro dissolution study on DYANAVEL XR extended-release oral suspension showed alcohol-induced dose dumping potential in the presence of 40% alcohol. A similar study on the DYANAVEL XR extended-release tablets showed no alcohol-induced dose dumping in the presence of 40% alcohol. Dose dumping was not observed in the presence of 5%, 10%, or 20% alcohol concentrations for either product.
Carcinogenesis
No evidence of carcinogenicity was found in studies in which d, l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 7, 5, and 2 times, respectively, the maximum recommended human dose of 20- mg/day (as base equivalents) given to adults, on a mg/m2 basis.
Mutagenesis
Amphetamine, in the enantiomer ratio (d- to l- ratio of approximately 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d, l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays.
Impairment of Fertility
Amphetamine, in the enantiomer ratio (d- to l- ratio of approximately 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day [approximately 10 times the maximum recommended human dose of 20 mg/day (as base equivalents) given to adults on a mg/m2 basis].
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 efficacy of DYANAVEL XR extended-release oral suspension was evaluated in a laboratory classroom study conducted in 108 pediatric patients (aged 6 to 12 years) with ADHD. The study began with an open-label dose optimization period (5 weeks) with an initial DYANAVEL XR dose of 2.5 or 5 mg once daily in the morning. The dose could be titrated weekly in increments of 2.5 to 10 mg until an optimal dose or the maximum dose of 20 mg/day was reached. Subjects then entered a 1-week randomized, double-blind treatment with the individually optimized dose of DYANAVEL XR or placebo. At the end of the week, school teachers and raters evaluated the attention and behavior of the subjects in a laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale. SKAMP is a 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting. Each item is rated on a 7-point impairment scale.
The primary efficacy endpoint was change from pre-dose in the SKAMP-Combined score at 4 hours post-dosing. The key secondary efficacy parameters were onset and duration of clinical effect. The change scores from pre-dose SKAMP-Combined scores at post-dose time points (1, 2, 4, 6, 8, 10, 12 and 13 hours) were used to evaluate the key secondary efficacy parameters. Results from the double-blind, placebo-controlled week of the study are summarized in Table 3 and Figure 3.
SKAMP-Combined change scores from pre-dose demonstrated a statistically significant improvement at all time points (1, 2, 4, 6, 8, 10, 12, 13 hours) post-dosing with DYANAVEL XR compared to placebo.
Table 3. Summary of Primary Efficacy Results in Pediatric Patients (6 to 12 years) with ADHD
| Study Number | Treatment Group | Primary Efficacy Measure: SKAMP-Combined Score | ||
| Mean Pre-dose Score (SD) | LS Mean Change from Pre-Dose at 4 Hours Post-Dosing (SE) | Placebo-subtracted Difference a (95% CI) | ||
| Study 1 | DYANAVEL XR Extended-Release Oral Suspension | 17.3 (8.88) | -8.8 (1.14) | -14.8 (-17.9, -11.6) |
| Placebo | 15.5 (7.35) | 6.0 (1.19) | -- | |
| SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a Difference (drug minus placebo) in least-squares mean change from pre-dose. | ||||
Figure 3. LS Mean Change from Pre-dose in SKAMP-Combined Score after Treatment with DYANAVEL XR Extended-Release Oral Suspension or Placebo in Pediatric Patients (6 to 12 years) with ADHD
Figure3 (Dyanavel Xr Oral Suspension And Tablets 4)
How Supplied
DYANAVEL XR (amphetamine) extended-release oral suspension: The concentration is 2.5 mg/mL amphetamine base equivalents and is supplied as light beige to tan viscous suspension with bubblegum flavor in bottles of 464 mL (NDC 24478-102-01).
The product is provided in a carton. Each carton also contains four oral dispensers and four bottle adapters.
DYANAVEL XR (amphetamine) extended-release tablets: Supplied in bottles (that contain a desiccant) with child-resistant closure as 5 mg, 10 mg, 15 mg, and 20 mg strengths.
Storage and Handling
Dispense in a tight container with child-resistant closure.
Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
DYANAVEL XR extended-release oral suspension: The pharmacist should insert the bottle adapter firmly into the neck of the bottle and provide the oral dosing dispenser to the patient when dispensing this product.
Disposal
Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired DYANAVEL XR at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix DYANAVEL XR with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard DYANAVEL XR in the household trash.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Controlled Substance Status/Potential for Abuse, Misuse, and Dependence
Advise patients that DYANAVEL XR is a federally controlled substance because it can be abused or lead to dependence. Advise patients to store DYANAVEL XR in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired DYANAVEL XR by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].
Dosage and Administration Instructions
Provide the following instructions on administration to the patient [see Dosage and Administration (2.3)]:
DYANAVEL XR extended-release oral suspension
DYANAVEL XR extended-release tablets
Serious Cardiovascular Risks
Advise patients and their caregivers of serious cardiovascular risk (including sudden death, myocardial infarction, stroke, and hypertension) with DYANAVEL XR. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)].
Blood Pressure and Heart Rate Increases
Instruct patients and their caregivers that DYANAVEL XR can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions(5.3)].
Psychiatric Risks
Advise patients and their caregivers that DYANAVEL XR, at recommended doses, may cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].
Long-Term Suppression of Growth
Advise patients and their caregivers that DYANAVEL XR may cause slowing of growth and weight loss [see Warnings and Precautions (5.5)].
Circulation Problems in Fingers and Toes [Peripheral vasculopathy, including Raynaud’s phenomenon]
Instruct patients and their caregivers beginning treatment with DYANAVEL XR about the risk of peripheral vasculopathy, including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.
Instruct patients and their caregivers to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.
Instruct patients and their caregivers to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking DYANAVEL XR.
Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].
Serotonin Syndrome
Caution patients and their caregivers about the risk of serotonin syndrome with concomitant use of DYANAVEL XR and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see Contraindications (4), Warnings and Precautions (5.7) and Drug Interactions (7.1)]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.
Concomitant Medications
Advise patients and their caregivers 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 Registry
Advise patients and their caregivers that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DYANAVEL XR during pregnancy [see Use in Specific Populations (8.1)].
Pregnancy
Advise patients and their caregivers to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with DYANAVEL XR. Advise patients of the potential fetal effects from the use of DYANAVEL XR during pregnancy [see Use in Specific Populations (8.1)].
Lactation
Advise women not to breastfeed if they are taking DYANAVEL XR [see Use in Specific Populations (8.2)].
Alcohol
Advise patients to avoid alcohol while taking DYANAVEL XR. Consumption of alcohol while taking
DYANAVEL XR may result in a more rapid release of the dose of amphetamine [see Clinical Pharmacology (12.3)].
Manufactured by:
Tris Pharma, Inc.
Monmouth Junction, NJ 08852
LB8684
Rev. 00
Revised May 2022
MEDICATION GUIDE DYANAVEL® XR (dī-an-uh-vel) | |||
What is the most important information I should know about DYANAVEL XR? DYANAVEL XR can cause serious side effects, including:
Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with DYANAVEL XR, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. | |||
What is DYANAVEL XR? DYANAVEL XR is a central nervous system (CNS) stimulant prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. DYANAVEL XR may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. It is not known if DYANAVEL XR is safe and effective in children under 6 years of age. DYANAVEL XR is a federally controlled substance (CII) because it contains amphetamine that can be a target for people who abuse prescription medicines or street drugs. Keep DYANAVEL XR in a safe place to protect it from theft. Never give your DYANAVEL XR to anyone else, because it may cause death or harm them. Selling or giving away DYANAVEL XR may harm others and is against the law. | |||
Do not take DYANAVEL XR if you or your child are:
| |||
Before taking DYANAVEL XR tell your healthcare provider about all medical conditions, including if you or your child:
DYANAVEL XR and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted during treatment with DYANAVEL XR. Especially tell your healthcare provider if you or your child take: Your healthcare provider will decide whether DYANAVEL XR can be taken with other medicines. Do not start any new medicine without talking to your healthcare provider first. | |||
How should I take DYANAVEL XR?
If you or your child takes too much DYANAVEL XR, call your healthcare provider or poison control center, or go to the nearest hospital emergency room right away. In case of poisoning call your poison control center at 1-800-222-1222. | |||
What should I avoid during treatment with DYANAVEL XR?
| |||
What are possible side effects of DYANAVEL XR? DYANAVEL XR can cause serious side effects, including:
The most common side effects of DYANAVEL XR include: | |||
|
|
|
|
These are not all the possible side effects of DYANAVEL XR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | |||
How should I store DYANAVEL XR?
Keep DYANAVEL XR and all medicines out of the reach of children. | |||
General information about the safe and effective use of DYANAVEL XR. Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide. Do not use DYANAVEL XR for a condition for which it has not been prescribed. Do not give DYANAVEL XR to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about DYANAVEL XR that was written for health professionals. | |||
What are the ingredients in DYANAVEL XR? DYANAVEL XR extended-release oral suspension: Active Ingredients: amphetamine, dextroamphetamine sulfate, and amphetamine aspartate. Inactive Ingredients: anhydrous citric acid, bubblegum flavor, glycerin, methylparaben, modified starch, polysorbate 80, povidone, polyvinyl acetate, propylparaben, sodium lauryl sulfate, sodium polystyrene sulfonate, sucralose, triacetin and xanthan gum. DYANAVEL XR extended-release tablets: Active Ingredients: amphetamine, dextroamphetamine sulfate, and amphetamine aspartate. Inactive Ingredients: bubblegum flavor, crospovidone, guar gum, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl acetate, povidone, silicon dioxide, sodium polystyrene sulfonate, sucralose, talc, triacetin and xanthan gum. Manufactured by: Tris Pharma, Inc., Monmouth Junction, NJ 08852 For more information about DYANAVEL XR call 1-732-940-0358. | |||
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised:05/2022
DYANAVEL® XR (dī-an-uh-vel)
(amphetamine)
extended-release oral suspension, CII
Read this Instructions for Use before taking DYANAVEL XR and each time you get a refill. There may be new information. This leaflet does not take the place of talking with the healthcare provider about your or your child’s medical condition or treatment.
Store DYANAVEL XR at room temperature between 68°F to 77°F (20°C to 25°C).
Store DYANAVEL XR in a safe place, like a locked cabinet.
Dispose of remaining, unused, or expired DYANAVEL XR by a medicine take-back program at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix DYANAVEL XR with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away DYANAVEL XR in the household trash.
Keep DYANAVEL XR and all medicines out of the reach of children.
Manufactured by:
Tris Pharma, Inc.
Monmouth Junction, NJ 08852
For more information about DYANAVEL XR call 1-732-940-0358.
This Instructions for Use has been approved by the U.S. Food and Drug Administration Approved: 05/2022
LB8684
Rev. 00
05/2022
NDC 24478-102-01
Dyanavel® XR CII
(amphetamine) extended-release oral suspension
2.5 mg/mL
Shake Well Before Use
464 mL Rx only
16oz Label (Dyanavel Xr Oral Suspension And Tablets 15) 
NDC 24478-106-01
Dyanavel®XR CII
(amphetamine) extended-release Tablets
5 mg
May be chewed or swallowed whole.
30 Tablets
Rx only
5mg Label (Dyanavel Xr Oral Suspension And Tablets 16)
NDC 24478-108-01
Dyanavel®XR CII
(amphetamine) extended-release Tablets
10 mg
May be chewed or swallowed whole.
30 Tablets
Rx only
10mg Label (Dyanavel Xr Oral Suspension And Tablets 17)
NDC 24478-109-01
Dyanavel®XR CII
(amphetamine) extended-release Tablets
15 mg
May be chewed or swallowed whole.
30 Tablets
Rx only
15mg Label (Dyanavel Xr Oral Suspension And Tablets 18)
NDC 24478-110-01
Dyanavel® XR CII
(amphetamine) extended-release Tablets
20 mg
May be chewed or swallowed whole.
30 Tablets
Rx only
20mg Label (Dyanavel Xr Oral Suspension And Tablets 19)
* Please review the disclaimer below.
