Xelstrym Drug Information

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) . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating XELSTRYM .

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.

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 . 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 . When heat is applied to XELSTRYM after application, both the rate and the extent of absorption are increased .

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 . Do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles .

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.

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.

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) . 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 . 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.

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.

Drugs Having Clinically Important Interactions with Amphetamine 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. 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) . 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. 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.

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. 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.

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. 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.

Pediatric Use The safety and effectiveness of XELSTRYM have not been established in pediatric patients below the age of 6 years. The safety and effectiveness of XELSTRYM have been established in pediatric patients with ADHD ages 6 to 17 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. 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.

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 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 Known hypersensitivity to amphetamine products or other ingredients in XELSTRYM Use with monoamine oxidase inhibitor (MAOI), or within 14 days of the last MAOI dose

Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.

CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.

Overdose Management Consider the possibility of multiple drug ingestion. Dextroamphetamine is not dialyzable. Remove all transdermal systems immediately and cleanse the area(s) to remove any remaining adhesive.

The continuing absorption of dextroamphetamine from the skin, even after removal of the transdermal system, should be considered when treating patients with overdose. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.