HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
` DYANAVEL™XR safely and effectively. See full prescribing
` information for DYANAVELXR.
`
`
`
` DYANAVELXR (amphetamine) extended-release oral suspension,
`CII
` Initial U.S. Approval: 1960
`
`
` WARNING: ABUSE AND DEPENDENCE
`See full prescribing information for complete boxed warning.
`
`
`● CNS stimulants, including DYANAVEL XR, other amphetamine-
`
`containing products, and methylphenidate, have a high
`
`potential for abuse and dependence (5.1, 9.3)
`● Assess the risk of abuse prior to prescribing and monitor for
`
`signs of abuse and dependence while on therapy (9.2, 9.3)
`
`-------------------------RECENT MAJOR CHANGES-----------------------------
`Contraindications (4)
`1/2017
`
`
`
`
`
`
`Warnings and Precautions (5.7)
`1/2017
`
`
`
`
`
`-------------------------INDICATIONS AND USAGE-------------------------------
`DYANAVEL XR is a central nervous system (CNS) stimulant indicated
`for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) (1)
`------------------------DOSAGE AND ADMINISTRATION-----------------------
` Before administering the dose, shake bottle (2.2)
`
`
` May be taken with or without food (2.2)
`
`In children 6 years of age and older, recommended starting dose is
`
`
`2.5 mg or 5 mg once daily in the morning (2.2)
` Dosage may be increased in increments of 2.5 mg to 10 mg per
`
`day every 4 to 7 days until optimal response is obtained (2.2)
` Daily dose above 20 mg is not recommended (2.2)
`
`
` Do not substitute for other amphetamine products on a milligram-
`
`per-milligram basis, because of different amphetamine base
`compositions and differing pharmacokinetic profiles (2.3)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
` Extended-release oral suspension containing 2.5 mg amphetamine
`
`base per mL (3)
`---------------------------------CONTRAINDICATIONS-----------------------------
`
` Known hypersensitivity to amphetamine products or other
`
`ingredients in DYANAVEL XR (4)
` Use of monoamine oxidase inhibitor (MAOI) or within 14 days of
`
`
`the last MAOI dose (4, 7.1)
`
`
`
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
` Serious Cardiovascular Reactions: Sudden death has been
`
`reported in association with CNS stimulant treatment at
`recommended doses in pediatric patients with structural cardiac
`abnormalities or other serious heart problems. In adults, sudden
`death, stroke, and myocardial infarction have been reported. Avoid
`use in patients with known structural cardiac abnormalities,
`cardiomyopathy, serious heart arrhythmia, or coronary artery
`
`
`disease (5.2)
` Blood Pressure and Heart Rate Increases: Monitor blood pressure
`
`and pulse. Consider benefits and risks before use in patients for
`whom blood pressure increases may be problematic (5.3)
`
` Psychiatric Adverse Reactions: May cause psychotic or manic
`
`symptoms in patients with no prior history, or exacerbation of
`symptoms in patients with pre-existing psychosis. Evaluate for
`bipolar disorder prior to stimulant use (5.4)
`
`Long-Term Suppression of Growth: Monitor height and weight in
`pediatric patients during treatment (5.5)
`
` Peripheral Vasculopathy, including Raynaud’s phenomenon:
`
`Stimulants used to treat ADHD are associated with peripheral
`vasculopathy, including Raynaud’s phenomenon. Careful
`observation for digital changes is necessary during treatment with
`
`ADHD stimulants (5.6)
` Serotonin Syndrome: Increased risk when co-administered with
`
`serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during
`overdosage situations. If it occurs, discontinue DYANAVEL XR and
`initiate supportive treatment (5.7, 17).
`
`-----------------------------ADVERSE REACTIONS--------------------------------
`Most common adverse reactions observed with amphetamine
`products: dry mouth, anorexia, weight loss, abdominal pain, nausea,
`
`insomnia, restlessness, emotional lability, dizziness, tachycardia (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Tris
`Pharma, Inc. 1-732-940-0358 and www.trispharma.com or FDA at
`
`1-800-FDA-1088 or www.fda.gov/medwatch.
`------------------------------DRUG INTERACTIONS--------------------------------
`
` Acidifying and Alkalinizing Agents: Agents that alter urinary pH can
`
`
`alter blood levels of amphetamine. Acidifying agents can decrease
`amphetamine blood levels, while alkalinizing agents can increase
`
`amphetamine blood levels. Adjust DYANAVEL XR dosage
`accordingly (7.1)
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
` Pregnancy: May cause fetal harm (8.1)
`
`
` Lactation: Breastfeeding not recommended (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`
`
`
`Revised: 1/2017
`
`
`
`
`_
` FULL PRESCRIBING INFORMATION CONTENTS*
`
` WARNING: ABUSE AND DEPENDENCE
`INDICATIONS AND USAGE
`1.
`
`
`2. DOSAGE AND ADMINISTRATION
`
`
`Important Information Prior to Initiating Treatment
`
`2.1
`2.2 General Dosing Information
`
`2.3 Switching from other Amphetamine Products
`2.4 Dosage Modifications due to Drug Interactions
`3. DOSAGE FORMS AND STRENGTHS
`
`
`4. CONTRAINDICATIONS
`
`
`5. WARNINGS AND PRECAUTIONS
`
`
`5.1 Potential for Abuse and Dependence
`
`5.2 Serious Cardiovascular Reactions
`
`5.3 Blood Pressure and Heart Rate Increases
`
`5.4 Psychiatric Adverse Reactions
`
`Long-Term Suppression of Growth
`5.5
`
`5.6 Peripheral Vasculopathy, including Raynaud’s
`Phenomenon
`
`5.7 Serotonin Syndrome
`
`6. ADVERSE REACTIONS
`
`6.1 Clinical Trial Experience
`
` Postmarketing Experience
`6.2
`
`7. DRUG INTERACTIONS
`
`
`7.1 Drugs having clinically important interactions with
`Amphetamines
`
`7.2 Drug/Laboratory Test Interactions
`
`
`
`
`
`
`
`
`
`
`8. USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
`
`8.2
` Lactation
`8.4
` Pediatric Use
`
` Geriatric Use
`8.5
`
`9. DRUG ABUSE AND DEPENDENCE
`
`
`9.1
` Controlled Substance
`
` Abuse
`9.2
`
` Dependence
`9.3
`
`10. OVERDOSAGE
`
`11. DESCRIPTION
`
`12. CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`12.3 Pharmacokinetics
`
`
`13. NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`14. CLINICAL STUDIES
`
`
`16. HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`16.2 Storage and Handling
`17. PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing
`information are not listed
`
`Reference ID: 4036504
`
`KVK-TECH EXHIBIT 1055
`
`

`

` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` WARNING: ABUSE AND DEPENDENCE
`
`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, 9.3), and Drug Abuse and Dependence (9.2, 9.3)].
`
`INDICATIONS AND USAGE
`1.
`
`DYANAVEL XR is a central nervous system (CNS) stimulant indicated for the treatment of Attention
`
`Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies (14)].
`
`
`DOSAGE AND ADMINISTRATION
`2.
`Important Information Prior to Initiating Treatment
`2.1
`
`Prior to treating children, adolescents, and adults with CNS stimulants, including 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 Precautions (5.1), and
`Drug Abuse and Dependence (9)].
`2.2 General Dosing Information
`
`DYANAVEL XR should be orally administered once daily in the morning with or without food. The dose
`should be individualized according to the needs and responses of the patient. Before administering the
`
`dose, shake the bottle of DYANAVEL XR.
`In children 6 years of age and older, start with 2.5 mg or 5 mg once daily in the morning. The dose may
`be increased in increments of 2.5 mg to 10 mg per day every 4 to 7 days up to a maximum dose of 20 mg
`
`per day.
`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.
`2.3 Switching from other Amphetamine Products
`
`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 base compositions and differing pharmacokinetic profiles [see Description (11), Clinical
`Pharmacology (12.3)].
`2.4 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 [see Drug Interactions
`
`(7.1)].
`
`
`DOSAGE FORMS AND STRENGTHS
`3.
`Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
`
`
`
`Reference ID: 4036504
`
`

`

`
`
`
` CONTRAINDICATIONS
`4.
`
`
`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)]
`
`5.
` WARNINGS AND PRECAUTIONS
`
`5.1 Potential for Abuse and Dependence
`
`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)].
`5.2 Serious Cardiovascular Reactions
`
`Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant
`treatment at recommended doses. Sudden death has been reported in children and adolescents 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.
`
`5.3 Blood Pressure and Heart Rate Increases
`CNS stimulants cause an increase in blood pressure (mean increase about 2-4 mm Hg) and heart rate
`(mean increase about 3-6 bpm). Monitor all patients for potential tachycardia and hypertension.
`5.4 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.
`
`
`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.
`5.5 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, including
`
`DYANAVEL XR.
`
`5.6
`
`Peripheral Vasculopathy, including Raynaud's Phenomenon
`
`
`Reference ID: 4036504
`
`

`

`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
`5.7
`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)]. Amphetamines and amphetamine
`derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) [see
`Clinical Pharmacology 12.3]. The potential for a pharmacokinetic interaction exists with the co-
`administration of CYP2D6 inhibitors which may increase the risk of serotonin syndrome 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)].
`If symptoms of serotonin syndrome occur, discontinue all serotonergic agents immediately, 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.
`
`
`
`
`
`
`
`
`
`
`6.
`ADVERSE REACTIONS
`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)]
`
`
`
`
` 6.1 Clinical Trial 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.
` Clinical Trials Experience with Other Amphetamine Products in Pediatric Patients and Adults with ADHD
`
`
`
`
`
`
`
`Reference ID: 4036504
`
`

`

`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 in 108 patients with ADHD (aged 6–12
`years) were: epistaxis, allergic rhinitis and upper abdominal pain.
` 
`
`
`
`
` Table 1. Common adverse reactions occurring in ≥2% of Subjects on DYANAVEL XR and greater than    
` 
`  
` 
` 
` 
` 
` 
` 
` 
` 
` 
`
`  Placebo during the double blind phase.        
`
`
`
`
`
`
`
`
`
`
`
`0%
`0%
`
`2.1%
`
`3.8%
`
`
`
`Placebo
`(N=48)
`
`
`DYANAVEL XR
`
`Preferred Term
`(N=52)
`
`Respiratory, thoracic and mediastinal disorders
`Epistaxis
`3.8%
`Rhinitis allergic
`3.8%
`Gastrointestinal disorders
` Abdominal pain upper
`
`6.2 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.
`Endocrine: frequent or prolonged erections.
`
`
`Musculoskeletal, Connective Tissue, and Bone Disorders: rhabdomyolysis.
`
`
`Psychiatric Disorders: dermatillomania.
`
`
`
`7.
`DRUG INTERACTIONS
`
`7.1 Drugs Having Clinically Important Interactions with Amphetamines
`
`
`Table 2. Drugs having clinically important interactions with amphetamines.
`
`
`
`MAO Inhibitors (MAOI)
`Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis.
`Clinical Impact:
`Potential outcomes include death, stroke, myocardial infarction, aortic dissection,
`
`Reference ID: 4036504
`
`

`

`
`
` ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
`
`Intervention:
`
`
`Do not administer DYANAVEL XR concomitantly or within 14 days after
`discontinuing MAOI [see Contraindications (4) and Warnings and Precautions (5.x)].
`
`
`Examples:
`
`
`Selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
`
`
`
` Serotonergic Drugs
`
`
`Clinical Impact
`
`
`Intervention
`
`
`Examples
`
`
`CYP2D6 Inhibitors
`
`The concomitant use of DYANAVEL XR and serotonergic drugs increases
`
`the risk of serotonin 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) [see Warnings and
`
`Precautions (5.7].
`Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine
`reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl,
`lithium, tramadol, tryptophan, buspirone, St.John’s Wort
`
`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.x), Overdosage (10)].
`
`
`
`Examples:
`
`Paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
`
`Alkalinizing Agents
`Clinical Impact
`Intervention
`
`Examples
`
`Acidifying Agents
`Clinical Impact
`Intervention
`
`
`Examples
`
`Tricyclic Antidepressants
`
`Increase blood levels and potentiate the action of amphetamine.
`
`Co-administration of DYANAVEL XR and gastrointestinal alkalinizing
`agents should be avoided.
`Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate).
`
`Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
`
`
`Lower blood levels and efficacy of amphetamines.
`Increase dose based on clinical response.
`Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic
`acid HCl, ascorbic acid).
`
`Urinary acidifying agents (e.g., ammonium chloride, sodium acid
`
`phosphate, methenamine salts).
`
`
`Reference ID: 4036504
`
`

`

`Clinical Impact
`
`
`Intervention
`
`Examples
`
`
`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.
`
`Desipramine, protriptyline
`
`
`
`7.2 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.
`
`
`8.
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`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 1.5 and 8 times, respectively, the maximum recommended human dose (MRHD).
`However, long-term neurochemical and behavioral effects have been reported in published animal
`developmental studies using clinically relevant doses of amphetamine (d- or d, l-) [see Data]. In the U.S.
` 
`
`general population, the estimated background risk of major birth defects and miscarriage in clinically
`recognized pregnancies is 2-4% and 15-20%, 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 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 1.5 and 8 times, respectively, the MRHD of
`20 mg/day (as base), on a mg/m2 body surface area basis for an adolescent. Fetal malformations and
`death have been reported in mice following parenteral administration of d-amphetamine doses of 50
`mg/kg/day (approximately 6 times the MRHD) 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.
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`8.2 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.
`8.4 Pediatric Use
`Safety and effectiveness have been established in pediatric patients with ADHD ages 6-17 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 children who
`are not growing or gaining weight as expected may need to have their treatment interrupted [see
`Warnings and Precautions (5.5)].
`8.5 Geriatric Use
`
`DYANAVEL XR has not been studied in the geriatric population.
`
`9.
`DRUG ABUSE AND DEPENDENCE
`
`9.1 Controlled Substance
`
`
`DYANAVEL XR contains amphetamine, which is a Schedule II controlled substance in the U.S. Controlled
`
`Substance Act (CSA).
`
`9.2 Abuse
`
`
`DYANAVEL XR, is a CNS stimulant that contains amphetamine which has a high potential for abuse.
`Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm,
`and craving.
`
`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. Abusers of amphetamines may use
`other 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.
`
`
`
`9.3
`
`Dependence
`
`
`Tolerance
`Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug's desired
`and/or undesired effects over time) may occur during the chronic therapy of CNS stimulants including
`DYANAVEL XR.
`Dependence
`Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation,
`rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS
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`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.
`
`10. 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.
`
`11. DESCRIPTION
`DYANAVEL XR (amphetamine) extended release oral suspension, a CNS stimulant, is an extended-
`release liquid formulation containing a 3.2 to1 ratio of d- to l-amphetamine.
`Each 1 mL of DYANAVEL XR contains 2.5 mg of amphetamine which is the same as the amount of
`amphetamine (base equivalent) found in a 4 mg strength amphetamine mixed salts product.
`Structural Formula:
`
`
`
`C9H13N MW 135.21
`
`
`DYANAVEL XR utilizes an ion exchange resin where the drug is bound to the resin (sodium polystyrene
`sulfonate) through an ionic binding reaction. DYANAVEL XR contains immediate release and extended-
`release components. The extended-release component is coated with an aqueous, pH-independent
`polymer. After drug release the ion-exchange resin is excreted in the feces.
` 
`Inactive Ingredients: anhydrous citric acid, bubblegum flavor, glycerin, methylparaben, modified food
`
`starch, polysorbate 80, povidone, polyvinyl acetate, propylparaben, sodium lauryl sulfate, sodium
`polystyrene sulfonate, sucralose, triacetin and xanthan gum.
`
`
`12. CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode
`of therapeutic action in ADHD is not known. Amphetamines are thought to block the reuptake of
`norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines
`
`into the extraneuronal space.
`
`12.3 Pharmacokinetics
`Absorption
`Following a single, 18.8 mg oral dose of DYANAVEL XR in 29 healthy adult subjects in a crossover study
`under fasting conditions, d-amphetamine and l-amphetamine, the median (range) time to peak plasma
`
`concentrations (Tmax) were 4.0 (2 – 7) hours after dosing and peak concentration (Cmax) were 102% and
`106%, respectively of the Cmax of immediate-release (IR) mixed amphetamine salts tablets. The relative
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`bioavailability of DYANAVEL XR compared to an equal dose of mixed amphetamine salts IR tablets is
`106% of d-amphetamine and 111% for l-amphetamine.
`Metabolism and Excretion
`
`
`DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1. Following a single 18.8
`
`mg oral dose of DYANAVEL XR in 29 healthy adult subjects under fasting conditions, the mean (± SD)
`plasma terminal elimination half-life of d-amphetamine was 12.36 (± 2.95 h) hours and the mean (± SD)
`
`plasma terminal half-life for l-amphetamine was 15.12 (± 4.40 h) hours. 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 co