Dyanavel XR
(amphetamine)Dosage & Administration
Dyanavel XR Prescribing Information
DYANAVEL XR has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including DYANAVEL XR, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Before prescribing DYANAVEL XR, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout 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 [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)].
DYANAVEL XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies (14)].
Pretreatment 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) [see Warnings and Precautions (5.2)].
- the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating DYANAVEL XR [see Warnings and Precautions (5.8)].
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.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 [see Clinical Pharmacology (12.3)].
- 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 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)].
Dosage Modifications due to DrugInteractions
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:
- Extended-release oral suspension contains 2.5 mg amphetamine base equivalents per mL.
DYANAVEL XR (amphetamine) extended-release tablets:
- 5 mg: Off-white, speckled, caplet shaped tablet with ‘5’ debossed on one side and functionally scored on the other side
- 10 mg: Off-white, speckled, diamond shaped tablet with ‘10’ debossed on one side and plain on the other side
- 15 mg: Off-white, speckled, triangle shaped tablet with ‘15’ debossed on one side and plain on the other side
- 20 mg: Off-white, speckled, oval shaped tablet with ‘20’ debossed on one side and plain on the other side
All strengths are expressed in terms of amphetamine base equivalents.
Pregnancy
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.
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/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.
Lactation
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.
Pediatric Use
The 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)].
The safety and efficacy of DYANAVEL XR in pediatric patients less than 6 years 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)].
Geriatric Use
DYANAVEL XR has not been studied in the geriatric population.
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 [see Adverse Reactions (6)].
- 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 [see Warnings and Precautions (5.7), Drug Interactions (7.1)].
Abuse, 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 [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including DYANAVEL XR, can result in overdose and death [see Overdosage (10)], 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.
Risks 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.
Increased 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.
Psychiatric 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.Long-Term Suppression of Growth in Pediatric Patients
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.
Peripheral 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.
Serotonin 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 [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.
Motor 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 [see Adverse Reactions (6.2)].
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.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
- Hypersensitivity to amphetamine, or other components of DYANAVEL XR [see Contraindications (4)]
- Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1) ]
- Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
- Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
- Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
- Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5)]
- Peripheral Vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions (5.6)]
- Serotonin Syndrome [see Warnings and Precautions (5.7)]
- Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.8)]
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.
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% |
Postmarketing 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
Drugs Having Clinically Important Interactions with Amphetamines
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. |
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.
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:
C9H13N MW 135.21
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 l-amphetamine 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 l-amphetamine 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 l-amphetamine 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 l-amphetamine 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.
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.
Mechanism of Action
Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known.
Pharmacodynamics
Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extra neuronal space.
Pharmacokinetics
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
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
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, Mutagenesis, Impairment of Fertility
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].
Animal Toxicology and/or Pharmacology
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
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.
- 5 mg DYANAVEL XR extended-release tablet is functionally scored and is available as an off-white, speckled, caplet shaped tablet with 5 debossed on one side and scored on the other side, supplied in bottles of 30 (NDC 24478-106-01).
- 10 mg DYANAVEL XR extended-release tablet is available as an off-white, speckled, diamond shaped tablet with 10 debossed on one side and plain on the other side, supplied in bottles of 30 (NDC 24478-108-01).
- 15 mg DYANAVEL XR extended-release tablet is available as an off-white, speckled, triangle shaped tablet with 15 debossed on one side and plain on the other side, supplied in bottles of 30 (NDC 24478-109-01).
- 20 mg DYANAVEL XR extended-release tablet is available as an off-white, speckled, oval shaped tablet with 20 debossed on one side and plain on the other side, supplied in bottles of 30 (NDC 24478-110-01).
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 15º to 30ºC (59º to 86ºF) [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.
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.
Check the DYANAVEL XR bottle to make sure that the bottle adapter has been inserted into the bottle by the pharmacist. Do not remove the bottle adapter.
Check to make sure your pharmacist has given you an oral dosing dispenser.
Tell your pharmacist if an oral dosing dispenser is not provided or the bottle adapter is missing from the neck of the bottle.
Shake the bottle well (up and down).
Check the DYANAVEL XR oral dosing dispenser to find the right dose in milliliters (mL) that you or your child’s healthcare provider has prescribed.
Step 4:
Place the DYANAVEL XR bottle upright and insert tip of the oral dosing dispenser into the bottle.
Step 5:
Push the plunger all the way down.
With the oral dosing dispenser in place, hold the DYANAVEL XR bottle with 1 hand and turn the bottle upside down. Pull the plunger down until the white end of the plunger reaches the number of mLs you need for the prescribed dose.
Turn the bottle over and place upright on a counter top, then remove the oral dosing dispenser from the bottle adapter.
Place the tip of the oral dosing dispenser into you or your child’s mouth. Point the tip toward the cheek and slowly push the plunger all the way down to give the DYANAVEL XR dose.
Put the DYANAVEL XR cap back on the bottle and close tightly.
Clean the oral dosing dispenser after each use by placing in the dishwasher, or by rinsing with tap water.
How should I store DYANAVEL XR?
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 a U.S. Drug Enforcement Administration (DEA) authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or DEA 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 go to www.dyanavelxr.com or call 1-732-940-0358.
This Instructions for Use has been approved by the U.S. Food and Drug Administration Revised: 10/2023
Mechanism of Action
Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known.