Dextroamphetamine

1 INDICATIONS AND USAGE 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 The use of XELSTRYM is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.5) , 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: The use of XELSTRYM is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.5 , 8.4 ).

2 DOSAGE AND ADMINISTRATION 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 ) 2.1 Pretreatment Screening 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) ] . 2.2 Recommended Dosage 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. 2.3 Important Administration Instructions 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) ] . 2.4 Switching from Other Amphetamine Products 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) ] . 2.5 Dosage in Patients with Renal Impairment 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) ]. 2.6 Dosage Modification due to Drug Interactions 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) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling Known hypersensitivity to amphetamine products or other ingredients of XELSTRYM [see CONTRAINDICATIONS (4) ] Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see CONTRAINDICATIONS (4) and DRUG INTERACTIONS (7.1) ] Abuse, Misuse, and Addiction [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1) and DRUG ABUSE AND DEPENDENCE (9.2, 9.3) ] 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) ] Contact Sensitization [see WARNINGS AND PRECAUTIONS (5.8) ] Application Site Reactions [see WARNINGS AND PRECAUTIONS (5.9) ] Use of External Heat [see WARNINGS AND PRECAUTIONS (5.10) ] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see WARNINGS AND PRECAUTIONS (5.11) ] Most common adverse reactions (incidence ≥2% and greater than the rate for placebo) in pediatric patients 6 to 17 years treated with XELSTRYM were decreased appetite, headache, insomnia, tic, abdominal pain, vomiting, nausea, irritability, blood pressure increased, and heart rate increased ( 6.1 ) Most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) in adults treated with lisdexamfetamine were decreased appetite, insomnia, dry mouth, diarrhea, nausea, and anxiety ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Noven Therapeutics, LLC at 1-877-567-7857 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. The safety of XELSTRYM for the treatment of ADHD in adults and pediatric patients 6 to 17 years is based on a study with XELSTRYM in pediatric patients (presented below) and adequate and well-controlled studies of lisdexamfetamine in adult and pediatric patients with ADHD. XELSTRYM was studied in pediatric patients 6 to 17 years with ADHD. The safety data are from a 7-week study including a 5-week open-label dose optimization phase (n=110) followed by a 2-week randomized, parallel-group, crossover, placebo-controlled double-blind treatment phase (n=105) [see CLINICAL TRIALS (14) ] . Adverse Reactions Leading to Discontinuation of Treatment In the dose-optimization phase (no placebo comparator in this phase), 2.7% (3/110) of patients treated with XELSTRYM discontinued due to adverse reactions. These adverse reactions reported in one patient each were abdominal pain (0.9%), irritability (0.9%) and decreased appetite (0.9%). There were no discontinuations due to adverse reactions during the double-blind phase. Adverse Reactions Occurring at an Incidence of 5% or More in XELSTRYM Treated Pediatric Patients Ages 6 to 17 Years During Dose-optimized Treatment Adverse reactions (incidence of ≥ 5%) that occurred during the dose-optimization phase of the clinical study include: decreased appetite (54%), insomnia 1 (32%), headache (21%), irritability (16%), abdominal pain 2 (16%) affect lability 3 (16%), application site pain 4 (13%), nausea (9%), application site pruritus (7%), and fatigue (5%). 1 insomnia includes insomnia, delayed sleep phase, initial insomnia, middle insomnia, and terminal insomnia 2 abdominal pain includes abdominal pain and abdominal pain upper 3 affect lability includes affect lability, emotional disorder, mood swings, and mood altered 4 application site pain includes application site pain and application site burn Adverse Reactions Occurring at an Incidence of 2% or More of XELSTRYM-Treated Pediatric Patients Ages 6 to 17 Years During Double-blind Treatment Adverse reactions (incidence of ≥ 2% and incidence greater than placebo) that occurred during the double-blind, placebo-controlled phase of the clinical study are shown in Table 1 . Table 1: Adverse Reactions Reported by ≥ 2% of Pediatric Patients 6 to 17 Years with ADHD Receiving XELSTRYM and Greater Incidence Than Placebo in the Double-Blind Phase * The following terms were combined: Insomnia includes insomnia, delayed sleep phase, initial insomnia, middle insomnia, and terminal insomnia Abdominal pain includes abdominal pain and abdominal pain upper Blood pressure increased includes blood pressure increased and blood pressure systolic increased Heart rate increased includes heart rate increased and tachycardia System Organ Class Preferred Term XELSTRYM All Doses (n = 105) % Placebo (n = 105) % Metabolism and nutrition disorders Decreased appetite 12 2 Nervous system disorders Headache 6 4 Psychiatric disorders Insomnia* 8 6 Affect lability 3 0 Tic 2 0 Gastrointestinal Disorders Vomiting 4 0 Abdominal pain * 4 2 Nausea 3 1 General disorders and administration site conditions Irritability 2 1 Investigations/Cardiac Disorders Blood pressure increased * 2 1 Heart rate increased * 2 0 Application Site Reactions Based on daily patient diaries and dermal reaction scales at clinic assessments, local skin reactions were reported with XELSTRYM. During the wear time or immediately after removal of XELSTRYM, patients experienced pain, pruritus, burning sensation, erythema, discomfort, edema, and swelling. Patients who experienced discomfort and pain at the application site during the wear time reported resolution within 2 to 4 hours after XELSTRYM application. Most dermal irritation was limited to the site of application. All patients who reported application site reactions in the 7-week pediatric classroom study continued to use XELSTRYM, and there were no discontinuations from the study due to application site reactions. During the dose-optimization phase of the clinical study, 45% of patients reported application site discomfort associated with the use of XELSTRYM in daily patient diaries; 72% of patients reported discomfort at clinic visit assessments; and 13% of patients reported severe discomfort at clinic visit assessments. XELSTRYM 4.5 mg was the starting dose for all patients undergoing titration during the dose optimization phase and the majority of application site discomfort was reported at this starting dose. During the dose-optimization phase, 73% of patients reported application site irritation. Application site reactions that occurred during the double-blind phase of the clinical study are presented in Table 2 . Table 2: Summary Application Site Reactions During the Double-Blind Phase XELSTRYM n/N Placebo n/N Discomfort Reported in patient diaries 8/96 (8%) 8/98 (8%) Clinic assessments Any discomfort 72/104 (69%) 9/101 (9%) Severe discomfort 10/104 (10%) 4/101 (4%) Irritation Reported in patient diaries 64/103 (62%) 41/105 (39%) Reported at Clinic assessments 97/103 (94%) 55/101 (54%) Weight Loss and Slowing Growth Rate In a 7-week trial of XELSTRYM with a 5-week dose optimization phase and a 2-week crossover placebo-controlled phase in pediatric patients ages 6 to 17 years, patients had a mean weight loss from baseline of -3.1 pounds after 5 weeks of XELSTRYM. Leukopenia and Neutropenia In the 2-week crossover phase of the 7-week trial of XELSTRYM in pediatric patients ages 6 to 17 years, shifts in WBCs from normal to low occurred in 10% of patients treated with XELSTRYM and 2% of patients treated with placebo. Shifts in neutrophils from normal to low occurred in 14% of patients treated with XELSTRYM and 6% of patients treated with placebo. Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD with Lisdexamfetamine and Other Stimulants Lisdexamfetamine The long-term safety of XELSTRYM for the treatment of ADHD relies on information from adequate and well-controlled studies of lisdexamfetamine. In a controlled trial of lisdexamfetamine in pediatric patients 6 to 12 years, mean weight loss from baseline after 4 weeks of therapy was -0.9, -1.9, and -2.5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of lisdexamfetamine, compared to 1 pound weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with 4 weeks of treatment. Careful follow-up for weight in pediatric patients 6 to 12 years who received lisdexamfetamine over 12 months suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a slowing in growth rate, measured by body weight as demonstrated by an age- and sex-normalized mean change from baseline in percentile, of -13.4 over 1 year (average percentiles at baseline and 12 months were 60.9 and 47.2, respectively). In a 4-week controlled trial of lisdexamfetamine in pediatric patients 13 to 17 years, mean weight loss from baseline to endpoint was -2.7, -4.3, and -4.8 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of lisdexamfetamine, compared to a 2 pound weight gain for patients receiving placebo. Other CNS stimulants Careful follow-up of weight and height in pediatric patients 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients 7 to 13 years (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In a controlled trial of amphetamine (d- and l-enantiomer ration of 3:1) in pediatric patients 13 to 17 years, mean weight change from baseline within the initial 4 weeks of therapy was -1.1 pounds and -2.8 pounds, respectively, for patients receiving 10 mg and 20 mg of amphetamine. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment [see WARNINGS AND PRECAUTIONS (5.5) ] . Clinical Trials Experience in Adult Patients with ADHD Treated with Lisdexamfetamine Adverse Reactions Associated with Discontinuation of Treatment in Adult ADHD Clinical Trials In a controlled trial of lisdexamfetamine in adults with ADHD, 6% (21/358) of lisdexamfetamine-treated patients discontinued due to adverse reactions compared to 2% (1/62) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%), hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included palpitations, diarrhea, nausea, decreased appetite, dizziness, agitation, depression, paranoia and restlessness. Adverse Reactions Occurring at an Incidence of ≥5% or More Among Lisdexamfetamine-Treated Patients with ADHD in Clinical Trials The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) were: Decreased appetite, insomnia, dry mouth, diarrhea, nausea, and anxiety. In addition, in the adult population, erectile dysfunction was observed in 2.6% of males on lisdexamfetamine and 0% on placebo; decreased libido was observed in 1.4% of subjects on lisdexamfetamine and 0% on placebo. Weight Loss in Adults with ADHD In a controlled adult trial of lisdexamfetamine, mean weight loss after 4 weeks of therapy was 2.8 pounds, 3.1 pounds, and 4.3 pounds, for patients receiving final doses of 30 mg, 50 mg, and 70 mg of lisdexamfetamine, respectively, compared to a mean weight gain of 0.5 pounds for patients receiving placebo. Adverse Reactions with Other Amphetamine Products in Pediatric Patients and Adults with ADHD Cardiac Disorders: Palpitations, tachycardia, and chest pain. Gastrointestinal Disorders: Dry mouth, abdominal pain upper, dyspepsia, diarrhea, constipation, vomiting, nausea, and tooth disorder (e.g., teeth clenching, tooth infection). General Disorders and Administration Site Conditions: Asthenia, fatigue, pyrexia, and feeling jittery. Infections and Infestations: Infection, urinary tract infection. Injury, Poisoning, and Procedural Complications: Accidental injury. Investigations: Weight decreased, blood pressure increased, and ECG voltage criteria for ventricular hypertrophy. Metabolism and Nutrition Disorders: Loss of appetite. Musculoskeletal and Connective Tissue Disorders: Muscle twitching, growth retardation. Nervous System Disorders: Somnolence, insomnia, tremor, dizziness, headache, tics, speech disorder (e.g., stuttering, excessive speech), psychomotor hyperactivity, and agitation. Psychiatric Disorders: Depression, anxiety, dermatillomania, mood swings, anger, affect lability, logorrhea, irritability, nervousness, paranoia, and restlessness. Reproductive System and Breast Disorders: Impotence, libido decreased, erectile dysfunction, and dysmenorrhea. Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea, rhinitis allergic. Skin and Subcutaneous Tissue Disorders: Rash, photosensitivity reaction, and hyperhidrosis. Vascular Disorders: Hypertension, epistaxis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of amphetamines. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Palpitations, chest pain, sudden death, and myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Eye Disorders: Vision blurred, diplopia, difficulties with visual accommodation, and mydriasis. Gastrointestinal Disorders: Dysgeusia, constipation, intestinal ischemia, and other gastrointestinal disturbances. Hepatobiliary Disorders: Eosinophilic hepatitis. Immune System Disorders: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylactic reaction. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported. Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis. Nervous System Disorders: Seizures, overstimulation, restlessness, dyskinesia, tremor, motor and verbal tics, and paresthesia (including formication). Psychiatric Disorders: Psychotic episodes at recommended doses, depression, logorrhea, aggression, anger, dermatillomania, bruxism, dysphoria, euphoria, and irritability. Reproductive System and Breast Disorders: Impotence, changes in libido, and frequent or prolonged erections. Skin and Subcutaneous Tissue Disorders: Alopecia. Vascular Disorders: Raynaud's phenomenon.

12.3 Pharmacokinetics 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