2.1 Important Information Prior to Initiating Treatment

Prior to initiating treatment with XELSTRYM, assess for the presence of cardiac disease (e.g., 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 XELSTRYM use [see WARNINGS AND PRECAUTIONS (5.1) and DRUG ABUSE AND DEPENDENCE (9)].

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.

Pharmacological treatment of ADHD may be needed for an extended period. Periodically re-evaluate the long-term use of XELSTRYM and adjust dosage as needed.

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. Follow recommendations for discarding used and unused XELSTRYM [see DOSAGE AND ADMINISTRATION (2.4)].
• 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 Disposal Instructions

Upon removal of XELSTRYM, used transdermal systems should be folded so that the adhesive side of the system adheres to itself and placed in a lidded container. Used XELSTRYM should not be flushed down the toilet.

If the patient stops using the prescription, the patient should comply with local laws and regulations on drug disposal of CNS stimulants [see HOW SUPPLIED/STORAGE AND HANDLING (16)].

2.5 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)].

2.6 Dosage in Patients with Renal Impairment

In patients with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m2), 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 m2) patients is 9 mg/9 hours [see USE IN SPECIFIC POPULATIONS (8.6)].

2.7 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)].

5.1 Potential for Abuse and Dependence

CNS stimulants, including XELSTRYM, 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 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 pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during XELSTRYM treatment.

5.3 Blood Pressure and Heart Rate Increases

CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Monitor all patients for potential tachycardia and hypertension.

5.4 Psychiatric Adverse Reactions

Exacerbation of Pre-existing Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder

CNS stimulants may induce a mixed/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, and 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 a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing XELSTRYM. 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 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 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)].

Patients who are 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)].

5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon

Stimulants, including XELSTRYM, 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 stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

5.7 Serotonin Syndrome

Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort [see DRUG INTERACTIONS (7.1)]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to 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.

5.8 Contact Sensitization

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 CONTRAINDICATIONS (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.

5.9 Application Site Reactions

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.

5.10 Use of External Heat

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 (AUC0-9h) 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.

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%), insomnia1 (32%), headache (21%), irritability (16%), abdominal pain2 (16%) affect lability3 (16%), application site pain4 (13%), nausea (9%), application site pruritus (7%), and fatigue (5%).

1insomnia includes insomnia, delayed sleep phase, initial insomnia, middle insomnia, and terminal insomnia
2abdominal pain includes abdominal pain and abdominal pain upper
3affect lability includes affect lability, emotional disorder, mood swings, and mood altered
4application 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.

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.

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, 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.

7.1 Drugs Having Clinically Important Interactions with Amphetamine

7.2 Drugs Having No Clinically Important Interactions with Amphetamine

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)].

8.1 Pregnancy

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.

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.

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.

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. 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.

8.4 Pediatric Use

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)].

Safety and effectiveness of XELSTRYM have not been established in pediatric patients below the age of 6 years.

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.

8.5 Geriatric Use

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.

8.6 Renal Impairment

Due to reduced clearance in patients with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m2), 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 m2) patients is 9 mg/9 hours XELSTRYM.

Dextroamphetamine is not dialyzable.

9.1 Controlled Substance

XELSTRYM contains dextroamphetamine, a Schedule II controlled substance.

9.2 Abuse

CNS stimulants, including XELSTRYM, other amphetamines, and methylphenidate-containing products have a high potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking XELSTRYM as prescribed.

Signs and symptoms of CNS stimulant 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, and suicidal or homicidal ideation have also been observed. Individuals who abuse CNS stimulants may chew, snort, inject, or use other unapproved routes of administration, which can result in overdose and death [see OVERDOSAGE(10)].

To reduce the abuse of XELSTRYM, 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 XELSTRYM use.

9.3 Dependence

Physical Dependence

XELSTRYM may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

XELSTRYM may produce tolerance from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

12.1 Mechanism of Action

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The exact mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics

Amphetamines 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

Following a single 9-hour application of XELSTRYM in pediatric patients 6 to 12 years with ADHD, the Cmax 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 (Cmax) of dextroamphetamine were 44.6 ng/mL and 67.6 ng/mL, respectively; and area under concentration curve (AUCinf) of dextroamphetamine were 996 ng*h/mL and 1260 ng*h/mL, respectively. Median time-to-peak concentrations (tmax) 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.

After multiple dosing of 18 mg/9 hours of XELSTRYM with application site rotation in adults or 70 mg of lisdexamfetamine (simulated), Cmax of dextroamphetamine were 68.8 ng/mL and 84.5 ng/mL, respectively; AUC0-24 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 Cmax 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 Cmax and 54% increase in AUC0-24 when applied with rotating application sites for each transdermal system. There was 86% increase in Cmax and 104% increase in AUC0-24 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 Tmax about 6.5 hours) as compared with XELSTRYM without a heating pad (median Tmax about 8.5 hours). Geometric least square mean ratios for dextroamphetamine exposure, calculated as Cmax and AUC0-9h, 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 were generally similar between the pediatric and the adult population. Based on population PK, the median Cmax 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 shows the geometric mean ratios and the 90% confidence limits for Cmax 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.

The effects of dextroamphetamine on the exposures of other drugs evaluated with lisdexamfetamine are summarized in Figure 5.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. 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.

13.2 Animal Toxicology and/or Pharmacology

Acute administration of high doses of amphetamine (d- or d,l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.