DailyMed Label: XELSTRYM

DailyMed Label: XELSTRYM

2023

DailyMed Prescription

XELSTRYM

DEXTROAMPHETAMINE

Noven Therapeutics, LLC

NDC: 68968-0205

NDC: 68968-0210

NDC: 68968-0215

NDC: 68968-0220

NDC: 68968-0205

NDC: 68968-0205

NDC: 68968-0210

NDC: 68968-0210

NDC: 68968-0215

NDC: 68968-0215

NDC: 68968-0220

NDC: 68968-0220

XELSTRYM (dextroamphetamine) transdermal system, contains dextroamphetamine, a CNS stimulant. Dextroamphetamine is the dextro isomer of the compound d , l -amphetamine. The chemical name for dextroamphetamine is (2S)-1-phenylpropan-2-amine. It is a clear to slightly amber colored liquid. Molecular weight of dextroamphetamine is 135.21 g/mol and the molecular formula is C 9 H 13 N. The chemical structure is: XELSTRYM is provided in four strengths: 4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours, and 18 mg/9 hours. The composition per unit area of all dosage strengths is identical. Inactive ingredients include: acrylic adhesives, green ink, polyester/polyurethane backing, and polyester release liner. Table 4: XELSTRYM (dextroamphetamine) transdermal system Dosage Strength (dextroamphetamine) Dextroamphetamine Content per Transdermal System Transdermal System Size 4.5 mg / 9 hours 5 mg 4.76 cm 2 9 mg / 9 hours 10 mg 9.52 cm 2 13.5 mg / 9 hours 15 mg 14.29 cm 2 18 mg / 9 hours 20 mg 19.05 cm 2 Transdermal System Components XELSTRYM consists of three layers ( Figure 1 ). The layers are (1) oversized protective silicone-coated polyester release liner that is removed and discarded prior to application (2) acrylic adhesive matrix containing dextroamphetamine, and (3) polyester and polyurethane laminate film (backing). Figure 1: XELSTRYM Transdermal System (Exploded View) chemical structure Figure1

XELSTRYM ® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older [ see CLINICAL STUDIES (14) ] . Limitations of Use Pediatric patients younger than 6 years of age experienced more long-term weight loss than patients 6 years and older [see  USE IN SPECIFIC POPULATIONS (8.4) ]. XELSTRYM is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older ( 1 ) Limitations of Use: Pediatric patients with ADHD younger than 6 years of age experienced more long-term weight loss than patients 6 years and older ( 8.4 )

Pediatric patients (6 to 17 years): Recommended starting dose is 4.5 mg/9 hours. Titrate dosage in weekly increments of 4.5 mg up to a maximum recommended dose of 18 mg/9 hours ( 2.2 ) Adults: Recommended starting dose is 9 mg/9 hours. Maximum recommended dose is 18 mg/9 hours ( 2.2 ) Apply one XELSTRYM transdermal system 2 hours before an effect is needed and remove within 9 hours ( 2.3 ) Apply XELSTRYM to one of the following sites: hip, upper arm, chest, upper back or flank. Change the site of application when applying a new transdermal system ( 2.3 ) Do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles ( 2.5 ) Severe renal impairment: Maximum recommended dose is 13.5 mg/9 hours ( 2.6 ) End stage renal disease (ESRD): Maximum recommended dose is 9 mg/9 hours ( 2.6 ) Prior to treating patients with XELSTRYM, 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 XELSTRYM  [see WARNINGS AND PRECAUTIONS (5.11) ] . Pediatric Patients 6 to 17 years Recommended starting dose of XELSTRYM in pediatric patients 6 to 17 years is 4.5 mg/9 hours. Dosage may be adjusted in weekly increments of 4.5 mg up to a maximum recommended dose of 18 mg/9 hours. Adults Recommended starting dose of XELSTRYM in adults is 9 mg/9 hours. Dosage may be adjusted up to a maximum recommended dose of 18 mg/9 hours. Apply XELSTRYM to the application site 2 hours before an effect is needed and remove within 9 hours after application. Dose titration and final dosage should be individualized depending on clinical response and tolerability. Apply one XELSTRYM transdermal system at a time for not more than 9 hours. Use only one XELSTRYM per 24 hours. Apply XELSTRYM to clean (void of lotions, oils, or gels), dry (not wet), and intact skin at the selected application site. Application sites include: hip, upper arm, chest, upper back, or flank. Select a different application site each time a new XELSTRYM transdermal system is applied [see WARNINGS AND PRECAUTIONS (5.9) ] . Avoid touching the adhesive side of XELSTRYM in order to avoid absorption of amphetamine. If the adhesive side is touched, immediately wash hands with soap and water. If the XELSTRYM transdermal system lifts at the edges, reattach XELSTRYM by pressing firmly and smoothing down the edges of the system. If XELSTRYM comes off completely, apply a new XELSTRYM transdermal system. XELSTRYM should not be applied or re-applied with dressings, tape or other common adhesives.  Avoid exposing the application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing XELSTRYM [see WARNINGS AND PRECAUTIONS (5.10) ] . When heat is applied to XELSTRYM after application, both the rate and the extent of absorption are increased [see CLINICAL PHARMACOLOGY (12.3) ] . For patients switching from another medication or any other amphetamine product, discontinue that treatment, and titrate with XELSTRYM using the titration schedule [see DOSAGE AND ADMINISTRATION (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 [see CLINICAL PHARMACOLOGY (12.3) ] . In patients with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m 2 ), the maximum dose should not exceed 13.5 mg/9 hours. The maximum recommended dose in end stage renal disease (GFR < 15 mL/min/1.73 m 2 ) patients is 9 mg/9 hours [see USE IN SPECIFIC POPULATIONS (8.6) ]. Agents that alter urinary pH can impact excretion and alter blood levels of amphetamines. Acidifying agents (e.g., ascorbic acid) decrease blood levels; adjust XELSTRYM dosage based on clinical response [see DRUG INTERACTIONS (7.1) ].

XELSTRYM is a translucent transdermal system with a printed backing on one side and a release liner on the other that is available in four strengths: 4.5 mg dextroamphetamine/9 hours 9 mg dextroamphetamine/9 hours 13.5 mg dextroamphetamine/9 hours 18 mg dextroamphetamine/9 hours Transdermal system: 4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours, 18 mg/9 hours ( 3 )

XELSTRYM is contraindicated in patients: with known hypersensitivity to amphetamine products or other components of XELSTRYM. Anaphylactic reactions, Stevens-Johnson Syndrome, angioedema, and urticaria have been observed in postmarketing reports [see ADVERSE REACTIONS (6.2) ] taking monoamine oxidase inhibitors (MAOI), 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) and DRUG INTERACTIONS (7.1) ] Known hypersensitivity to amphetamine products or other ingredients in XELSTRYM ( 4 ) Use with monoamine oxidase inhibitor (MAOI), or within 14 days of the last MAOI dose ( 4 , 7.1 )

Risks to Patients with Serious Cardiac Disease:  Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse ( 5.3 ) Psychiatric Adverse Reactions:  Prior to initiating XELSTRYM, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing XELSTRYM ( 5.4 ) Long-Term Suppression of Growth in Pediatric Patients:  Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted ( 5.5 ) Peripheral Vasculopathy, including Raynaud’s phenomenon:  Careful observation for digital changes is necessary during XELSTRYM treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 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 XELSTRYM and initiate supportive treatment ( 5.7 , 10 ) Contact Sensitization:  Use of XELSTRYM may lead to contact sensitization. Discontinue XELSTRYM if contact sensitization is suspected ( 5.8 ) Application Site Reactions:  During wear time or immediately after removal of XELSTRYM, local skin reactions may occur. Select a different application site each day to limit the occurrence of skin reactions ( 5.9 ) External Heat:  Avoid exposing XELSTRYM to external heat sources during wear because both the rate and extent of absorption are increased ( 5.10 ) Motor and Verbal Tics, and Worsening of Tourette's Syndrome:  Before initiating XELSTRYM, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate ( 5.11 ) XELSTRYM has a high potential for abuse and misuse. The use of XELSTRYM exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. XELSTRYM 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 XELSTRYM, 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 XELSTRYM, 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 XELSTRYM in a safe place, preferably locked, and instruct patients to not give XELSTRYM to anyone else. Throughout XELSTRYM treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 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 dosage. Avoid XELSTRYM use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 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 XELSTRYM-treated patients for potential tachycardia and hypertension. 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 Disorder CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating XELSTRYM 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, and 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 a 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 XELSTRYM. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in XELSTRYM-treated pediatric patients treated with CNS stimulants, including XELSTRYM. In a 7-week trial with a dose-optimization phase and a placebo-controlled phase of XELSTRYM in pediatric patients 6 to 17 years old with ADHD, there was a mean decrease in weight while taking XELSTRYM. Additionally, in studies of another CNS stimulant, there was slowing of the increase in height [see ADVERSE REACTIONS (6.1) ] . Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. XELSTRYM is not approved for use in pediatric patients below 6 years of age  [see USE IN SPECIFIC POPULATIONS (8.4) ] . CNS stimulants, including XELSTRYM, 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 XELSTRYM treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for XELSTRYM-treated patients who develop signs or symptoms of peripheral vasculopathy. 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 XELSTRYM. 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 XELSTRYM with MAOI drugs is contraindicated [see CONTRAINDICATIONS (4) ] . Discontinue treatment with XELSTRYM and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. If concomitant use of XELSTRYM with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate XELSTRYM with lower doses, monitoring patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome. Use of XELSTRYM may lead to contact sensitization (allergic contact dermatitis). Erythema is commonly seen with use of XELSTRYM and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the application site. Confirmation of a diagnosis of contact sensitization may require further diagnostic testing [see CONTRAINDICATION (4) ] . Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive patch-test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting. No cases of systemic sensitization have been observed in clinical trials of XELSTRYM. Patients who develop contact sensitization to XELSTRYM and require oral treatment with amphetamine should be initiated on oral medication under close medical supervision. Discontinue XELSTRYM if contact sensitization is suspected. It is possible that some patients sensitized to amphetamine by exposure to XELSTRYM may not be able to take amphetamine in any form. Local skin reactions, such as pain, pruritus, burning sensation, erythema, discomfort, edema, and/or swelling were reported during the wear time or immediately after removal of XELSTRYM [see ADVERSE REACTIONS (6.1) ] . Patients who experienced discomfort and/or pain during the wear time reported resolution within 2 to 4 hours after application. The potential for application site reactions and increased skin irritation, discomfort or pain may occur with XELSTRYM if the same application site is used repeatedly. Patients should select a different application site each day to minimize skin reactions. When heat is applied to XELSTRYM after application, both the rate and extent of absorption are increased. After application of a heating pad, amphetamine exposure (AUC 0-9h ) was about 1.5-times greater than without heating pad application [see CLINICAL PHARMACOLOGY (12.3) ]. Advise patients to avoid exposing XELSTRYM to direct external heat sources such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing XELSTRYM. 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 XELSTRYM, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor XELSTRYM-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

Acidifying and Alkalinizing Agents:  Agents that alter GI and urinary pH can alter blood levels of amphetamine. Acidifying agents can decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels ( 2.6 , 7.1 ) Table 3: Drugs Having Clinically Important Interactions with Amphetamines MAO Inhibitors (MAOI) Clinical Impact MAOI antidepressants slow amphetamine metabolism, increasing amphetamine’s 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 XELSTRYM during or within 14 days following the administration of MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.7) ]. Serotonergic Drugs Clinical Impact The concomitant use of XELSTRYM 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 XELSTRYM initiation or dosage increase. If serotonin syndrome occurs, discontinue XELSTRYM and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.7) ] . CYP2D6 Inhibitors Clinical Impact The concomitant use of XELSTRYM and CYP2D6 inhibitors may increase the exposure of XELSTRYM 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 XELSTRYM initiation and after a dosage increase. If serotonin syndrome occurs, discontinue XELSTRYM and the CYP2D6 inhibitor [see  WARNINGS AND PRECAUTIONS (5.7) and OVERDOSAGE (10) ]. Alkalinizing Agents Clinical Impact Urinary alkalinizing agents can increase blood levels and potentiate the action of amphetamine. Intervention Co-administration of XELSTRYM and urinary alkalinizing agents should be avoided. Acidifying Agents Clinical Impact Urinary acidifying agents can 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 dextroamphetamine in the brain; cardiovascular effects can be potentiated. Intervention Monitor frequently and adjust or use alternative therapy based on clinical response. From a pharmacokinetic perspective, no dose adjustment of XELSTRYM is necessary when XELSTRYM is co-administered with guanfacine, venlafaxine, or omeprazole. In addition, no dose adjustment of guanfacine or venlafaxine is needed when XELSTRYM is co-administered [see CLINICAL PHARMACOLOGY (12.3) ]. From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g. theophylline, duloxetine, melatonin), CYP2D6 (e.g. atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g. omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g. midazolam, pimozide, simvastatin) is necessary when XELSTRYM is co-administered [see CLINICAL PHARMACOLOGY (12.3) ].

Pregnancy: May cause fetal harm ( 8.1 ) Lactation: Breastfeeding not recommended ( 8.2 ) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including XELSTRYM, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/adhd-medications/. Risk Summary Available data from published epidemiologic studies and postmarketing reports on use of prescription amphetamine in pregnant women have not identified a drug-associated risk of major birth defects and miscarriage (see DATA ). Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers taking amphetamines during pregnancy [see CLINICAL CONSIDERATIONS ]. No apparent effects on morphological development were observed in embryo-fetal development studies, with oral administration of amphetamine to rats and rabbits during organogenesis. However, in a pre- and post-natal development study, amphetamine ( d - to l - ratio of 3:1) administered orally to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine (see DATA ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 XELSTRYM, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions, increasing the risk of premature delivery. Infants born to mothers taking amphetamines during pregnancy have an increased risk of premature delivery and low birth weight. 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 administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. Fetal malformations and death have been reported in mice following parenteral administration of amphetamine doses of 50 mg/kg/day or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity. A study was conducted in which pregnant rats received daily oral doses of amphetamine ( d - to l - enantiomer ratio of 3:1) of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg. A number of studies from the literature 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. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of amphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, including serious cardiovascular reactions, blood pressure and heart rate increase, suppression of growth, and peripheral vasculopathy, advise patients that breastfeeding is not recommended during treatment with XELSTRYM. The safety and effectiveness of XELSTRYM have been established in pediatric patients with ADHD ages 6 to 17 years [see ADVERSE REACTIONS (6.1) , CLINICAL PHARMACOLOGY (12.3) , and CLINICAL STUDIES (14) ]. The safety and effectiveness of XELSTRYM in pediatric patients less than 6 years have not been established. Safety and efficacy of lisdexamfetamine were evaluated in a double-blind, randomized, parallel-group, placebo-controlled, fixed-dose study in pediatric patients 4 to 5 years with ADHD, followed by a 1-year open-label extension study. In these studies, patients experienced elevated rates of adverse reactions, including weight loss, decreased BMI, decreased appetite, insomnia, infections (upper respiratory and nasopharyngitis), irritability, and affect lability. Growth Suppression Growth should be monitored during treatment with stimulants, including XELSTRYM, 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) and ADVERSE REACTIONS (6.1) ]. Juvenile Animal Data Juvenile rats treated with mixed amphetamine salts early in the postnatal period through sexual maturation demonstrated transient changes in motor activity. Learning and memory were impaired. No recovery was seen following a drug free period. A delay in sexual maturation was observed, although there was no effect on fertility. In a juvenile developmental study, rats received daily oral doses of amphetamine ( d- to l- enantiomer ratio of 3:1) of 2, 6, or 20 mg/kg on days 7-13 of age; from day 14 to approximately day 60 of age, these doses were given twice daily for total daily doses of 4, 12, or 40 mg/kg. Post dosing hyperactivity was seen at all doses; motor activity measured prior to the daily dose was decreased during the dosing period but the decreased motor activity was largely absent after an 18 day drug-free recovery period. Performance in the Morris water maze test for learning and memory was impaired at the 40 mg/kg dose, and sporadically at the lower doses, when measured prior to the daily dose during the treatment period; no recovery was seen after a 19 day drug-free period. A delay in the developmental milestones of vaginal opening and preputial separation was seen at 40 mg/kg but there was no effect on fertility. Clinical studies of XELSTRYM did not include subjects over 65 years to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data [see CLINICAL PHARMACOLOGY (12.3) ] have not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Due to reduced clearance in patients with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m 2 ), the maximum XELSTRYM dose should not exceed 13.5 mg/9 hours. The maximum recommended dose in end stage renal disease (GFR < 15 mL/min/1.73 m 2 ) patients is 9 mg/9 hours XELSTRYM. Dextroamphetamine is not dialyzable.

How Supplied XELSTRYM (dextroamphetamine) transdermal system is a translucent product with a printed backing on one side and a release liner on the other packaged in an individual pouch supplied as: 4.5 mg/9 hours transdermal system (system size: 4.76 cm 2 ) Carton of 30 transdermal systems, each transdermal system is packaged in an individual pouch NDC 68968-0205-3 9 mg/9 hours transdermal system (system size: 9.52 cm 2 ) Carton of 30 transdermal systems, each transdermal system is packaged in an individual pouch NDC 68968-0210-3 13.5 mg/9 hours transdermal system (system size: 14.29 cm 2 ) Carton of 30 transdermal systems, each transdermal system is packaged in an individual pouch NDC 68968-0215-3 18 mg/9 hours transdermal system (system size: 19.05 cm 2 ) Carton of 30 transdermal systems, each transdermal system is packaged in an individual pouch NDC 68968-0220-3 Storage and Handling Store at 68°F to 77° F (20°C to 25° C); excursions permitted between 15°C to 30° C (59 to 86° F) [see USP Controlled Room Temperature]. Protect from light. Store XELSTRYM in the individual sealed pouch until use. Apply immediately upon removal from the protective pouch.

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The exact 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. Following a single 9-hour application of XELSTRYM in pediatric patients 6 to 12 years with ADHD, the C max and AUC of dextroamphetamine were dose-proportional over the dose range of 4.5 mg/9 hours to 18 mg/9 hours. After a single dose of 18 mg/9 hours of XELSTRYM or 70 mg of lisdexamfetamine in adults, the peak plasma concentration (C max ) of dextroamphetamine were 44.6 ng/mL and 67.6 ng/mL, respectively; and area under concentration curve (AUC inf ) of dextroamphetamine were 996 ng*h/mL and 1260 ng*h/mL, respectively. Median time-to-peak concentrations (t max ) was 9 hours for XELSTRYM and 4 hours for lisdexamfetamine. The plasma PK profiles of dextroamphetamine following administration of XELSTRYM and lisdexamfetamine are shown in Figure 2. Figure 2: Mean Plasma Concentrations versus Time Profile of Dextroamphetamine After a Single Dose Administration of XELSTRYM and Lisdexamfetamine in Healthy Adults After multiple dosing of 18 mg/9 hours of XELSTRYM with application site rotation in adults or 70 mg of lisdexamfetamine (simulated), C max of dextroamphetamine were 68.8 ng/mL and 84.5 ng/mL, respectively; AUC 0-24 of dextroamphetamine were 1150 ng*h/mL and 1248 ng*h/mL, respectively. Absorption The amount of dextroamphetamine absorbed systemically is a function of both wear time and transdermal system size. Peak plasma levels of dextroamphetamine were typically reached at 6 to 9 hours after single application and 6 hours after repeat applications of XELSTRYM when worn up to 9 hours. On average, approximately 90% of dextroamphetamine is delivered from the transdermal system over 9 hours. Inter-individual variability for XELSTRYM as coefficient of variation (%CV) for the dextroamphetamine C max and AUC was generally about 20% to 30%. After repeat applications of XELSTRYM for 4 weeks in adults with ADHD, there was 46% increase in C max and 54% increase in AUC 0-24 when applied with rotating application sites for each transdermal system. There was 86% increase in C max and 104% increase in AUC 0-24 when XELSTRYM was applied on the same site for 28 days. Application of a heating pad on XELSTRYM for 6 consecutive hours led to a faster absorption rate (median T max about 6.5 hours) as compared with XELSTRYM without a heating pad (median T max about 8.5 hours). Geometric least square mean ratios for dextroamphetamine exposure, calculated as C max and AUC 0-9h , were about 116% and 150%, respectively, compared with XELSTRYM without a heating pad, indicating the apparent heat effect on dextroamphetamine absorption. The application of XELSTYRM to different sites (hip, upper arm, chest, upper back and flank) did not alter dextroamphetamine PK. Elimination When XELSTRYM is removed after 9 hours wear time, the mean apparent elimination half-life of dextroamphetamine ranged from 6.4 to 11.5 hours in the pediatric and adult population, respectively. Metabolism Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β 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. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility. Excretion With normal urine pHs, approximately half of an administered oral 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. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. 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 dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that affect urinary pH are known to alter the elimination of amphetamine, and 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) ] . Specific Populations The shapes of pharmacokinetic profiles after XELSTRYM application were generally similar between the pediatric and the adult population. Based on population PK, the median C max in pediatric patients 6 to 17 years are predicted to be 120% and 180%, respectively, the median AUC in pediatric patients are predicted to be 112% and 148%, respectively, of those in adults with a dose of 18 mg/9 hours. Exposures of dextroamphetamine in specific populations evaluated with lisdexamfetamine are summarized in Figure 3 . Figure 3: Dextroamphetamine Exposures in Specific Populations *Figure 3 shows the geometric mean ratios and the 90% confidence limits for C max and AUC of dextroamphetamine. Comparison for gender uses males as the reference. Comparison for age uses 55-64 years as the reference Drug Interaction Studies Effects of other drugs on the exposures of dextroamphetamine evaluated with lisdexamfetamine are summarized in Figure 4 . Figure 4: Effect of Other Drugs on Dextroamphetamine The effects of dextroamphetamine on the exposures of other drugs evaluated with lisdexamfetamine are summarized in Figure 5 . Figure 5: Effects of Dextroamphetamine on Other Drugs figure2 figure3 figure4 figure5

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. Dermal carcinogenicity studies with dextroamphetamine were not conducted. Mutagenesis Amphetamine, in the enantiomer ratio d- to l- ratio of 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 3:1, did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day. 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 XELSTRYM for the treatment of ADHD in adults and pediatric patients 6 to 17 years was established in a study with XELSTRYM in pediatric patients (presented below) and also based on adequate and well-controlled studies of lisdexamfetamine in pediatric and adult patients. Efficacy of lisdexamfetamine in the treatment of ADHD has been established in three short-term trials in pediatric patients 6 to 12 years, one short-term trial in pediatric patients 13 to 17 years, one short-term trial in pediatric patients 6 to 17 years, two short-term trials in adults 18 to 55 years, and two randomized withdrawal trials in pediatric patients 6 to 17 years and adults 18 to 55 years. Pediatric Patients 6 to 17 years with ADHD The efficacy of XELSTRYM for the treatment of ADHD in pediatric patients 6 to 17 years was evaluated in a multi-center, randomized, double-blind, placebo-controlled, cross-over design, modified analog classroom study (Study 1; NCT01711021 ). The study was conducted in 110 patients who met DSM-IV-TR criteria for ADHD. Following a 5-week open-label, dose optimization phase with XELSTRYM (4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours and 18 mg/9 hours), patients were randomized to one of two treatment sequences: 1) XELSTRYM (optimized dose) followed by placebo, each for one week, or 2) placebo followed by XELSTRYM (optimized dose), each for one week. Efficacy was assessed at the end of each week using the Swanson, Kotkin, Agler, M.Flynn, and Pelham (SKAMP) total score, a validated 13-item rating scale to assess manifestations of ADHD in a classroom setting. Items are specific to place (classroom setting) and time (during a typical classroom period), and the scale is used to assess multiple ratings taken within a day. Efficacy was solely based on data from Period 1, which was the first week of the two-week double-blind, placebo-controlled, crossover treatment phase. A statistically significant separation from placebo was observed with use of XELSTRYM in Period 1 ( Table 5 ). Changes in SKAMP total scores assessed at pre-dose (-0.5 hours) and at 1, 2, 3, 4.5, 6, 7, 9, 10, and 12 hours post-application are presented in Figure 6 . Table 5: Summary of Primary Efficacy Results: SKAMP Total Score Averaged Over Classroom Day in Pediatric Patients (6 to 17 years) with ADHD (Period 1 Data only) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a  Statistically significant to placebo. b  Pre-dose score on Period 1 classroom day. c  LS mean over hours 1, 2, 3, 4.5, 6, 7, 9, 10, and 12 hours post-dose on Period 1 classroom day. d  Difference (drug minus placebo) in least-squares means on Period 1 classroom day. Study Number Treatment Group Pre-Dose Score on Classroom Day b Mean (SD) LS Mean c (SE) Placebo-subtracted Difference d (95% CI) Study 1 XELSTRYM a 13.6 (5.9) 12.4 (1.2) -4.7 (-8.0, -1.4) Placebo 12.7 (7.9) 17.1 (1.2) -------- Figure 6: LS Mean SKAMP Total Score After Treatment with XELSTRYM or Placebo in Period 1 Classroom Day in Pediatric Patients (6 to 17 years) with ADHD (Study 1) Adhesion Based on a clinical study in adult subjects wearing XELSTRYM 18 mg/9 hours, 233 of 238 transdermal systems (98%) exhibited 75% or greater surface area adhesion at all timepoints evaluated (every hour) throughout the 9-hour wear period. In another study in which pediatric patients 6 to 17 years and adult patients wearing XELSTRYM 4.5 mg/9 hours or 18 mg/9 hours were not confined to the clinical unit, 50 out of 58 transdermal systems (86%) exhibited 75% or greater surface area adhesion at 9 hours; 3 transdermal systems (5%) were reported as fully detached during the study. figure6

NDC 68968-0205-3 Xelstrym ® (dextroamphetamine) transdermal system 4.5 mg/9 hours For Transdermal Use Only 30 Transdermal Systems Rx only CII Noven Contents: 30 Transdermal Systems Rx Only Each 4.76 cm 2 system contains 5 mg of dextroamphetamine. Inactive components: Acrylic adheseives, green ink, polyester/polyurethane backing, and polyester release liner. Dosage and Administration: See package insert Important: Follow the enclosed Instructions for Use. Wear patch for no more than 9 hours per day. Do not wear more than one patch at a time. Wash hands with soap and water. Do not store unpouched. Store at room temperature between 68° and 77°F (20° to 25°C). Keep out of reach of children. Fold used patch and discard according to Instructions for Use. Find out more at www.xelstrym.com STOP Before using XELSTRYM, read the Instructions for Use to learn how to apply, remove and dispose of the patch For additional safety information see Medication Guide in enclosed Prescribing Information. Manufactured/Distributed by: Noven Pharmaceuticals, Inc. Miami FL, 33186 Carton Label - 4.5 mg